Oxytocin-Dopamine Interactions Mediate Variations in Maternal Behavior in the
Rat
Dara K. Shahrokh, Tie-Yuan Zhang, Josie Diorio, Alain Gratton and Michael J. Meaney
Endocrinology 2010 151:2276-2286 originally published online Mar 12, 2010; , doi: 10.1210/en.2009-1271

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NEUROENDOCRINOLOGY

Oxytocin-Dopamine Interactions Mediate Variationsin Maternal Behavior in the Rat
Dara K. Shahrokh, Tie-Yuan Zhang, Josie Diorio, Alain Gratton,
and Michael J. Meaney
Sackler Program for Epigenetics and Psychobiology at McGill University, Douglas Mental Health
University Institute, McGill University, Montréal, Canada H4H 1R3

Variations in maternal behavior among lactating rats associate with differences in estrogen-oxytocin interactions in the medial preoptic area (mPOA) and in dopamine levels in the nucleus
accumbens (nAcc). Thus, stable, individual differences in pup licking/grooming (LG) are abolishedby oxytocin receptor blockade or treatments that eliminate differences in the nAcc dopamine
signal. We provide novel evidence for a direct effect of oxytocin at the level of the ventral tegmental area (VTA) in the regulation of nAcc dopamine levels. Mothers that exhibit consistently
increased pup LG (i.e. high LG mothers) by comparison with low LG mothers show increased
oxytocin expression in the mPOA and the paraventricular nucleus of the hypothalamus and increased projections of oxytocin-positive cells from both mPOA and paraventricular nucleus of the
hypothalamus to the VTA. Direct infusion of oxytocin into the VTA increased the dopamine signal
in the nAcc. Finally, high compared with low LG mothers show greater increases in dopamine signal
in the nAcc during bouts of pup LG, and this difference is abolished with infusions of an oxytocin
receptor antagonist directly into the VTA. These studies reveal a direct effect of oxytocin on
dopamine release within the mesocorticolimbic dopamine system and are consistent withprevious reports of oxytocin-dopamine interactions in the establishment and maintenance ofsocial bonds. (Endocrinology 151: 2276 –2286, 2010)

aternal behavior in the rat is dependent on hormonal changes in late pregnancy that include elevations in estradiol levels (1– 4) and accompanying increases in estrogen receptor activation in the brain regions,such as the medial preoptic area (mPOA) (5). The estrogenic effect is critical for hormonal mediators of maternal
behavior such as prolactin or oxytocin (3, 6). Estradiol
implants into the mPOA stimulate maternal behavior, inpart, through effects on oxytocin receptor activity (7, 8).
Treatment with an oxytocin-antisera or an oxytocin receptor antagonist (OTA) directly into the mPOA blocks
the effect of estradiol on maternal behavior (8, 9). Intracerebroventricular (ICV) administration of oxytocin
stimulates maternal behavior in virgin rats (10). Thiseffect is abolished by ovariectomy and reinstated withM

estradiol treatment (11), reflecting the interdependenceof estrogens and oxytocin in the regulation of maternal
behavior in the rat.
Individual differences in specific forms of maternal behavior are also related to estrogen-oxytocin interactions.
Lactating female rats that exhibit increased pup licking/grooming (LG; i.e. high LG mothers) show enhanced expression of estrogen receptor-␣ and increased oxytocin
receptor binding in the mPOA by comparison to low LG
dams (12–15). An ICV infusion of OTA on d 3 postpartum
completely eliminates the difference in pup LG between
high and low LG mothers (13).
An obvious question concerns the relevant neural target
for the estrogen-oxytocin signaling. Projections from the
mPOA to the ventral tegmental area (VTA), which con-ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2010 by The Endocrine Society
doi: 10.1210/en.2009-1271 Received October 27, 2009. Accepted February 12, 2010.
First Published Online March 12, 2010

Abbreviations: AA, Ascorbic acid; DAB, 3,3⬘-diaminobenzidine; ICC, immunocytochemistry; ICV, intracerebroventricular; LG, licking/grooming; mPOA, medial preoptic area;
MPN, medial preoptic nucleus; nAcc, nucleus accumbens; OTA, oxytocin receptor antagonist; PVNh, paraventricular nucleus of the hypothalamus; red:ox, reduction to oxidation
ratio; RT, room temperature; VTA, ventral tegmental area.

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Endocrinology, May 2010, 151(5):2276 –2286

tains dopamine neurons, regulate maternal behavior in therat (16). Nursing bouts increase both Fos expression (17)and extracellular dopamine levels in the nucleus accumbens (nAcc) (18, 19). Chemical lesions of the dopamine
projections to the nAcc (18) or direct infusion of dopamine
receptor antagonists into the nAcc (20, 21) disrupt maternal behavior. High LG mothers show significantly increased dopamine levels in the nAcc shell during periods of
pup LG compared with low LG mothers; treatment of dams
with a dopamine reuptake blocker eliminates the group differences in both nAcc dopamine levels and pup LG (19).
Pedersen et al. (9) found that OTA infusions into the
VTA impair maternal behavior. These findings and thoseof Numan and Stolzenberg (22) suggest that oxytocin projections from the mPOA might act directly on the VTA toregulate dopamine release during mother-pup interactions. The results of studies reported here support thishypothesis and suggest that variations in mother-pup interactions are associated with differences in oxytocinergic
regulation of the mesolimbic dopamine system.

