Dopamine efflux in the nucleus accumbens during within-session extinction , outcome-dependent , and habit-based instrumental responding for food reward Rationale Dopamine -LRB- DA -RRB- activity in the nucleus accumbens -LRB- NAc -RRB- is related to the general motivational effects of rewarding stimuli . Dickinson and colleagues have shown that initial acquisition of instrumental responding reflects action -- outcome relationships based on instrumental incentive learning , which establishes the value of an outcome . Given that the sensitivity of responding to outcome devaluation is not affected by NAc lesions , it is unlikely that incentive learning during the action -- outcome phase is mediated by DA activity in the NAc . Introduction Despite more than 25 years of intensive research there is still a vigorous and ongoing debate concerning the specific aspects of complex and adaptive behaviors that are mediated by brain dopamine -LRB- DA -RRB- function -LRB- Ikemoto and Panksepp 1999 ; Redgrave et al. 1999 ; Salamone and Correa 2002 ; Schultz 2002 ; Berridge and Robinson 2003 ; Joseph et al. 2003 ; Wise 2004 ; Kelley et al. 2005 ; Salamone et al. 2005 ; Young et al. 2005 -RRB- . Much of the attention is focused on the nucleus accumbens -LRB- NAc -RRB- and a consensus has formed around the theory that DA innervation of this structure plays a key role in incentive motivation , a Pavlovian conditioned appetitive state that can influence the vigor of approach behavior -LRB- Fibiger and Phillips 1986 ; Robbins et al. 1989 ; Berridge and Robinson 1998 ; Cardinal et al. 2002 ; Parkinson et al. 2002 -RRB- . Consistent with the importance of conditional stimuli -LRB- CS + -RRB- in the initiation of approach behavior , visual and olfactory stimuli associated with natural rewards such as food or sexually receptive conspecifics can evoke significant increases in DA efflux in the NAc that precede similar changes observed during consummatory behavior -LRB- Fiorino et al. 1997 ; Ahn and Phillips 1999 , 2002 -RRB- . Depletion or antagonism of DA function in the NAc eliminates or diminishes the influence of Pavlovian CSs on the level of instrumental responding , i.e. , Pavlovian to instrumental transfer -LRB- Cardinal et al. 2002 ; Parkinson et al. 2002 -RRB- , and additionally , shifts response choice from that with higher work demand and a food reward of greater value to that with lower work cost and lower reward value -LRB- Salamone et al. 1994 ; Salamone and Correa 2002 -RRB- . Contemporary views of instrumental conditioning propose that performance of an instrumental task is controlled by two distinct processes . Based on carefully designed experiments , Dickinson et al. -LRB- 1995 -RRB- have demonstrated that during initial learning trials -LRB- i.e. , after exposure to 120 outcomes -RRB- , an animal 's performance is based on the knowledge -LRB- or expectation -RRB- that an instrumental action will lead to a specific biologically significant outcome . After many more trials -LRB- i.e. , after exposure to 360 outcomes -RRB- , responses gradually shift from being outcome-dependent to habit-based . It is only in the early action -- outcome controlled stage that instrumental performance is sensitive to manipulations that alter the incentive value of the outcome , underscoring the remarkable ability of rats to acquire and encode information relating current incentive value to an action -- outcome contingency in as little as 120 outcome trials . Using outcome devaluation and Pavlovian to instrumental transfer tests , lesions of the basolateral amygdala have been reported to impair the capacity of rats to encode the relation between a specific action and the value of an outcome -LRB- Corbit and Balleine 2005 -RRB- . Given the generally accepted role of DA in the NAc in Pavlovian-based incentive motivation , the question arises as to whether DA activity in this region is involved in action -- outcome and/or habit-based based stages of instrumental responding . A role for either the core or shell region of the NAc in the formation of action -- outcome associations has not been confirmed -LRB- Balleine and Killcross 1994 ; Corbit et al. 2001 ; de Borchgrave et al. 2002 -RRB- , but deficits in the acquisition of instrumental responding have been reported after blockade of the NMDA class of glutamate receptors in the NAc core -LRB- Kelley et al. 1997 -RRB- . In a recent study , Yin et al. -LRB- 2006 -RRB- examined DA function during early action -- outcome as distinct from later habit-based stages of instrumental responding . Mice , with a knockdown of the DA transporter and chronically elevated levels of DA , showed no deficits in acquisition of an instrumental task and responding early in training was still sensitive to tests of outcome devaluation -LRB- Yin et al. 2006 -RRB- . However , in rats with bilateral 6-OHDA lesions of the nigrostriatal DA system , responding on instrumental tasks remained sensitive to reward devaluation despite extensive training sessions -LRB- Faure et al. 2005 -RRB- . Thus , the nigrostriatal DA system , and more specifically , its innervation of the posterior lateral striatum , appears to be necessary for transition of instrumental conditioning from an action -- outcome stage to a habit-based stage . Important insights into the role of DA transmission at different stages of instrumental behavior may be gained by examining in vivo changes in DA levels in major areas of DA innervation . Therefore , we conducted microdialysis experiments in the NAc and mediodorsal -LRB- MD -RRB- striatum at early -LRB- 5th day -RRB- and later -LRB- 16th day -RRB- stages of instrumental learning employing a protocol used successfully to demonstrate that responding after 120 but not 360 reinforced responses is sensitive to outcome devaluation and is therefore action -- outcome as distinct from habit-based -LRB- Dickinson et al. 1995 -RRB- . Given the finding that quinolinic acid or NMDA-induced cytotoxic lesions of the NAc failed to alter suppression of instrumental responding after outcome devaluation -LRB- de Borchgrave et al. 2002 -RRB- , it is unlikely that activity in the NAc is involved in instrumental incentive learning . Rather , the finding that lesions restricted only to the NAc completely abolished Pavlovian to instrumental transfer is consistent with the involvement of DA function in this nucleus in conditioned appetitive states . Therefore , we hypothesize that DA efflux in the NAc may be comparable during both early action -- outcome and later habit-based stages of instrumental responding . We also examined changes in DA levels in the MD striatum , as a control site for generalized activity ; hence , we predicted no significant changes in DA efflux associated with instrumental responding . The design of this study also incorporated a `` within-trial '' extinction phase to test the hypothesis that DA efflux in the NAc but not MD striatum would be increased significantly by presentation of a Pavlovian CS + paired previously with food pellets during instrumental responding in extinction . The relationship between response rate and magnitude of DA efflux in either NAc or MD striatum was also of interest . Materials and methods Surgery Long -- Evans male rats -LRB- Charles River , Canada -RRB- weighing 280 -- 310 g were implanted bilaterally with stainless steel guide cannulae -LRB- 19 gauge , 15 mm -RRB- under anesthesia induced by xylazine -LRB- 7 mg/kg -RRB- and ketamine hydrochloride -LRB- 100 mg/kg -RRB- delivered intraperitoneally . Cannulae were implanted 1 mm below dura immediately above the NAc -LSB- in millimeter : +1.7 anteroposteriorly -LRB- AP -RRB- and ± 1.1 mediolaterally -LRB- ML -RRB- from bregma -RSB- or MD striatum -LRB- +1.2 AP , 2.5 ML -RRB- and secured with dental acrylic and four stainless steel screws . Stylets maintained patency of the cannulae until probe implantation . An additional sham-cannula was embedded within the back half of the acrylic head cap for purposes of habituation -LRB- see Behavioral apparatus and training -RRB- . Immediately