bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAergic mechanism of interaction of lithium and valproate in discrete rat brain regions following their combind treatment and subsequent withdrawal
Authors: Shukla Girja S.
Published: January 2005

Rats administered intraperitoneally with 1 mmol lithium carbonate/kg/day, 300 mg valproic acid/kg/day, and their combination for 12 days lithium treatment were found to increase the levels of γ‐aminobutyric acid (GABA) and its synthesizing enzymes, glutamic acid decarboxylase (GAD), in corpus striatum and midbrain regions. However, these elevated treatment alone increased GABA and GAD in the cerebral cortex and hippocampus regions. in adition, an increased cerebellar GABA concentration was observed. The combined treatment of lithium and valproic acid enhanced GABA and GAD levels in all brain regions, except for GABA and GAD in the pons‐medulla. A statistically significant synergistic effect of the two drugs was noticed in elevating GABA and GAD levels in the corpus striatum, cerebral cortex, and midbrain region. Furthermore, the elevated levels remained stable even 2 days after cessation of the combined therapy. The observed stable and synergistic increase in the regional GABA and GAD suggested a possible role of facilitated GABAergic transmission in the mechanism of therapeutic action of lithium and valproic acid combination in the treatment of mania.
Withdrawal from ingested diazepam produces a pentylenetetrazol‐like stimulus in rats
Authors: Harris Cynthia M. , Idemudia Smart O. , Benjamin Daniel , Bhadra Samiran , Lal Harbans
Published: January 2005

An interoceptive stimulus produced by withdrawal from chronic diazepam is similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). Because the PTZ stimulus can be measured objectively in animals, its use was proposed as a bioassay for diazepam‐withdrawal stimuli. In previous studies, diazepam was given chronically by the intraperitoneal route. The purpose of the present study was to determine whether withdrawal from diazepam given in the diet would similarly produce a PTZ‐like subjective effect. Administering drug through the diet has the advantage that it eliminates the necessity of giving injections every 6–8 hr and more closely parallels human chronic dosing. Rats were trained with food‐reward in a two‐lever operant task. Presses on one lever were reinforced after injections of PTZ, 20 mg/kg, and on the other lever after saline. After rats had acquired the PTZ discrimination, training was halted, and they were given diazepam, 240 mg/kg/day, in a nutritionally complete liquid diet. Withdrawal was precipitated after 3 or 4 days of chronic diazepam with the benzodiazepine receptor blocker Ro 15–1788, either after a bolus dose of diazepam, given intraperitoneally, or during continued dietary diazepam. During precipitated withdrawal, the rats selected the PTZ lever, indicating the presence of a PTZ‐like stimulus, and this stimulus was blocked by phenobarbital, 80 mg/kg. The percentage of rats selecting the PTZ lever depended on the dose of Ro 15–1788. By 3.5 days after cessation of chronic diazepam, Ro 15–1788 no longer produced a PTZ‐like stimulus and by 11 days, rats recovered baseline discrimination performance, as indicated by saline‐lever selection after saline injections and PTZ‐lever selection after PTZ. These data indicate that a subjective effect of withdrawal similar to that obtained after parenteral diazepam can be produced after chronic diazepam given daily in the diet.
Behavioral pharmacology of the gamma carboline Wy 47,384: A potential antipsychotic agent
Authors: Moyer John A. , Abou‐Gharbia Magid , Muth Eric A.
Published: January 2005

Wy 47,384 was examined in an extensive series of in vivo preclinical behavioral tests to determine its possible efficacy and side effect liability as a novel antipsychotic agent. Wy 47,384 was found to suppress avoidance responding following both i.p. and p.o. administration at doses that did not generally impair escape performance. Wy 47,384 also was found to be considerably more potent in antagonizing climbing behavior than stereotyped behavior produced by apomorphine. However, this compound demonstrated some cataleptogenic potential in catalepsy and global behavioral assessment tests. Wy 47,384 also produced limited sedation in motor activity, conflict, and rotorod ataxia tests, but the compound did not interact with ethanol. Wy 47,384 did not demonstrate preclinical anxiolytic activity in conflict behavior tests, and it did not show antidepressant effects in tests designed to assess beta‐adrenergic sensitivity. These studies show that Wy 47,384 is a specific putative antipsychotic agent with limited extrapyramidal and sedative side effect potential.
Suppressive action of propentofylline on coupled and uncoupled glucose oxidations in brain synaptosomes
Authors: Andjus R. K. , Ćirković T. , Marjanović M. , Stefanovich V.
Published: January 2005