Materials and Methods
Animals and maternal behavior
The animals were outbred Long-Evans, hooded rats born inour colony and housed in 46 ⫻ 18 ⫻ 30-cm Plexiglas cages. Foodand water were provided ad libitum. The colony was maintainedon a 12-h light, 12-h dark schedule with lights on at 0900 h. Allprocedures were performed according to guidelines from the
Canadian Council on Animal Care and approved by the McGill
University Animal Care Committee. Animals were mated withmales obtained from Charles River Canada (St. Constant, Québec, Canada) and singly housed 2 wk after mating. Maternal
behavior was observed for five 75-min periods per day for the
first 6 d postpartum at three periods during the light (1000, 1300,
and 1700 h) and two during the dark (0600 and 2100 h) phasesof the light/dark cycle. The behavior of each mother was scoredevery 3 min (25 observations/period ⫻ 5 periods per day ⫽ 125
observations/mother/day) for the following behaviors: motheroff pups, mother carrying pup, mother LG any pup, and mothernursing pups in an arched-back posture, a blanket posture inwhich the mother lays over the pups, or a passive posture inwhich the mother is lying either on her back or side while the pups
nurse (see Ref. 23 for a detailed description). Pup LG included
both anogenital and body licking. High LG mothers were definedas females for which the mean frequency scores for LG over the
first 6 d postpartum were greater than 1 SD above the cohortmean. Low LG mothers were defined as females for which themean frequency scores for LG over the first 6 d postpartum
greater than 1 SD below the cohort mean.

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allowed to give birth. On postpartum d 3, dams were anesthetized using ketamine/xylazine/acepromazine (0.1 ml per 100 g,
im). Animals were placed in a stereotaxic apparatus with theincisor bar adjusted to maintain the skull horizontal between
bregma and ␭. Animals were infused with 1 ␮l of 4% fluorogold(Sigma, St. Louis, MO), a retrograde tracer, into the VTA (24)(coordinates: 4.8 mm posterior to bregma, 0.8 mm lateral to themidline, and 8.0 mm ventral to the surface of the cortex) using
an infusion pump fitted with a 10-␮l Hamilton syringe attached tothe stereotaxic arm. The infusion rate was 0.2 ␮l/min, and after thecompletion of the infusion, the needle remained in place for 10 min.
The animals were allowed to recover under a heat lamp for 1 h
before being returned to their pups. Antibiotic powder (Cicatrin
GSK, Montréal, Canada) was applied to the site of incision and a
1-ml solution of 0.9% saline (sc) was given for fluid replacement.

Oxytocin and fluorogold immunocytochemistry
Brains were taken from perfused, postpartum d 6 dams, postfixed overnight, and then transferred to a 25% sucrose/PBS solution for 2– 4 d. Brains were sliced at 30 ␮M and stored in
cryoprotectant (pH 7.4) at ⫺25 C. Free-floating sections weretransferred from Eppendorf tubes into wells and washed fivetimes in 0.9% PBS (pH 7.6) for 8 min for preparation for the
double-labeling immunocytochemistry (ICC). Sections were incubated for 90 min in 1% hydrogen peroxide and 3% normal
goat serum in PBS at room temperature (RT) and then incubatedin 0.4% Triton X-100/PBS containing a monoclonal rabbit anti-FG (antifluorogold) antibody for 24 h at RT (1:20,000,
AB153; Millipore, Billerica, MA). Sections were then rinsed
three times in PBS for 5 min and incubated for 2 h in PBS with 1%
normal goat serum containing a biotinylated secondary antibody(goat antirabbit IgG, 1:200; Vector Laboratories, Burlingame,
CA). Sections were rinsed three times in PBS for 5 min and incubated in the ABC reagent for 2 h at RT (ABC kit; Vector
Laboratories). The sections were removed from the ABC solution and rinsed three times in PBS for 5 min and visualized with
3,3⬘-diaminobenzidine (DAB) solution [DAB is a water-soluble
tetrahydrochloride used for permanent immunohistochemical
staining]. Sections were then rinsed five times in PBS for 5 min
and incubated for 60 min in 1% hydrogen peroxide and 3%
normal horse serum in PBS at RT. After blocking, sections wereincubated in mouse monoclonal antioxytocin antibody at RT
overnight (1:8000, MAB5296; Millipore). On the third day, sections were rinsed three times in PBS for 5 min and incubated for
2 h in PBS with 1% normal horse serum containing a biotinylated
secondary antibody (horse antimouse IgG, 1:200; Vector Laboratories), followed by further rinses (three times in PBS for 5min) and incubated in the ABC reagent for 2 h at RT (ABC kit;
Vector Laboratories). Finally, the sections were removed fromthe ABC solution and rinsed three times in PBS for 5 min andvisualized with NOVA RED solution (Vector Laboratories). Sections were mounted on gelatin-coated slides, dehydrated, andcoverslipped. Counts of oxytocin and fluorogold-positive cells(four to five sections/animal) were determined using a computerassisted densitometry program (MCID Systems; Imaging Research, St. Catherine’s, Ontario, Canada).