after surgery , rats were moved to a reverse light-cycle -LRB- lights on 7 a.m.to 7 p.m. -RRB- colony room maintained at 20 °C and housed individually in plastic bins lined with corncob bedding . Novel objects -LRB- e.g. , egg cartons and paper rolls -RRB- were placed weekly in the cages to promote exploratory and play behavior . Rats were handled and weighed by the experimenter on a daily basis . Four days after surgery , rats were placed on a food restriction schedule for the duration of the experiment , maintaining their body weight at ∼ 85 % of their free-feeding weight . The daily ration of food -LRB- 20 -- 25 g Purina Rat Chow -RRB- was given to the rats in their home cages following each day 's operant responding session . Water was available at all times except during the operant training and testing sessions . Behavioral apparatus and training Training and experiment sessions were conducted in a Plexiglas chamber -LRB- 30 × 23 × 23 cm -RRB- with wire-mesh flooring . It was equipped with a retractable lever , a dispenser that delivered 45 mg Noyes pellets , and a light source -LRB- 1 W , 12 V -RRB- located on the wall opposite the location of the lever . Pellets were dispensed into a photocell-equipped magazine located just left of the lever . The chamber was enclosed in a sound-attenuated ventilated box -LRB- Colbourn Instruments ; Allentown , PA , USA -RRB- which had a small hole in the ceiling to allow passage of dialysis lines . Training began 8 days into the food-deprivation schedule . Before a rat was placed in a testing chamber , a stainless steel coil was attached to the sham-cannula . This allowed the rat to habituate to the weight and feel of being tethered to the stainless steel coil which normally sheathes microdialysis lines during experiments . Each session began with rats being placed in operant chambers under baseline conditions -LRB- coil attached , lever retracted , and light off -RRB- , the length of which was varied from day to day . Illumination of the light and insertion of the lever signaled the availability of pellets contingent on lever presses . A computer was used to control the equipment and record the number of lever presses and nose poke entries into the magazine . At the start of the study , rats were trained to approach the magazine to retrieve 30 pellets delivered on a random-time 60-s schedule . Instrumental training sessions began the next day -LRB- day 1 -RRB- on a RI 2-s schedule of pellet delivery . The schedule was changed to RI 15-s on day 2 and then to RI 30-s on day 3 , and remained so for the remainder of the training and microdialysis sessions . Each instrumental training session was terminated when rats had responded for 30 pellets , except on days 4 and 15 when rats were allowed to press for 60 pellets -LRB- see Fig. 2 -RRB- . To minimize the effect of stress before microdialysis tests , rats remained overnight in the chambers under baseline conditions with water , after the training session on day 2 . Microdialysis probes and high pressure liquid chromatography system Microdialysis probes were constructed as previously described -LRB- Ahn and Phillips 1999 ; Fiorino et al. 1997 -RRB- . They were concentric in design with a 2-mm semipermeable membrane -LRB- 340 μm outer diameter , 65 kD MW cut-off , Filtral 12 , Hospal ; Neurnberg , Germany -RRB- with PE50 inlet and silica outlet tubing . A probe assembled in this manner typically had , at 21 °C , in vitro recoveries of ∼ 22 % DA . Once a probe was implanted in the brain through the guide cannula -LRB- see `` Microdialysis experiments '' section below for implant coordinates -RRB- , a cylindrical brass collar secured the probe in place . The inlet tubing was connected to a liquid swivel -LRB- Instech 375s ; Plymouth Meeting , PA , USA -RRB- which was mounted on top of the Colbourn box . Both inlet and outlet tubing were encased in a protective stainless steel coil which extended from the liquid swivel to the brass collar . A 2.5-ml gas-tight syringe -LRB- Unimetrics -RRB- and syringe pump -LRB- Model 22 , Harvard Apparatus ; South Natick , MA , USA -RRB- were used to perfuse a modified Ringer 's solution -LRB- in millimolar : 10 sodium phosphate buffer , 1.3 CaCl2 , 3.0 KCl , 1.0 MgCl2 , 147 NaCl , pH 7.4 -RRB- through the probe at 1 μl/min . DA content in microdialysis samples were separated by high pressure liquid chromatography -LRB- HPLC -RRB- and quantified by electrochemical detection . The HPLC system consisted of , in sequence of flow , a Bio-Rad pump -LRB- Hercules , CA , USA -RRB- , an SSI pulse damper -LRB- State College , PA , USA -RRB- a Valco Instruments two-position auto-Injector -LRB- EC10W ; Houston , TX , USA -RRB- , a Beckman reverse-phase column -LRB- Ultrasphere , ODS 5 μm , 15 cm , 4.6 mm internal diameter ; Fullerton , CA , USA -RRB- , an ESA guard cell -LRB- Model 5020 ; Chemlsford , MA , USA -RRB- , an ESA analytical cell -LRB- Model 5011 -RRB- , an ESA Coulochem II Electrochemical detector , and a dual channel chart recorder . The electrochemical detection parameters were : +450 mV for the oxidation channel , − 300 mV for the reduction channel , and − 450 mV for the guard cell output . The mobile phase -LRB- in millimolar : 83 sodium acetate buffer , 27 EDTA , and 1.30 sodium octyl sulfate at pH 3.5 , 10 % methanol -RRB- flowed through the system at 1 ml/min . Microdialysis experiments In all experiments , each rat was tested with microdialysis on days 5 and 16 . The side of probe implantation -LRB- i.e. , left or right brain structure -RRB- was counterbalanced for each experiment day . The two microdialysis sessions were conducted using an identical protocol . The day before an experiment , rats were implanted unilaterally with probes in the NAc -LRB- exposed membrane spanned − 6.0 to − 8.0 mm DV from dura -RRB- or MD striatum -LRB- − 4.0 to − 6.0 mm DV from dura -RRB- after the day 's training session and kept overnight -LRB- ∼ 16 -- 18 h -RRB- in the test chamber with water under baseline conditions . The next morning , microdialysis samples were collected at 10-min intervals -LRB- 10 μl volume -RRB- and analyzed immediately with HPLC . Baseline conditions were continued until four consecutive samples showed stable DA levels -LRB- i.e. , < 10 % fluctuation between samples ; times 1 -- 4 -RRB- . In `` Experiment 1 '' , the baseline period was followed by the concurrent illumination of the chamber and insertion of the lever . Rats were then allowed a 30-min period -LRB- times 5 -- 7 -RRB- during which they could lever press for food on a RI 30-s schedule . The session concluded with the retraction of the lever and a 40-min time-out period with the lights off -LRB- times 8 -- 11 -RRB- . In `` Experiment 2 '' , a 30-min extinction phase was incorporated -LRB- times 5 -- 7 -RRB- before a food reward phase . All aspects of the extinction phase were identical to previous rewarded training sessions except that lever presses did not lead to food delivery . A 20-min time-out period under baseline conditions -LRB- times 8 -- 9 -RRB- preceded a 10-min priming period when the light was on and five pellets were delivered randomly and noncontingently -LRB- time 10 -RRB- . The start of a food-rewarded phase -LRB- times 11 -- 13 -RRB- was marked by the insertion of the lever into the already illuminated chamber . During this period , rats were allowed to lever press for pellets on a RI 30-s schedule for 30 min . An experiment concluded with an additional 40-min postsession baseline period -LRB- times 14 -- 17 -RRB- . Histology Rats were deeply anesthetized with chloral hydrate and intracardially perfused first with 0.9 % NaCl and then phosphate-buffered formalin -LRB- 3.7 % formaldehyde -RRB- . The removed brains were stored in 15 % -LRB- w/v -RRB- sucrose in formalin for at least 24 h before being prepared as 50 μm coronal sections on 2 % gel-coated slides . Cresyl violet staining was used to help verify placement of probe tracts . Only data from those rats with tracts in the shell/core region of the NAc -LRB- 16 of 18 rats -RRB- and MD striatum -LRB- six of seven rats -RRB- of both hemispheres were included in the statistical analyses . Data analyses Neurochemical data were transformed into percentage of change from baseline -LRB- i.e. , 0 % representing the average concentration of the three samples preceding the final 4th baseline sample -RRB- . Neurochemical data were analyzed using either a one-way -LRB- time -RRB- or two-way -LRB- day × time -RRB- repeated measures ANOVA followed by the Dunnett method of multiple comparisons , using the final baseline sample -LRB- time 4 -RRB- as the control sample . The Huynh -- Feldt correction for nonsphericity was applied to the degrees of freedom for all within-subject analyses . Comparisons between two means were assessed using paired t tests . A coefficient of determination -LRB- R2 -RRB- was computed based on a linear regression of a scatter plot between lever presses/10 min -LRB- y-axis -RRB- and corresponding percent changes in DA efflux -LRB- x-axis -RRB- , for data obtained on test days 5 and 16 . Statistical analyses were performed using Systat or SPSS statistical packages . Results Experiment 1 Changes in extracellular DA levels in the NAc were compared after limited and extended training sessions , while rats lever pressed for food reward on a RI 30-s schedule . As shown in Fig. 1 , the rates of responding approximately doubled from days 5 to 16 , even though rats obtained and consumed a similar number of rewards during the two sessions -LSB- 43.3 pellets -LRB- ∼ 2.0 g -RRB- on day 5 and ∼ 46.2 pellets -LRB- ∼ 2.1 g -RRB- on day 16 -RSB- . The number of magazine entries also did not differ between test days . Separate one-way ANOVAs revealed a significant main effect of time on DA efflux on day 5 -LRB- F7 ,49 = 12.038 , p < 0.001 -RRB- and day 16 -LRB- F7 ,49 = 5.325 , p < 0.044 -RRB- . Further analyses indicated that on both days , there was a significant increase in DA efflux above their respective baselines that remained elevated for the 30-min duration of instrumental responding for food pellets -LRB- Dunnett 's , p < 0.05 -RRB- . Despite the doubling of response rates from days 5 to 16 , the pattern and magnitudes of DA efflux on the two test days were not statistically different -LRB- maximal increase of 69 ± 16 % on day 5 and 71 ± 28 % on day 16 -RRB- , as a two-way repeated measures ANOVA failed to show a significant interaction of day × time on DA efflux -LRB- F7 ,98 = 0.598 , p = 0.528 -RRB- . However , a paired t test showed that during the first 10 min -LRB- time 5 -RRB- , DA efflux was significantly higher on day 16 than day 5 -LRB- 68 ± 24 vs 30 ± 12 % , respectively ; p < 0.05 -RRB- . Basal values of DA in the NAc -LRB- uncorrected for recovery -RRB- were 2.72 ± 0.61 and 2.19 ± 0.29 nM for days 5 and 16 , respectively , and were not statistically different from each other . Fig. 1Change in DA efflux in the NAc -LRB- line graph -RRB- during instrumental conditioning on day 5 -LRB- left panel -RRB- and day 16 -LRB- right panel -RRB- in the same group of rats -LRB- n = 8 -RRB- . Dotted lines highlight the Reward phase in which food pellets were delivered on a RI 30-s schedule -LRB- times 5 -- 7 -RRB- . Lever presses -LRB- gray bars -RRB- and magazine entries -LRB- black bars -RRB- are shown per 10 min bin . Data are represented as mean ± SEM . * indicates significant difference from the final baseline value -LRB- time 4 -RRB- according to Dunnett 's method of multiple comparisons , p < 0.05 . † indicates significant difference from the corresponding data point on day 5 according to a paired t test , p < 0.05 Experiment 2 Instrumental behavior As shown in Fig. 2 , all rats in the NAc and MD striatal microdialysis groups learned to lever press for food pellets on a RI 30-s schedule and to retrieve the pellets , as indicated by the number of magazine entries . Training data for one rat in the MD striatal group was lost and not included in the following analyses . Instrumental behavior became more efficient through the initial days of training , and during the third and fourth training sessions , rats made significantly more lever presses than magazine entries . This increase in ratio of lever presses to magazine entries , from limited to extended training experience , may be explained by proposing that rats learned to use the auditory click made by the dispenser with the delivery of a pellet . Thus , rats learned to enter the magazine only when they heard the click . On days -LRB- 4 and 15 -RRB- before microdialysis tests , rats were allowed to press for 60 pellets , rather than the normal 30 pellets available on other days , and accordingly increased the rate of lever presses on these days . The mean number of lever press responses per training session across the RI 30-s schedule tended to be higher in the NAc group -LRB- from 327 to 835 -RRB- than in the MD striatal group -LRB- from 367 to 436 -RRB- . However , an ANOVA test revealed no main effect of group -LRB- F1 ,11 = 2.414 , p = 0.149 -RRB- . ANOVA of magazine entry data similarly indicated that counts were comparable between the NAc and MD striatal groups -LRB- F1 ,11 = 0.366 , p = 0.557 -RRB- . Fig. 2Instrumental performance of rats in the NAc or MD striatal group over 16 training sessions . Rats were trained to lever press for food pellets on a RI 2-s schedule the first day , RI 5-s the next day , and then RI 30-s for the remainder of the study . Each training session terminated upon delivery of 30 pellets -LRB- exception : * 60 pellets delivered on days before test -RRB- . Test days -LRB- day 5 and 16 -RRB- were composed of two phases , Extinction and Reward , which lasted 30 min each . Lever presses -LRB- gray and striped bars -RRB- and magazine entries -LRB- black bars -RRB- are shown per training session . Data are represented as mean + SEM On test days , rats were tested for instrumental responding in extinction and then with food reward . During the extinction phase , the pellet dispenser was disconnected from the magazine , but still produced an auditory click according to the RI 30-s schedule . During the rewarded phase , all rats consumed every pellet delivered during the lever press sessions . During the rewarded component of the experiment , rats consumed ∼ 45.7 pellets -LRB- ∼ 2.1 g -RRB- on day 5 and ∼ 46.2 pellets -LRB- ∼ 2.1 g -RRB- on day 16 . The similarity in food consumption and difference in magnitude of DA efflux -LRB- see below -RRB- , across days 5 and 16 , again supports the view that DA response is not a function of food reward . In both the NAc and MD striatal groups -LRB- Figs. 3 and 4 -RRB- , rate of instrumental performance approximately doubled from day 5 to day 16 , during both the extinction and rewarded phases of the sessions . Over the 30-min extinction phase , rats displayed a typical decline in rate of lever presses , whereas over the 30-min reward phase , there was a slight increase in rate of responding . In the NAc group , the number of lever presses was significantly higher on day 16 than on day 5 during the first 10 min of the extinction -LRB- t test , p = 0.003 -RRB- and rewarded -LRB- t test , p = 0.002 -RRB- phases . In the MD striatal group , the lever press rates during the first 10 min of the extinction phase were comparable on days 5 and 16 , but differed significantly between the 2 days during the first 10 min of the rewarded phase -LRB- p = 0.038 -RRB- . In both the NAc and MD striatal groups , an ANOVA indicated that the number of magazine entries did not differ significantly between days 5 and 16 . Fig. 3Change in DA efflux in the NAc -LRB- line graph -RRB- during instrumental conditioning on day 5 -LRB- left panel -RRB- and day 16 -LRB- right panel -RRB- in the same group of rats -LRB- n = 8 -RRB- . Dotted lines highlight the Extinction phase during which an auditory CS + was activated on an RI 30-s schedule in the absence of food pellet rewards -LRB- times 5 -- 7 -RRB- and a Reward phase in which food pellets were delivered on a RI 30-s schedule -LRB- times 11 -- 13 -RRB- . P represents the period during which five priming pellets