Fluorogold infusion
Primiparous female rats were precharacterized as high or low
LG mothers. Importantly, individual differences in pup LG arehighly stable across multiple litters (23). High and low LG mothers reared pups to weaning and were then mated 2 wk later andProbe and guide cannula implantation
Lactating females were prepared for surgery 1–2 d after parturition. The animals were pretreated with atropine sulfate (0.1mg/kg, ip) to reduce bronchial secretions, anesthetized with so-2278

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Oxytocin-Dopamine Interactions Mediate Maternal Behavior

dium pentobarbital (60 mg/kg, ip), and placed in a stereotaxic
apparatus with the incisor bar adjusted to maintain the skull
horizontal between bregma and lambda. Electrochemical probes
were lowered into the nAcc shell (24) (coordinates: 1.2 mm anterior to bregma, 0.8 mm lateral to the midline, and 7.0 mm
ventral to the surface of the cortex). Animals were also implantedwith an Ag/AgCl reference electrode in the contralateral parietal
cortex. Miniature pin connectors soldered to the voltammetricand reference electrodes were inserted into a Carleton connector(Ginder Scientific, Ottawa, Ontario, Canada). Subsequent to theprobe placements, guide cannulae (10 mm long, 23 gauge; Plastic
One, Roanoke, VA) were lowered into the VTA (24) (coordinates: 5.2 mm posterior to bregma, 0.8 mm lateral to the midline,
and 8.0 mm ventral to the surface of the cortex). The assembly
was secured with acrylic dental cement to four stainless steelscrews threaded into the cranium. Animals were returned to theirhome cages after a 2.5-h recovery period and observed to be alert
and to engage in full maternal behavior toward pups (i.e. retrieve
pups and initiate a nursing bout).

In vivo electrochemical recordings
Electrochemical probes
The voltammetric electrodes consisted of a bundle of three30-␮m-diameter carbon fibers (Textron Systems, Wilmington,MA) extending 50 –100 ␮m beyond the sealed tip of a pulledglass capillary (outer diameter 0.5 mm), and repeatedly coatedwith a 5% solution of Nafion (Aldrich, Milwaukee, WI), a perfluorinated ionomer that promotes the exchange of cations suchas dopamine but impedes the exchange of interfering anionicspecies such as ascorbic acid (AA) and 3,4 dihydroxyphenylacetic acid. Each electrode was calibrated to determine dopamine
sensitivity and selectivity compared with AA in 0.1 M PBS (pH7.4) that contained 250 ␮M AA to mimic brain extracellularconditions. We used only electrodes with a highly linear response(r ⱖ 0.997) to increasing concentrations of dopamine and anominal dopamine to AA selectivity ratio of greater than
1000:1. Electrodes used had a mean (⫾SEM) dopamine to AA
selectivity ratio of 1619:1 ⫾ 133:1. These Nafion-coated carbon fiber electrodes retain dopamine sensitivity and selectivity
for dopamine against both AA and 3,4-dihydroxyphenylacetic acid for several days after implantation (25).

Electrochemical measurements
Electrochemical recordings were performed using a computer-controlled, high-speed chronoamperometric apparatus(Quanteon, Lexington, KY). An oxidation potential of ⫹0.55
mV (with respect to the reference electrode) was applied to theelectrode for 100 msec at a rate of 5 Hz. The oxidation current
was digitally integrated during the last 80 msec of each pulse. The
sums of every 10 digitized oxidative cycles of the chronoamperometric waveform were automatically converted into equivalentvalues of dopamine concentration using the in vitro calibration
factor. The reduction current generated when the potential was
returned to resting level (0.0 V for 100 msec) was digitized andsummed in the same manner and served as an index to identify
the main electroactive species contributing to the electrochemical signals. With Nafion-coated electrodes and a sampling rate of
5 Hz, the magnitude of the increase in reduction current elicitedby an elevation in dopamine concentration is typically 60 – 80%of the corresponding increase in oxidation current [reduction to

Endocrinology, May 2010, 151(5):2276 –2286

oxidation ratio (red:ox)], 0.6 – 0.8 (26 –32). These studies also
indicate that the oxidation of AA is virtually irreversible (red:ox
0 – 0.1), whereas that of DOPAC is almost entirely reversible(red:ox 1.0); the red:ox for norepinephrine and serotonin are
0.4 – 0.5 and 0.1– 0.3, respectively.

Testing procedure
Electrochemical recordings began on postpartum d 4 and 5.
The in vitro calibration factor was entered in the data acquisition
software before recordings. Dams were placed in a sound-attenuating chamber containing bedding material and connected tothe chronoamperometric instrument by a shielded cable and a
low-impedance computator (Airflyte, Bayonne, NJ). A preamplifier configured as a current-to-voltage converter (gain, 1 ⫻108) was connected onto the head assembly to minimize electrical interference. The pups were introduced into the recording
chamber with bedding from the home cage before the dams wereconnected to the chronoamperometric instrument. Electrochemical recordings were allowed to stabilize for 60 min before drug
infusions (see below). The monitoring of behavior began after a
5-min recovery period and continued for 1.5 h after the stabilization period. The time of onset of each behavior, including an
LG bout, was recorded to associate ongoing maternal behavior
with the electrochemical signal. An LG bout was defined as acontinuous period of LG of at least 5 sec in duration (14, 19).

Electrochemical data
Because of the inherent variations in the sensitivity of Nafioncoated electrodes, the changes in oxidation current recordedwith different electrodes (i.e. in different animals) cannot be assumed to be equivalent. Thus, valid comparisons are possible
only if the sensitivity of each electrode is calibrated against a
standard and the electrochemical data are expressed as standard
equivalent values. The in vivo changes in oxidation current are
expressed as nanomoles equivalent values of dopamine concentration. Data are presented as changes in electrochemical signal(nanomoles dopamine equivalent) relative to the signal level after
stabilization. The electrochemical signal level at this time (baseline) is 0 nM. A value of 0 nM is not the absolute concentration of
extracellular dopamine; rather, the electrochemical data reflect
relative changes in dopamine signal associated with bouts of pup
LG. Group comparisons are based on the peak dopamine signal
increases during each LG bout as well as the dopamine signal
amplitude taken at the onset of each bout of LG.
The similarity in the red:ox ration of norepinephrine and dopamine is inherent to electrochemical analyses. However, any
contribution of norepinephrine should be minor relative to thatof dopamine. The Nafion-coated carbon fiber electrodes used inthis study are five to 10 times less sensitive to norepinephrine
than to dopamine; thus, increases in extracellular norepinephrine in the order of 1–3 ␮M, typical only of K⫹-induced efflux
would be required to elicit increases in electrochemical signals
comparable with those we report for dopamine. Second, whereas
the nAcc shell is innervated by norepinephrine, the density of
norepinephrine terminals is considerably lower than that of dopamine. Third, LG-elicited increases in nAcc dopamine signals
are potentiated by selective DAT blockade (19), suggesting that
dopamine contributes significantly to the nAcc signal increases
reported here. Finally, given that the norepinephrine input tonAcc shell originates primarily in the nucleus tractus solitarius
and that LG-elicited increases in nAcc electrochemical signals areEndocrinology, May 2010, 151(5):2276 –2286

blocked by intra-VTA application of OTA (see below) would
suggest that the relevant signal is that of dopamine.

Histology
Animals were deeply anesthetized with sodium pentobarbital(75 mg/kg, ip) and transcardially perfused with 0.9% saline followed by 10% formalin. The brains were stored in 10% formalinand subsequently cryoprotected in a 30% sucrose-formalin solution. Electrode and cannulae placements were confirmed from 40
␮m thionin-stained coronal sections using the atlas of Paxinos andWatson (24). Only animals with electrodes and cannulae placed in
the nAcc and VTA, respectively, were included in the study.

Drug infusion into the VTA
A 1-␮l Hamilton syringe attached to a polyethylene tube carrying an infusion cannula was used for VTA infusions. On postpartum d 4 lactating females were infused unilaterally with a 1-␮l solution of 0.25 ␮g/␮l of the oxytocin antagonist [(␤-mercapto-␤,␤cyclopentamethylenepropionyl1, O-Me-Tyr2, Orn8)oxytocin;
OTA; Sigma; no. O6887] or with a 0.9% sterile saline solution. The
OTA concentration was based on previous studies examining theeffects of OTA infusions into the mPOA or VTA on sexual receptivity (33) or maternal behavior (9) in the rat. Previous studies (9)show a decrease in maternal behavior after a bilateral infusion of
OTA in the VTA using the same OTA concentration (2.4 nM). We
used a unilateral infusion of OTA into the VTA to limit the behavioral effect and to permit recording of the dopamine signal from theipsilateral nAcc shell during periods of pup LG. This approach was
based on previous studies (34) showing that a unilateral lesion of the
VTA does not disrupt maternal behavior unless combined with alesion of the contralateral mPOA. For virgin females, a 1-␮l solution
containing 0.24 ␮g of oxytocin (oxytocin acetate salt hydrate or␣-hypophamine, no. O6379; Sigma) in sterile saline was infused
unilaterally into the VTA. Adult, nonlactating female rats were infused with 1 ␮l of oxytocin (0.25 ␮g/␮l) or 0.9% saline into the
VTA. This oxytocin concentration is similar to that used in studies
examining the effects of central oxytocin on maternal behavior in
the rat (11). All infusions were performed over a 3-min time period.
The interior of the polyethylene tube was coated with rat bovine
serum (Sigma) to minimize the adhesion of the peptide to the tube.
Oxytocin and OTA infusions were performed after the stabilizationof the electrochemical recordings.