were delivered noncontingently . Lever presses -LRB- gray bars -RRB- and magazine entries -LRB- black bars -RRB- are shown per 10 min bin . Data are represented as mean ± SEM . * Indicates significant difference from the final baseline value -LRB- time 4 -RRB- according to Dunnett 's method of multiple comparisons , p < 0.05 . † Indicates significant difference from the corresponding data point on day 5 according to a paired ttest , p < 0.05 . § Indicates significant difference from the final baseline value -LRB- time 4 ; ttest , p < 0.05 -RRB- Fig. 4Change in DA efflux in the MD striatum -LRB- line graph -RRB- during instrumental conditioning on day 5 -LRB- left panel -RRB- and day 16 -LRB- right panel -RRB- in the same group of rats -LRB- n = 6 -RRB- . See Fig. 3 for explanation of symbols . No statistically significant results were observed for neurochemical data set . † Indicates significant difference from the corresponding behavioral score on day 5 according to a paired ttest , p < 0.05 DA efflux Basal values of DA in the NAc -LRB- uncorrected for recovery -RRB- were 2.58 ± 0.32 and 2.16 ± 0.16 nM for days 5 and 16 , respectively , and were not statistically different from each other . Basal values of DA in the MD striatum -LRB- uncorrected for recovery -RRB- were 2.71 ± 0.23 and 2.95 ± 0.34 nM for days 5 and 16 , respectively , and also did not differ statistically . In the NAc , the overall pattern of DA efflux across the different phases of the microdialysis test on day 5 appeared comparable to that observed on day 16 -LRB- Fig. 3 -RRB- , but statistical analyses revealed several key differences . Accordingly , an ANOVA identified a significant day × time interaction on DA efflux -LRB- F13 ,182 = 2.760 , p = 0.022 -RRB- , with a significant simple main effect of Time on day 5 -LRB- F13 ,91 = 8.690 , p < 0.001 -RRB- and day 16 -LRB- F13 ,91 = 14.649 , p < 0.001 -RRB- . On both days , there was an increase in NAc DA levels during the initial 10 min of responding in extinction -LRB- 10 ± 7 % above baseline on day 5 and 19 ± 6 % on day 16 -RRB- , but this increase was only significant after extended training on day 16 -LRB- paired samples t test , p = 0.005 -RRB- . DA efflux then returned to baseline for the remainder of the extinction phase and time-out period . During the 10-min period preceding the rewarded responding phase , five pellets were noncontingently dispensed into the magazine ; the purpose of this was to prime the rats to lever press again for food reward . During this period , DA levels did not differ from baseline values on day 5 -LRB- 4 ± 9 % -RRB- but by day 16 , were increased significantly above baseline -LRB- 27 ± 7 % ; Dunnett 's test , p < 0.05 -RRB- . The reward phase of the session was accompanied by significant elevation of DA efflux on both days -LRB- maximal increase of 37 ± 12 % on day 5 and +83 ± 15 % on day 16 ; Dunnett 's test , p < 0.05 -RRB- that remained elevated after retraction of the lever and cessation of instrumental responding . DA levels then gradually declined towards baseline values over the remaining 60 min of the test session . During the initial 10 min of the reward phase -LRB- time 11 -RRB- , the magnitude of change on day 16 -LRB- 83 ± 15 % -RRB- was significantly greater than the change in efflux observed on day 5 -LRB- 37 ± 12 % ; t test , p = 0.013 -RRB- . In the MD striatum , there were no statistically significant changes in DA levels during the entire instrumental responding session on both days 5 and 16 -LRB- Fig. 4 -RRB- . Despite performing lever presses and magazine entries at rates comparable to the NAc group , DA levels in this group showed only slight fluctuations around baseline . Correlation between response rate and DA efflux Based on a linear regression of a scatter plot between lever presses/10 min and percent change in DA efflux , R2 values of 0.0014 for data from day 5 and 0.0065 on day 16 indicated that < 1 % of the variation in lever presses could be explained by a linear correlation between lever presses and DA levels , on both test days -LRB- Fig. 5 -RRB- . Fig. 5Correlation between instrumental response rates and NAc DA efflux . Scatter plot of lever presses/10 min -LRB- y-axis -RRB- and corresponding percent change in DA efflux -LRB- x-axis -RRB- for data obtained on day 5 -LRB- left panel -RRB- and day 6 -LRB- right panel -RRB- . Shown on each graph is the best fit linear regression line and R2 value Histology The locations of all microdialysis probes are presented in Fig. 6 . The 2-mm lengths of the dialysis membrane were in the NAc -LRB- shell-core boundary -RRB- or medial aspect of the MD striatum -LRB- just dorsal and lateral of the anterior commissure -RRB- . Fig. 6Location of microdialysis probes in the NAc and MD striatum . Black bars represent 2 mm length of dialysis membranes . Numbers beside each plate correspond to millimeter from bregma . Coronal drawings were modified from Paxinos and Watson -LRB- 1997 -RRB- Discussion The present study examined the role of DA activity in the NAc in behaviors maintained by instrumental and Pavlovian incentive learning . DA efflux in the NAc was increased significantly during both early and later training stages of an instrumental response for food on a RI-30-s schedule of reinforcement -LRB- Figs. 1 and 3 -RRB- . It is important to note that this pattern of results was observed whether a period of extinction preceded a 30-min period of instrumental responding reinforced by food pellets . As such , the present findings confirmed previous reports of increased DA release in the NAc during lever pressing for food , employing fixed interval or ratio schedules of reinforcement -LRB- Salamone et al. 1994 ; Richardson and Gratton 1996 ; Cousins et al. 1999 -RRB- . Response actions during the early phase of training on interval schedules -LRB- i.e. , in rats having received as few as 120 outcomes -RRB- have been characterized as goal - or outcome-directed -LRB- Adams and Dickinson 1981 ; Balleine and Dickinson 1992 ; Dickinson et al. 1995 -RRB- and accordingly may represent instrumental incentives , as distinct from Pavlovian incentive processes related to incentive motivation -LRB- Parkinson et al. 2002 -RRB- . Continued performance of these instrumental actions leads to habitual responding which , unlike action -- outcome learning , is impervious to outcome devaluation or contingency degradation -LRB- Dickinson et al. 1995 -RRB- . We failed to observe a selective increase in DA efflux when rats had limited as compared to extended training experience , as might be expected if dopaminergic activity in the NAc is related to instrumental incentive learning . Indeed , the magnitude of DA efflux was significantly greater after extended training when behavior is said to be no longer controlled by incentive learning and is based instead on habit . These increases in DA efflux were site-specific , as no significant changes in medial MD striatal DA efflux were observed throughout the different phases of this experiment -LRB- Fig. 4 -RRB- . Performance on instrumental tasks is often conducted under nonrewarded or extinction conditions to evaluate the control of behavior by Pavlovian incentive stimuli , unconfounded by unconditioned reward stimuli . In the present study , a significant increase in DA efflux in the NAc was observed only during the initial 10-min sample of responding in extinction on training day 16 , but not on day 5 -LRB- Fig. 3 -RRB- . The specific CS + present in this experiment was a distinct auditory `` click '' of the pellet dispenser which occurred on a RI 30-s schedule , by itself during extinction or accompanied by delivery of food pellets into the magazine during rewarded responding . As such , these data are consistent with previous reports of increased DA efflux in the NAc elicited by a CS + -LRB- Phillips et al. 1993 ; Datla et al. 2002 -RRB- . In a Pavlovian to instrumental transfer protocol , a CS + previously paired noncontingently to food reward can facilitate the acquisition of an instrumental response -LRB- Parkinson et