Statistical analysis
A two-tailed t test was performed for all ICC experiments. For
the infusion studies, a repeated-measures ANOVA with drug asa between-subject factor and time as a within-subject factor wasused. Pair-wise comparisons were conducted with a Bonferroni
adjustment for multiple comparisons.

Results
Oxytocin projections from the mPOA to VTA
Sections were analyzed for fluorogold staining to examine
differences in projections from the mPOA [specifically fromthe medial preoptic nucleus (MPN) of the mPOA] to the VTA(Fig. 1A). Only animals in which the fluorogold injection site
was histologically confirmed to lie within the VTA were in-endo.endojournals.org

2279

cluded in the study (Fig. 1H; n ⫽ 5/group). Statistical analysis
revealed no significant differences between the two groups[t (5) ⫽ 0.92, P ⫽ 0.40] in the number of fluorogold-positive cells in the MPN (Fig. 1, B and C).
Immunohistochemistry was performed to examine thenumber of oxytocin-positive cells (n ⫽ 5/group). The results
revealed that high LG dams showed a significantly higher
number of oxytocin-immunoreactive cells in the MPN ofhigh compared with low LG mothers compared with low LG
dams [(t (8) ⫽ 2.67, P ⬍ 0.05; and Fig. 1, D and E].
Sections from the same d 6 postpartum females weredouble labeled for both oxytocin and fluorogold immunoreactivity (n ⫽ 5/group). Statistical analysis revealed a significantly increased number of fluorogold-positive/oxytocinpositive cells in the MPN from high compared with low LG
mothers [t (8) ⫽ 6.40, P ⬍ 0.001; see Fig. 1, F and G]. Thesefindings reveal an increased number of oxytocin-expressing
cells in the MPN with direct projections to the VTA in thehigh compared with low LG mothers. This difference in thenumber of oxytocin/fluorogold-labeled cells was primarily
due to a higher number of oxytocin neurons in the high LG
dams. In the MPN, the percentage of oxytocin neurons thatwere fluorogold positive was comparable across the groups(high ⫽ 37.9%; low ⫽ 35.0%). In addition, ODs were used
to distinguish between single-labeled (oxytocin positive) anddouble-labeled (oxytocin/fluorogold positive) staining.
Oxytocin projections from the paraventricular
nucleus of the hypothalamus (PVNh) to VTA
Analysis of the ICC data for singly labeled oxytocin
cells revealed a significantly increased number of oxytocin-positive cells in the parvocellular region of the PVNhof high compared with low LG mothers [t (6) ⫽ 4.34, P ⬍0.05; Fig. 2A]. In contrast, we found no differences between high and low LG mothers in the number of oxytocin-positive cells in the magnocellular region of the PVNhon postpartum d 6 [t (6) ⫽ 0.42, P ⫽ 0.68; Fig. 2A]. The
number of oxytocin cells was also analyzed in the supraoptic nucleus of the hypothalamus. High LG mothers
showed a significant increase in the number of oxytocinpositive cells compared with low LG mothers at postpartum d 6 [t (8) ⫽ 2.48, P ⬍ 0.05; Fig. 2B].
A single-labeling ICC for fluorogold revealed no significant difference between the number of fluorogold-positive
cells in the parvocellular region of the PVNh of high compared with low LG mothers at d 6 postpartum [t (11) ⫽ 1.03,
P ⫽ 0.32; Fig. 2C]. Double-labeling ICC for oxytocin andfluorogold showed a significantly greater number of oxytocin-positive/fluorogold-positive cells in the parvocellular region of the PVNh of high compared with low LG
mothers on postpartum d 6 [t (9) ⫽ 2.85, P ⬍ 0.05; Fig. 2,
D and E]. These findings suggest that high LG dams have

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Endocrinology, May 2010, 151(5):2276 –2286

FIG. 1. Photomicrograph outlining the boundaries of the MPN of the mPOA used for the quantification of ICC experiments (A). Mean ⫾ SEM
number of fluorogold-labeled cells in the MPN of lactating high or low LG mothers (n ⫽ 5/group) after injection in the VTA on postpartum d 6 (B).
Photomicrograph depicting cells that stained positively for fluorogold (FG) (C). Mean ⫾ SEM number of MPN cells positive for oxytocin (OT)
immunoreactivity in high or low LG mothers (*, P ⬍ 0.05) (D). Photomicrograph of oxytocin-positive cells in the MPN of high and low LG motherson postpartum d 6 (E). Mean ⫾ SEM number of oxytocin- and fluorogold-positive cells in the MPN of high or low LG mothers on postpartum d 6(*, P ⬍ 0.001) (F). Photomicrograph of single- (positive for oxytocin but not fluorogold immunoreactivity) or double-labeled (positive for bothoxytocin and fluorogold immunoreactivity) cells. NOVA RED was used to visualize oxytocin immunoreactivity and DAB to visualize fluorogold
immunoreactivity (G). Schematic illustration of the sites of fluorogold infusions of the five high and five low LG dams. All animals included in theanalysis had confirmed infusion placement in the VTA (H).

an increased number of oxytocin projections from the parvocellular region of the PVNh to the VTA compared withlow LG dams. The proportion of oxytocin-positive cells in
the PVNh that were fluorogold positive did not differ
across groups (high ⫽ 71.4%; low ⫽ 66.7%), suggestingthat the difference in the absolute values was due to anincrease in the number of oxytocin-positive cells in highLG dams.
The effect of oxytocin on nAcc dopaminetransmission
These findings suggest an increased oxytocinergic projection from both the mPOA and the PVNh to the VTA inhigh LG mothers. We then examined whether oxytocin
might act at the level of the VTA to alter the nAcc dopamine signal and whether the activation of nAcc dopamine
signal during bouts of LG is mediated by oxytocin receptors in the VTA.
Oxytocin infusion into the VTA increases the
dopamine signal in the nAcc
We used in vivo voltametry to examine the acute effects of
intra-VTA oxytocin infusions on dopamine signals recordedin the nAcc shell. The results (Fig. 3, A and B) revealed anincreased dopamine signal in response to both saline and, toa greater extent, the oxytocin infusion. Thus, a repeated-

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FIG. 2. Mean ⫾ SEM number of oxytocin-labeled cells (OT⫹) in the parvocellular and magnocellular regions of the paraventricular nucleus of the
hypothalamus PVNh (A) and in the supraoptic nucleus (SON; B) of lactating high and low LG mothers on postpartum day 6 (n ⫽ 5/group/*, P ⬍0.05). Mean ⫾ SEM number of fluorogold (FG⫹)-labeled cells in the parvocellular region of the PVNh (pPVNh) of high or low LG mothers on
postpartum d 6 (n ⫽ 5/group) (C). Mean ⫾ SEM number of oxytocin⫹/fluorogold⫹ double-labeled cells in the parvocellular region of the PVNh ofhigh and low LG dams on post partum d 6 (n ⫽ 5/group, *, P ⬍ 0.05) (D). Photomicrograph outlining the magnocellular (MNCs) and parvocellular(PVCs) regions of the PVNh used for the quantification of immunocytohistochemistry experiments. NOVA RED was used to visualize oxytocin
immunoreactivity and DAB to visualize fluorogold immunoreactivity (E).

measures ANOVA revealed a significant main effect of treatment [F (1, 6) ⫽ 7.99; P ⫽ 0.03] and time [F (7, 42) ⫽ 14.83; P ⫽0.0001] as well as a significant treatment-by-time interaction
effect [F (7, 42) ⫽ 2.50; ⫽ 0.03]. Pair-wise post hoc comparisons confirmed that the increases in the dopamine signal inoxytocin-treated animals were significantly greater than insaline-treated animals at postinjection times 2–14, 18, and22–24 min (all P values ⬍0.05) but not at later time points,
reflecting the relatively short half-life for oxytocin (35). In
addition, the difference between the dopamine signal of theoxytocin- and saline-treated animals is partially masked by
the acute stress of the infusion, which increases the extracellular dopamine signal. An area under the curve analysis (Fig.
3B) taken from t ⫽ 0 (min) to t ⫽ 24 (min) confirmed that theincreases in the dopamine signal in oxytocin-treated animals
were significantly greater than those seen in saline-treatedanimals [t (6) ⫽ 2.81; P ⬍ 0.05].
We then examined whether the differences in the dopamine signal in the nAcc shell between high and low LG
mothers during periods of pup LG were associated withoxytocin effects at the level of the VTA. Consistent withprevious findings (34), we found no effect of the unilateral
OTA infusion into the VTA on the frequency or durationof pup LG (data not shown). Although the characterization of high-low LG mothers relies on multiple observations per day performed over 6 consecutive days, suchdifferences were apparent, even during a single recording
period, the equivalent of a single period of observation. As

in our previous study (19), the duration of pup LG bouts
in high LG mothers was significantly (P ⬍ 0.05) longer
than that of low LG mothers. This finding is consistent

FIG. 3. The mean ⫾ SEM increase in dopamine (DA; nanomoles) in the
nucleus accumbens shell of virgin females after the infusion of salineor oxytocin (2.4 nmol) into the VTA (n ⫽ 5/group). Infusion of oxytocin
increased the dopamine (nanomoles) signal at min 2–14, 18, 22, and24 after infusion by comparison with saline-treated animals (*, P ⬍0.05) (A). Mean ⫾ SEM of total area under the curve (AUC) for
dopamine levels measured over the period depicted in A for virgin
females infused with oxytocin or saline (*, P ⬍ 0.05) (B). Repeatedmeasures ANOVA was followed by a pair-wise post hoc test.