al. 2002 -RRB- . Systemic administration of DA receptor antagonists during Pavlovian pairings of a CS + with food reward blocks Pavlovian to instrumental transfer -LRB- Beninger and Phillips 1981 ; Dickinson et al. 2000 -RRB- . Damage to the shell or core of the NAc spares the acquisition of Pavlovian to instrumental transfer , but disrupts the potentiation by intra-NAc amphetamine on responding for the CS + -LRB- Parkinson et al. 2002 -RRB- . Together , these findings suggest that a phasic increase of DA in the NAc , shown to occur after treatment with amphetamine -LRB- Taepavarapruk and Phillips 2003 ; Brebner et al. 2005 -RRB- , may mediate the facilitatory effects of a Pavlovian CS + on instrumental responding . It is also of interest to note that the inclusion of an extinction session before a reinforced phase of instrumental responding attenuated the magnitude of DA efflux in the NAc observed when food reward was available on day 5 , but not on day 16 . This finding may be attributed to attenuation in the secondary reinforcement property of the CS + associated with the delivery of food reward or possibly , an influence of frustrative nonreward engendered by extinction . In either case , it is apparent that these effects of extinction are restricted to the early phase of instrumental training . In earlier studies , Salamone et al. -LRB- 1994 -RRB- proposed that an important aspect of dopaminergic activity in the NAc is related to behavioral activation , exertion of effort , and possibly cost benefit analyses relating effort to value of reward stimuli -LRB- Salamone et al. 2003 , 2005 -RRB- . In support of this hypothesis , consumption of large quantities of freely available food pellets or lab chow was not accompanied by increased DA efflux . It must be noted in passing that consumption to satiety of a large meal of a palatable food such as fruit loops , onion rings -LRB- Ahn and Phillips 1999 -RRB- , or sucrose -LRB- Hajnal and Norgren 2002 -RRB- , is accompanied by a significant increase in DA efflux in both the NAc and medial prefrontal cortex . Salamone et al. -LRB- 1994 -RRB- also observed a significant relationship between response rates of individual rats and the magnitude of DA efflux in the NAc . Specifically , an increase in DA release was only observed in rats that responded at medium to high rates of responding , whereas in rats with low response output , this measure did not differ from controls . Our data are also relevant to the relationship between response output and DA activity . In both Experiments 1 and 2 , there was no evidence of a simple relationship between response rates and magnitude of DA efflux . As shown in Fig. 1 , although the rate of lever presses were twice as high on day 16 compared to day 5 , the magnitude of DA efflux did not different significantly between the 2 days . In Fig. 3 , on day 5 , initial response rates during the extinction and reward phases of the test were comparable during the first 10 min -LRB- times 5 and 11 -RRB- , yet the corresponding magnitude of DA efflux during the reward phase was three times greater than the extinction phase . A similar pattern was observed on day 16 . Thus , different rates of responding were associated with similar magnitudes of DA efflux , and similar rates of responding were associated with different magnitudes of DA activity . Accordingly , no positive correlations between rate of lever press responding and magnitude of DA efflux in the Nac were observed after limited and extended training -LRB- Fig. 5 -RRB- . Finally , with respect to the appealing hypothesis that dopaminergic activity in the NAc is related to behavioral activation -LRB- Salamone et al. 2003 , 2005 -RRB- , it must be emphasized that although the present data challenge this hypothesis , it can not be refuted simply on the basis of the lack of a correlation between magnitude of DA efflux and intensity or degree of behavioral activation . The failure to observe a significant increase in DA efflux in the MD striatum during either action -- outcome or habit-based instrumental responding provides a clear indication that DA transmission in this region of the striatum is not involved in instrumental conditioning or stimulus -- response habit formation . These data are consistent with the finding that neither excitotoxic lesions nor reversible inactivation of the anterior MD striatum had any effect on acquisition or expression of action -- outcome associations in instrumental conditioning -LRB- Yin et al. 2005 -RRB- . In contrast , lesions or inactivation of the MD striatum , posterior to the probe placements in the present study , impaired instrumental performance based on outcome -- expectancy -LRB- Yin et al. 2004 -RRB- . Blockade of NMDA receptors in the dorsomedial striatum also disrupted action -- outcome learning consistent with a role for glutamate-mediated synaptic plasticity in the encoding of action -- outcome associations -LRB- Yin et al. 2005 -RRB- . The MD -LRB- `` associative '' -RRB- striatum receives inputs from association cortices -LRB- e.g. , prelimbic region of the prefrontal cortex and premotor areas -RRB- , as well as the basolateral amygdala , which appears to mediate the assignment of incentive value to the consequences of instrumental actions -LRB- Corbit and Balleine 2005 -RRB- . Integrity of the dorsolateral striatum has been shown to be required for habit formation in instrumental learning , and furthermore , rats with damage to this region of the striatum reverted to a state in which instrumental actions were goal-directed -LRB- Yin et al. 2005 -RRB- . This finding implies that the system involving the dorsolateral striatum responsible for habit formation can inhibit the circuit that mediates action -- outcome or goal-directed instrumental actions . This in turn raises the possibility that the increase in NAc DA efflux observed in the present study after extended training provides a representation of instrumental incentive learning that is held in check by activity in the dorsolateral striatum . In conclusion , the present findings provide neurochemical evidence in support of previous data questioning the role of DA in the NAc in coupling incentive value to representations of instrumental outcomes -LRB- de Borchgrave et al. 2002 -RRB- . The data showing elevated DA efflux in the NAc during extinction in the presence of a Pavlovian CS + , in turn are consistent with a role for the NAc in incentive motivation -LRB- Fibiger and Phillips 1986 ; Robbins et al. 1989 ; Phillips et al. 1993 ; Balleine and Killcross 1994 ; Berridge and Robinson 1998 -RRB- . Rats received an apportionment of ∼ 60 food pellets during microdialysis test on days 5 and 16 , yet the magnitude of DA efflux was significantly greater after extended training sessions . These data refute the hypothesis that dopaminergic activity in the NAc is a reflection of either reward value or reinforcement of instrumental responses -LRB- Wise 2004 -RRB- . The present `` within subject '' design revealed a hitherto unappreciated effect of extended training of instrumental responding with an interval schedule on the magnitude of DA efflux in the NAc . For reasons discussed above , this does not appear to be related to motor responding per se . Rather , we speculate that this effect may reflect the specific condition of a random or variable interval schedule of outcome presentation , in which extended training is necessary to appreciate that the probability of receiving a beneficial outcome at any particular time in the 30-min test session is always unpredictable . This degree of uncertainty may be highly compatible with the optimal conditions for activating midbrain DA neurons -LRB- Fiorillo et al. 2003 -RRB- , which in turn would result in a sustained increase in DA release in the NAc throughout a period of random reinforcement . This pattern of DA release could play an important role in maintaining a high level of motivation at the service of a variety of response strategies available to ensure access to objects essential for survival .