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FIG. 4. Mean ⫾ SEM peak increase in dopamine (DA; nanomoles) in the nAcc shell of highand low LG lactating females on postpartum d 4 or 5 after infusion with either an oxytocin
antagonist (OTA) or saline in the VTA (n ⫽ 4 –5/group). The saline-treated high LG mothers
showed a significantly higher dopamine signal (*, P ⬍ 0.05) compared with all other groups(A). Representative recordings depicting the change in the dopamine (nanomoles) signal in
the nAcc shell of high and low LG mothers before, during, and at the end of a period of pup
LG on postpartum d 4/5 after infusion of an oxytocin antagonist (OTA) or saline into the VTA(red dashed line represents baseline) (B). Schematic illustration of the sites of electrochemicalprobe placement in the high and low LG dams included in the electrochemical and behavioral
analysis. All animals included in the analysis had confirmed probe placement in the nAcc shell(n ⫽ 4 –5/group) (C). Schematic illustration of the sites of cannulae placements in the highand low LG dams included in the electrochemical and behavioral analysis. All animals
included in the analysis had confirmed cannulae placement in the VTAea (F, OTA; ‚, saline)(D). A two-way ANOVA was used followed by Bonferroni’s post hoc test. Figure continued on
next page.

with previous reports (19, 23) showing that the differencesin pup LG are associated with differences in the durationof individual LG bouts.
As previously described (19), increases in nAcc dopamine signals were recorded during periods of pup LG andthe peak amplitude of such increases differed significantly
in high vs. low LG dams (Fig. 4, A–C). We found that thedifference in LG-related activation of nAcc dopamine

Endocrinology, May 2010, 151(5):2276 –2286

transmission was also associated witha differential sensitivity to intra-VTA
blockade of oxytocin receptors with
OTA. A two-way ANOVA revealed amain effect of treatment [F (1, 11) ⫽12.66; P ⫽ 0.01] such that an intraOTA infusions significantly attenuatedthe peak nAcc dopamine responses associated with LG. Most importantly,
the analysis revealed a significant treatment by maternal phenotype interaction [F (1, 11) ⫽ 4.58; P ⬍ 0.05]. As expected from our previous studies (19),post hoc analyses revealed that among
saline-treated animals, the peak LG-related nAcc increases in the dopamine
signal in the nAcc shell during a bout of
pup LG were significantly (P ⬍ 0.05;
Fig. 4A) greater in high LG than low LG
mothers. Importantly, intra-VTA OTA
infusions significantly attenuated LGrelated dopamine signal increases inhigh LG mothers but had no effect on
the dopamine responses seen in low LG
mothers. Thus, OTA-treated high andlow LG animals showed comparable
LG-related increases in nAcc dopamine
signals. Interestingly, the mean increasein the amplitude of the dopamine signal
in the nAcc of high LG mothers associated with pup LG (⬃400 nM) was comparable with that obtained in nonlactating females rats (⬃300 nM) after
oxytocin infusion into the VTA.

Discussion

Variations in pup LG among lactatingrats is associated with differences in the
dopamine signal in the nAcc shell (19).
There is an increase in the nAcc dopamine
signal that accompanies the onset of pup
LG and the termination of the increased
dopamine signal corresponds that of pup
LG. The magnitude of the increase in the dopamine signal in
the nAcc is strongly correlated to the duration of the pup
LG bout (19). The differences between high and low LG
mothers in the nAcc dopamine signal and in pup LG are
abolished by pretreatment with a dopamine reuptake
blocker (19). These findings are consistent with previous studies (18, 20, 21, 36, 37), revealing the impor-Endocrinology, May 2010, 151(5):2276 –2286

endo.endojournals.org

2283

FIG. 4. Continued.

tance dopamine activity in the nAcc for maternal behavior in the rat.
Differences between high and low LG mothers in mesolimbic dopamine activity are associated with the effects ofoxytocin at the level of the VTA. Individual differences in pup
LG among lactating females derive, in part, from alterations
in central oxytocin systems that regulate maternal behavior.
Thus, ICV infusions of OTA eliminate the differences in pup
LG between high and low LG mothers (13). We found increased oxytocin expression in the parvocellular region of the
PVNh of high compared with low LG mothers; the PVNh
projects to the mPOA and VTA (38). There were no suchdifferences in the magnocellular neurons that project to theneurohypophysis and regulate milk ejection. Oxytocin commonly acts at oxytocin receptors to increase the firing rate ofoxytocin neurons and enhance oxytocin synthesis (i.e. a positive feedback effect) (39 – 41). Lactating high LG mothers
show increased oxytocin receptor binding in the mPOA, suggesting greater sensitivity to oxytocin (12, 13, 15). Increased
oxytocin receptor binding in the mPOA of high LG mothers(12, 13) combined with a positive feedback effect on oxytocin expression is consistent with the finding of an increased
oxytocin expression in the mPOA of high compared with the
low LG mothers.
Numan and colleagues (34, 42) described the importance of mPOA projections to the VTA for maternal be-