B O O O B I O O O O O O O O O O O B I O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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nucleus accumbens


Understanding

the

meaning

of

medications

for

patients

The

medication

experience

Objective

To

understand

and

describe

the

meaning

of

medications

for

patients

Methods

A

metasynthesis

of

three

different

yet

complementary

qualitative

research

studies

was

conducted

by

two

researchers

The

first

study

was

a

phenomenological

study

of

patients

medication

experiences

that

used

unstructured

interviews

The

second

study

was

an

ethnographic

study

of

pharmaceutical

care

practice

which

included

participant

observation

in-depth

interviews

and

focus

groups

with

patients

of

pharmaceutical

care

The

third

was

a

phenomenological

study

of

the

chronic

illness

experience

of

medically

uninsured

individuals

in

the

United

States

and

included

an

explicit

aim

to

understand

the

medication

experience

within

that

context

The

two

researchers

who

conducted

these

three

qualitative

studies

that

examined

the

medication

experience

performed

the

meta-synthesis

The

process

began

with

the

researchers

reviewing

the

themes

of

the

medication

experience

for

each

study

The

researchers

then

aggregated

the

themes

to

identify

the

overlapping

and

similar

themes

of

the

medication

experience

and

which

themes

are

sub-themes

within

another

theme

versus

a

unique

theme

of

the

medication

experience

The

researchers

then

used

the

analytic

technique

free

imaginative

variation

to

determine

the

essential

structural

themes

of

the

medication

experience

Results

The

meaning

of

medications

for

patients

was

captured

as

four

themes

of

the

medication

experience

a

meaningful

encounter

bodily

effects

unremitting

nature

and

exerting

control

The

medication

experience

is

an

individual

's

subjective

experience

of

taking

a

medication

in

his

daily

life

It

begins

as

an

encounter

with

a

medication

It

is

an

encounter

that

is

given

meaning

before

it

occurs

The

experience

may

include

positive

or

negative

bodily

effects

The

unremitting

nature

of

a

chronic

medication

often

causes

an

individual

to

question

the

need

for

the

medication

Subsequently

the

individual

may

exert

control

by

altering

the

way

he

takes

the

medication

and

often

in

part

because

of

the

gained

expertise

with

the

medication

in

his

own

body

Conclusion

The

medication

experience

is

a

practice

concept

that

serves

to

understand

patients

experiences

and

to

understand

an

individual

patient

's

medication

experience

and

medication-taking

behaviors

in

order

to

meet

his

or

her

medication-related

needs

Introduction

Medications

are

one

of

the

main

options

in

the

cure

treatment

and

prevention

of

numerous

medical

conditions

However

there

is

still

a

gap

in

society

regarding

who

must

be

held

accountable

for

the

outcomes

of

pharmacotherapy

Pharmacists

have

recently

recognized

the

societal

need

to

take

responsibility

for

drug

therapy

outcomes

-LSB-

-RSB-

However

if

a

health

care

practitioner

strives

to

meet

a

patient

's

drug-related

needs

then

that

practitioner

must

understand

the

meaning

of

medications

for

that

patient

-LSB-

-RSB-

However

the

medication

experience

as

a

practice

concept

has

not

been

comprehensively

researched

in

pharmacy

Medical

and

social

scientists

have

examined

the

subjective

experience

of

medications

for

patients

typically

within

the

illness

experience

Studies

have

been

conducted

on

the

meaning

of

medications

for

patients

with

specific

medical

conditions

including

asthma

-LSB-

-RSB-

hypertension

-LSB-

-RSB-

and

schizophrenia

-LSB-

-RSB-

Moreover

studies

have

explored

the

meaning

of

therapeutic

classes

including

selective

serotonin

reuptake

inhibitors

-LSB-

-RSB-

hormone-replacement

therapy

-LSB-

-RSB-

and

antipsychotic

medications

-LSB-

-RSB-

Studies

have

also

focused

on

patients

medication

practices

or

medication-taking

behaviors

-LSB-

-RSB-

decision-making

-LSB-

-RSB-

and

cultural

ideas

of

drug

use

-LSB-

-RSB-

Conrad

-LSB-

-RSB-

introduced

the

concept

of

medication

practices

or

how

patients

manage

their

medications

He

found

that

patients

with

epilepsy

interpret

the

prescribed

regimen

and

create

medication

practices

that

may

vary

from

the

prescribed

one

Though

many

studies

have

examined

the

meaning

of

medications

most

have

focused

on

specific

diseases

or

classes

of

drugs

The

authors

surmise

that

there

could

be

a

common

experience

of

taking

medications

chronically

that

transcends

the

specificity

of

diseases

and

medications

Additionally

most

studies

on

the

meaning

of

medications

have

focused

on

patients

decision-making

medication-taking

behaviors

or

compliance

Synthesizing

the

findings

from

three

studies

that

investigate

the

meaning

of

taking

medications

for

patients

with

many

chronic

conditions

could

provide

a

deeper

level

of

understanding

about

a

concept

of

importance

to

pharmacy

practitioners

These

three

studies

focused

on

understanding

how

patients

experience

taking

medications

on

a

daily

basis

meaning

how

they

feel

react

and

think

about

medications

This

understanding

may

help

pharmacists

to

better

comprehend

how

and

why

patients

make

the

decisions

and

take

the

actions

they

do

It

is

the

goal

of

this

article

to

present

an

understanding

of

the

meaning

of

medications

for

patients

introduced

here

as

the

medication

experience

Methods

This

paper

is

the

result

of

a

meta-synthesis

of

three

different

yet

complementary

qualitative

studies

that

included

aims

to

understand

the

medication

experience

These

three

studies

were

conducted

by

the

two

authors

Table

describes

each

study

's

method

and

participants

demographics

Table

methods

and

participant

attributesStudyMedication

experiencePharmaceutical

care

practiceIllness

experience

of

medically

uninsuredMethodologyPhenomenologyEthnographyInterpretive

phenomenologyMethods

InterviewsInterviews

focus

groups

participant

observationInterviewsSetting

of

interviewsUniversity

conference

rooms

and

officesParticipants

homes

and

clinic

exam

roomsParticipants

homes

public

library

rooms

university

roomsParticipantsStaff

and

faculty

at

public

universityPatients

of

pharmaceutical

care

-LRB-

PC

-RRB-

Medically

uninsured

individualsSelection

months

taking

a

chronic

medication

-LRB-

actual

years

-RRB-

years

experience

with

year

uninsured

medical

conditions

prescribed

medsNumber

of

of

women

women

women

menAverage

number

of

medical

conditions

per

The

first

study

was

a

phenomenological

study

of

individuals

experiences

taking

at

least

two

prescription

medications

The

methods

were

guided

by

Van

Manen

's

-LSB-

-RSB-

insights

using

in-depth

interviews

which

were

audio-taped

and

transcribed

The

analysis

involved

reading

and

coding

each

interview

transcript

for

the

meaning

units

of

each

participant

's

experience

Meaning

units

are

phrases

or

text

sections

that

illustrate

a

segment

of

the

meaning

distinct

from

the

adjacent

text

Then

the

codes

were

reviewed

to

identify

the

common

themes

of

the

medication

experience

for

all

participants

The

second

study

was

an

ethnography

that

used

a

triangulation

of

methods

to

reach

a

comprehensive

understanding

of

pharmaceutical

care

practice

-LSB-

-RSB-

The

study

revealed

patients

medication

experiences

as

a

significant

part

of

patients

experiences

with

pharmaceutical

care

The

study

was

conducted

over

a

period

of

eight

months

in

six

clinics

and

one

community

pharmacy

The

sampling

was

theoretical

sampling

which

involved

selecting

participants

who

would

yield

information

that

was

relevant

to

the

understanding

of

experiences

of

those

in

the

pharmaceutical

care

practices

The

data

analysis

was

conducted

following

the

techniques

of

Wolcott

-LSB-

-RSB-

The

third

study

was

an

interpretive

phenomenological

study

that

used

in-depth

interviews

to

understand

medically

uninsured

individuals

-LRB-

in

the

United

States

-RRB-

chronic

illness

experiences

including

the

medication

experience

-LSB-

-RSB-

The

interviews

were

audiotaped

and

transcribed

The

interview

transcripts

and

field

notes

were

segmented

and

labeled

for

one

of

the

three

experiential

units

the

illness

medication

and

uninsured

experience

A

thematic

analysis

of

the

lived

experience

of

each

segment

of

text

was

conducted

coding

each

segment

with

a

descriptive

code

that

captured

the

meaning

conveyed

The

codes

were

iteratively

refined

and

removed

as

appropriate

This

was

in

part

conducted

using

an

analytic

method

called

free

imaginative

variation

Free

imaginative

variation

involves

removing

a

theme

then

asking

if

the

essence

of

the

phenomenon

withstands

-LSB-

-RSB-

The

resultant

essential

codes

became

the

themes

of

the

illness

and

medication

experience

of

medically

uninsured

individuals

The

researchers

used

meta-synthesis

of

the

three

studies

to

reach

a

greater

breadth

of

understanding

about

individuals

medication

experiences

Meta-synthesis

is

an

analytic

method

that

facilitates

a

fuller

understanding

of

a

phenomenon

by

providing

an

interpretive

integration

of

qualitative

findings

The

meta-synthesis

of

qualitative

findings

is

increasingly

seen

as

essential

to

enhance

the

generalizability

of

qualitative

research

-LSB-

-RSB-

The

two

researchers

who

conducted

these

three

qualitative

studies

performed

the

meta-synthesis

The

process

began

with

the

researchers

reviewing

the

themes

of

the

medication

experience

for

each

study

The

researchers

then

aggregated

the

themes

to

identify

the

overlapping

and

similar

themes

of

the

medication

experience

The

researchers

used

free

imaginative

variation

to

determine

the

essential

themes

of

the

medication

experience

and

from

these

the

prevailing

themes

were

identified

The

findings

from

the

meta-synthesis

of

the

three

studies

informed

the

meaning

of

medications

-LRB-

i.e.

the

medication

experience

-RRB-

that

is

presented

in

this

paper

Results

The

meaning

of

medications

for

participants

was

revealed

as

the

following

themes

a

meaningful

encounter

bodily

effects

unremitting

nature

and

exerting

control

A

meaningful

encounter

The

medication

experience

is

first

revealed

as

an

encounter

with

a

medication

It

is

an

encounter

that

is

embedded

with

meaning

long

before

it

occurs

The

meaningful

encounter

can

be

revealed

as

a

sense

of

losing

control

a

sign

of

getting

older

cause

questioning

and

a

meeting

with

stigma

Each

of

these

sub-themes

of

the

meaningful

encounter

is

described

below

The

encounter

with

a

chronic

medication

for

the

first

time

can

be

experienced

as

a

sense

of

losing

control

as

one

participant

states

I

used

to

think

I

was

immune

to

disease

This

body

is

so

tremendous

that

it

will

never

let

me

down

but

here

I

was

I

had

to

start

taking

medication

One

participant

explicitly

characterized

her

medical

need

for

chronic

medications

as

a

loss

of

control

I

lost

control

of

my

health

I

wish

I

could

handle

it

myself

Another

participant

describes

a

similar

desire

to

treat

her

condition

without

medication

I

felt

like

if

I

took

lorazepam

that

I

'm

failing

If

I

could

fight

it

myself

get

over

it

myself

without

the

drug

then

I

'm

getting

better

Participants

commonly

ascribed

a

negative

meaning

to

medications

when

they

first

encountered

them

or

when

they

began

taking

an

increasing

number

of

medications

chronically

Another

study

found

loss

of

control

as

part

of

the

meaning

of

medications

for

patients

-LSB-

-RSB-

Many

participants

described

medications

as

signifying

aging

One

participant

characterized

starting

a

medication

as

depressing

because

it

indicated

he

was

getting

older

However

for

a

participant

in

her

mid-twenties

using

several

medications

the

significance

was

even

greater

I

feel

like

a

woman

Like

my

grandpa

he

's

on

all

these

pills

If

you

're

an

old

person

that

's

okay

but

if

you

're

young

it

's

really

odd

Medications

distinguish

the

healthy

from

the

sick

and

the

young

from

the

old

Taking

chronic

medications

often

made

participants

feel

that

they

were

now

part

of

that

group

of

people

who

take

medications

because

they

are

getting

older

As

part

of

the

initial

encounter

with

a

chronic

medication

many

participants

question

the

actual

need

for

the

medication

they

are

prescribed.I

'm

not

sure

what

I

'll

get

from

these

medications

Uncertainty

arises

when

participants

realize

they

are

supposed

to

take

a

medication

chronically.I

thought

about

what

would

happen

to

me

if

I

just

decided

not

to

take

it

Questioning

the

need

for

a

medication

when

it

is

first

prescribed

can

be

interpreted

as

resistance

by

health

care

professionals

whereas

for

participants

it

is

a

way

to

reclaim

a

degree

of

control

Participants

sensed

that

their

individual

autonomy

was

undermined

when

taking

chronic

medications

until

the

point

they

questioned

the

taken-for-granted

notion

that

medications

are

the

right

option

The

first

reactions

to

initiating

a

medication

can

also

be

shaped

by

the

social

views

of

the

medical

condition

For

example

the

reaction

of

individuals

to

initiating

psychotropic

medications

can

be

a

response

to

the

stigma

of

mental

illness

As

expressed

by

participants

in

these

studies

taking

an

antidepressant

carries

the

shame

associated

with

mental

illness.Maybe

I

'm

just

embarrassed

even

if

nobody

would

know

I

think

people

would

see

me

as

weak

When

initiating

a

chronic

medication

participants

encountered

different

meanings

that

shaped

their

initial

experience

of

the

medication

Participants

experienced

the

meaningful

encounter

with

a

chronic

medication

as

a

sense

of

losing

control

a

sign

of

getting

older

causing

them

to

question

and

a

meeting

with

stigma

Bodily

effects

Medications

have

expected

pharmacological

benefits

as

well

as

anticipated

side

effects

and

unanticipated

adverse

events

all

of

which

are

bodily

experiences

When

a

patient

's

experience

of

their

body

in

illness

is

debilitating

a

medication

can

provide

relief

and

allow

the

patient

to

regain

their

healthy

body

However

medications

also

can

cause

negative

bodily

sequelae

that

are

part

of

a

patient

's

medication

experience

The

bodily

effects

of

medications

theme

was

revealed

as

the

experience

of

a

magic

elixir

and

trade-offs

The

medication

can

normalize

the

patient

or

bring

her

body

as

a

whole

together

At

first

I

was

very

grateful

that

insulin

existed

it

saved

my

life

I

am

grateful

that

I

'm

alive

It

is

scary

that

you

're

reliant

on

this

magic

elixir

to

be

alive

Participants

who

characterized

their

medications

as

magic

elixirs

often

had

medical

conditions

that

incapacitated

them.I

've

struggled

with

depression

all

my

life

My

psychiatrist

started

me

on

antidepressants

I

'm

very

grateful

for

these

drugs

I

would

n't

be

able

to

work

if

it

was

n't

for

them

Sometimes

the

body

disrupted

by

a

disease

can

be

brought

back

into

balance

with

medications

Conrad

-LSB-

-RSB-

found

that

epileptic

patients

perceived

taking

their

anticonvulsants

as

a

ticket

to

normality

An

important

component

of

the

bodily

effects

stemmed

from

what

the

medications

did

to

improve

their

lives

In

contrast

other

participants

experienced

the

negative

sequelae

of

a

medication

However

if

the

benefit

experienced

was

sufficiently

good

they

would

be

willing

to

accept

the

side

effects

as

a

trade-off

One

participant

indicates

You

learn

to

decide

if

you

're

gon

take

the

side

effect

over

how

well

it

helps

with

your

depression

Citalopram

worked

so

well

for

me

that

I

did

n't

care

that

I

was

peeing

my

pants

Another

participant

describes

I

'm

not

worried

about

taking

them

mostly

because

if

they

're

going

to

kill

me

earlier

I

do

n't

care

because

I

just

want

the

problem

to

go

away

Another

study

identified

that

patients

are

aware

of

the

trade-offs

that

must

be

made

while

trying

to

maximize

their

well-being

-LSB-

-RSB-

Participants

also

expressed

concern

about

taking

a

medication

until

they

experienced

the

benefits.Even

though

I

was

hesitant

at

the

beginning

after

seeing

the

benefits

and

realizing

how

life

can

be

with

just

a

medication

and

feel

good

This

theme

illustrates

how

patients

may

rationally

approach

the

decision

to

take

or

continue

a

medication

and

that

they

are

willing

to

take

a

medication

once

they

believe

that

the

medication

's

benefits

outweigh

its

risks

Unremitting

nature

The

unremitting

nature

of

a

chronic

medication

like

a

chronic

condition

is

a

burden.The

first

time

somebody

told

me

I

would

have

to

take

that

for

the

rest

of

my

life

I

got

mad

Another

participant

states

I

feel

that

part

of

my

life

now

is

going

to

be

me

taking

more

and

more

medicine

and

relying

on

medications

to

continue

living

The

expectation

of

taking

a

medication

regularly

positions

the

patient

as

a

passive

agent

and

the

medication

then

becomes

a

symbol

of

dependence.I

think

what

if

I

went

a

couple

months

without

taking

anything

But

I

do

n't

feel

I

have

that

choice

Those

pills

keep

you

prisoner

If

you

go

on

a

trip

that

's

one

of

the

major

factors

it

's

more

important

than

packing

enough

underclothes

This

participant

has

lost

autonomy

and

in

her

words

she

is

held

captive

by

her

medications

Additionally