havior in the rat. Thus, unilateral mPOA lesions combinedwith lesions of the contralateral VTA impairs maternal
behavior (16), as do bilateral OTA infusions into the VTA(9). The tract-tracing study suggests direct projections
from oxytocin-positive cells in the mPOA to the VTA as amechanism for a direct effect of oxytocin on dopamine
release from VTA neurons. The results also revealed increased oxytocin projections in high LG mothers (Fig. 1),
consistent with the increased oxytocin expression in the
mPOA. Whereas these findings focus on the importance ofmPOA-VTA projections, it is worth noting an alternative
pathway that includes the lateral preoptic area, with subsequent projections to the VTA (43). There was also an
increased number of oxytocin-positive cells in the PVNh
with projections to the VTA in high compared with low
LG mothers.
Infusion of oxytocin directly into the VTA enhanced
the dopamine signal in the nAcc shell (also see Ref. 44),suggesting an effect of oxytocin on the dopamine neuronsof the VTA. We replicated previous studies showing an
increased dopamine signal in the nAcc during periods of
pup LG in high compared with low LG mothers (19) andshowed that this difference was abolished with an intraVTA infusion of an oxytocin receptor antagonist (Fig.
4A). These findings suggest that under normal conditions
the increased dopamine signal in the nAcc of the high LG

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Shahrokh et al.

Oxytocin-Dopamine Interactions Mediate Maternal Behavior

mothers is oxytocin dependent. Note, however, that thesefindings do not necessarily imply a direct effect of oxytocin
on dopamine neurons, nor can we exclude the possibilityof diffusion from the VTA as a complication.
The oxytocin receptor is expressed in the rat VTA (16)and is a class I G protein-coupled receptor that is primarily
coupled via Gq proteins to phospholipase C (45, 46)
with the capacity to regulate calcium-mediated neuronal events, such as dopamine release. The present findings
are also consistent with those showing oxytocin enhanced
psychostimulant-induced sensitization (47); such effects
are commonly mediated by the activation of the dopamine
neurons in the VTA (48). Our findings are also consistent
with reports of oxytocin-dopamine interactions in the regulation of social behavior. Thus, an interaction between
oxytocin and mesocorticolimbic dopamine systems is implicated in the maintenance of social bonds (e.g. Refs. 49 –53). The dopamine signal in the nAcc might mediate anincreased expression of appetitive behaviors directed toward pups (22, 54). Such maternally initiated (or active)
behaviors would include pup LG, and likely pup retrieval,
which is also subject to disruption by manipulations thattarget oxytocin-dopamine pathways (22). The mesocorticolimbic dopamine system modulates behavioral responses to incentive stimuli through projections from the
VTA to the nAcc (48, 55–59). Pups hold remarkable salience for the lactating female rat and postpartum females
bar-press vigorously for access to neonates, a behavior
that is abolished by lesions to the mPOA abolish such
responses (60). Suckling pups are more reinforcing for
lactating rats than is cocaine or food (61, 62).
Dopamine levels in the nAcc shell are increased during
a nursing bout (18) and 6-hydroxydopamine lesions ofeither the VTA or nAcc severely disrupt maternal behavior(36, 37). Microinjection of mixed dopamine type 1/type 2
receptor antagonists into the nAcc shell impairs maternal
behavior, including pup LG (20, 21). Activation of the D1
receptor increases FOS expression; maternal contact withpups increases FOS expression in the nAcc (17, 63). Ourfindings suggest that individual differences in maternal
behavior associate with variations in the activity of themesolimbic dopamine system during periods of motherpup interactions. Thus, Champagne et al. (19) found that
infusion of a dopamine reuptake blocker enhanced the
dopamine signal in the low LG mothers to that observedin high LG dams and completely eliminated the groupdifferences in pup LG (19). Febo et al. (64) used functional
magnetic imaging and showed that suckling from pups
increases the BOLD signal in the VTA and nAcc. These
effects were reduced with OTA infusion. Likewise functional magnetic imaging studies (65, 66, and Popeski N.,
C. Scherling, A. S. Fleming, J. Lydon, J. C. Pruessner, M.

Endocrinology, May 2010, 151(5):2276 –2286

J. Meaney, submitted for publication) with human mothers revealed that activity along dopamine sensitive pathways, including the nAcc, is associated with individual
differences in maternal responsivity; increased activity
within these systems predicts greater responsivity to infant-related stimuli. Thus, studies across a range of species
suggest that individual differences in maternal behaviors
derive from variation within mesolimbic oxytocin-dopamine systems.

Acknowledgments
Address all correspondence and requests for reprints to: Michael
Meaney, Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montréal (Vérdun) Québec, Canada H4H 1R3.
E-mail: michael.meaney@mcgill.ca.
Disclosure Summary: D.K.S., T.-Y.Z., J.D., A.G., and
M.J.M. have nothing to declare.

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