due

to

the

chronicity

of

medications

participants

have

to

take

responsibility.It

's

this

constant

thing

you

wish

you

could

have

a

break

from

but

you

ca

n't

In

order

to

achieve

normal

function

some

participants

have

to

take

medications

indefinitely

yet

they

still

wish

that

was

n't

the

case.You

feel

sorry

for

yourself

because

you

're

still

on

these

pills

I

do

n't

want

to

think

it

's

been

this

long

and

I

'm

still

on

them

Exerting

control

The

last

theme

of

the

medication

experience

was

revealed

as

participants

exerting

control

over

their

medications

After

encountering

the

meaning

of

a

medication

questioning

it

realizing

the

bodily

effects

and

the

continuous

nature

of

medications

participants

experimented

with

becoming

the

managers

of

their

treatment

regimens

After

taking

chronic

medications

for

a

period

of

time

participants

became

familiar

with

the

effects

of

medications

on

their

bodies

They

discovered

creative

ways

to

manage

their

medications

and

exert

control

over

them

in

part

because

they

were

now

knowledgeable.I

do

n't

think

people

understand

how

much

you

have

to

think

about

it

I

call

it

thinking

like

a

pancreas

You

have

to

do

all

the

work

You

have

to

determine

how

much

you

take

-LSB-

insulin

-RSB-

and

that

changes

from

day

to

day

and

from

hour

to

hour

Participants

have

their

own

method

of

learning

pharmacology

through

experience

They

know

their

bodies

and

perceive

the

changes

produced

by

medications

As

a

result

exerting

control

is

a

common

practice

in

individuals

taking

medications

chronically.I

know

how

to

go

off

of

it

decrease

it

very

slowly

or

you

get

sick

Health

care

professionals

rarely

acknowledge

this

practice

as

a

form

of

exerting

control

instead

it

is

labeled

as

noncompliance

Another

participant

offers

a

description

of

being

attuned

to

her

body

and

taking

control

As

the

doctor

upped

the

dose

I

felt

like

I

was

high

I

started

getting

a

really

weird

feeling

in

my

head

I

even

had

pains

in

my

chest

I

thought

to

myself

I

'm

just

gon

quit

taking

this

So

I

quit

and

then

as

the

week

went

on

I

was

slowly

getting

better

Participants

also

self

manage

their

medications

by

reducing

the

dose

particularly

when

they

are

uncertain

about

the

effects

or

concerned

about

becoming

dependent

I

like

being

able

to

adjust

my

sertraline

as

I

find

necessary

I

like

to

have

that

control

As

the

participants

in

these

studies

convey

and

Carrick

et

al.

-LSB-

-RSB-

also

observed

patients

are

the

ultimate

managers

of

their

treatments

and

create

their

own

medication

practices

From

the

patient

's

perspective

such

behaviors

are

rational

and

help

them

preserve

control

Ramalho

de

Oliveira

and

Shoemaker

-LSB-

-RSB-

argued

that

pharmacists

typically

take

a

paternalistic

perspective

viewing

patients

non-compliant

behavior

as

an

irrational

act

The

understanding

of

patients

exerting

control

over

their

medications

provides

a

context

in

which

to

challenge

the

notion

that

patients

medication

practices

are

illogical

Discussion

The

authors

define

the

medication

experience

as

an

individual

's

subjective

experience

of

taking

a

medication

in

his

daily

life

It

begins

as

an

encounter

with

a

chronic

medication

It

is

an

encounter

that

is

given

meaning

before

it

happens

and

is

often

a

reaction

to

the

symbol

that

medication

holds

The

experience

may

include

positive

or

negative

bodily

effects

The

unremitting

nature

of

a

chronic

medication

often

causes

an

individual

to

question

the

need

for

the

medication

Subsequently

the

individual

may

exert

control

by

altering

the

way

he

takes

the

medication

and

often

in

part

because

of

the

gained

expertise

with

the

medication

in

his

own

body

In

this

paper

the

themes

of

the

medication

experience

are

described

as

being

essentially

independent

of

one

another

however

there

was

a

temporal

location

in

which

the

meanings

seemed

to

arise

in

the

participants

stories

It

appeared

that

the

four

themes

are

essentially

stages

of

the

medication

experience

or

the

experience

of

taking

a

chronic

medication

has

a

natural

progression

from

a

meaningful

encounter

to

participants

exerting

control

Other

scholars

have

recognized

a

pattern

or

stages

that

patients

go

through

with

specific

medications

A

study

of

young

women

using

selective-serotonin

reuptake

inhibitors

-LRB-

SSRIs

-RRB-

for

depression

revealed

that

SSRI

users

passed

through

stages

corresponding

to

how

they

felt

about

themselves

-LSB-

-RSB-

Further

research

is

needed

to

explore

the

validity

of

patients

medication

experiences

as

a

progression

through

stages

or

a

journey

Since

medications

are

among

the

most

common

options

in

the

treatment

and

mitigation

of

diseases

it

is

essential

for

health

care

practitioners

to

acknowledge

an

individual

's

medication

experience

in

order

to

positively

influence

patients

medication-taking

behaviors

Patients

decisions

which

at

first

appear

irrational

might

be

seen

as

intelligent

when

a

practitioner

understands

a

patient

's

unique

medication

experience

Cipolle

et

al.

-LSB-

-RSB-

state

a

practitioner

can

not

make

sound

clinical

decisions

without

a

good

understanding

of

the

patient

's

medication

experience

and

urge

practitioners

to

take

responsibility

for

improving

each

patient

's

medication

experience

The

findings

of

this

study

provide

pharmacists

insights

on

the

meanings

that

medications

can

have

for

patients

which

may

explain

and

certainly

impact

their

medication-taking

behavior

For

example

understanding

the

potential

meaning

of

initiating

a

chronic

medication

-LRB-

e.g.

losing

control

-RRB-

may

help

explain

a

patient

's

reticence

to

taking

the

medication

A

limitation

of

this

study

is

that

the

synthesis

of

findings

was

from

studies

that

explored

the

medication

experience

across

multiple

chronic

conditions

which

makes

it

difficult

to

discern

the

aspects

of

participants

experiences

related

to

the

unique

illness

experience

of

a

specific

disease

Additionally

the

participants

were

all

in

the

U.S.

-LRB-

though

not

all

native

born

-RRB-

and

the

medication

experiences

may

vary

in

different

cultures

Even

though

meta-synthesis

addresses

the

issue

of

small

sample

sizes

in

qualitative

research

this

study

still

has

a

relatively

small

sample

size

-LRB-

n

-RRB-

which

limits

the

applicability

of

these

findings

to

others

experiences

Lastly

the

authors

re-analyzed

their

own

work

which

could

have

led

to

bias

and

reinforcement

of

the

original

findings

Conclusions

The

medication

experience

is

a

practice

concept

that

serves

to

understand

patients

experiences

and

to

understand

an

individual

patient

's

medication

experience

in

order

to

meet

his

or

her

medication-related

needs

The

understanding

of

the

medication

experience

presented

in

this

paper

can

serve

as

a

guide

for

health

care

practitioners

who

are

interested

in

meeting

a

patient

's

medication-related

needs

and

provide

a

foundation

from

which

to

interpret

each

individual

's

unique

medication

experience

Additional

research

is

needed

to

further

understand

the

medication

experience

and

examine

how

it

can

be

used

to

optimize

patients

medication-taking

behaviors

as

well

as

if

there

are

stages

of

the

medication

experience

that

patients

pass

through

O O O O O O B O O B I O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O 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