In view of a possible beneficial action of some of the xanthine derivatives in brain ischemia or anoxia, metabolic effects of synthetic propentofylline (3‐methyl‐[5′ oxohexyl]‐7‐propyl‐xanthine) have been studied in multiple‐dose experiments with suspensions of rat brain synaptosomes incubated at various temperatures. The rate of D‐[14C] glucose conversion to 14CO2 was measured in the absence or in the presence of 2,4‐dinitrophenol (DNP) used to uncouple oxidative phosphorylations and thus simulate mitochondrial uncoupling accompanying neuronal damage in brain ischemia. Propentofylline suppressed synaptosomal glucose oxidations in a dose‐dependent logit‐linear manner. At 15°C, ED50 concentrations (responsible for the suppression of initial oxidation rates by one half) were highest (8 × 10−3 M) in the case of low‐rate oxidations in Na‐free media and were lowest (7.4 × 10−4 M) in respect to the high‐rate DNP‐stimulated metabolism, which thus appeared as particularly susceptible to propentofylline. Cold‐induced modifications of the metabolic responsiveness of snaptosomes to DNP (flattening of the biphasic DNP log dose‐response profile at reduced incubation temperatures) were intensified by propentofylline, suggesting a synergism between hypothermia and the depressant action of the drug. At equal concentrations, propentofylline strongly inhibited uncoupled oxidations while theophylline remained ineffective or induced even additional stimulatory effects. This is similar to the differential in vivo effects of the two xanthines on brain metabolism and blood flow coupling and further supports the possibility of a protective energy‐sparing role of propentofylline in brain ischemia, particularly effective in association with hypothermia.
Teratological effects of industrial solvents
Authors: Pradhan Sikta , Ghosh Tushar K. , Pradhan Sachin N.
Published: January 2005

Increasing exposure of pregnant mothers to various industrial solvents due to voluntary abuse or involuntary exposure in the work place is raising the possibility of production of teratological effects in the offsprings. Ethanol, which can be broadly categorized as a solvent and which is also extensively abused, is well known for its teratological deragements in humans, termed as “fetal alcohol syndrome” as well as in animals. Benzene and its derivatives (xylene and toluene), alcohols, glycols and glycol ethers, and other solvents have also been reported to produce various types of teratogenic effects in animal (e.g., mice, rats, and rabbits) studies. In the case of toluene, some teratogenic anomalies have been reported in three children of mothers exposed to pure toluene vapor throughout the pregnancy.
Further characterization of 5‐hydroxytryptamine1‐like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5‐hydroxytryptamine1 binding site
Authors: Saxena Pramod R.
Published: January 2005

5‐Hydroxytryptamine (5‐HT) increases heart rate in the spinal‐transected cat by acting on 5‐HT1‐like receptors, since this effect is not modified by ketanserin or MDL 72222 but is blocked by methysergide [Saxena et al., 1985]. These 5‐HT1‐like receptors in the cat heart have been further characterized in this investigation using compounds that have high affinities for 5‐HT1 binding site subtypes. Like 5‐HT, the putative 5‐HT1‐like receptor agonists 5‐carboxamidotryptamine (5‐CT; nanomolar affinities for 5‐HT1A, 5‐HT1B, and 5‐HT1D subtypes) and N‐(3‐acetylaminophenyl) piperazine (BEA 1654; preferential and nanomolar affinity for 5‐HT1A site) elicited dose‐dependent tachycardia. The doses needed to increase heart rate by 50 beats·min−1 were calculated to be 84 ± 6, 4 ± 1 and 21,720 ± 5,200 nmol·kg−1 for 5‐HT, 5‐CT, and BEA 1654, respectively. 8‐Hydroxy‐2‐(di‐N,N‐n‐propylamino)tetralin (8‐OH DPAT; selective nanomolar affinity for 5‐HT1A site) and 5‐methoxy‐3‐(1,2,3,6‐tetrahydro‐4‐pyridinyl)‐1H‐indole (RU 24969; preferential nanomolar affinity for 5‐HT1B site) had little activity. Among antagonists that have nanomolar affinities for all four (5‐HT1A, 5‐HT1B, 5‐HT1C, and 5‐HT1D) 5‐HT1 binding site subtypes, methiothepin, followed by methysergide, showed potent activity against tachycardia induced by 5‐HT, 5‐CT, and/or BEA 1654; metergoline was poorly effective. Mesulergine, which has highest affinity for 5‐HT1C binding subtype, also showed antagonist activity, but this effect was less than that of methiothepin or methysergide. It was concluded that the functional 5‐HT1‐like receptors mediating cardioacceleration in the cat do not seem to be related to any of the 5‐HT1 binding site subtypes identified so far.
Comparison of L‐ and D‐celiprolol in ganglionic‐blocked dogs
Authors: Jolly S. R. , Van Inwegen R. , Schwab A. , Pruss T. P. , Smith R. D. , Wolf P. S.
Published: January 2005

The present study examined effects of the stereoisomers of celiprolol and further examined cardiostimulatory effects of celiprolol. In the anesthetized, ganglionicblocked dog, both I‐ and d‐celiprolol, 3 mg/kg, i.v., showed cardioselective beta adrenoceptor antagonist activity, although blockade of isoproterenol‐induced increases in heart rate and contractile force with I‐celiprolol was more effective. The two stereoisomers had equivalent cardiostimulatory effects, increasing heart rate by 24 ± 7 and 18 ± 3 beats/min and right ventricular contractile force by 37 ± 11 and 24 ± 11%, respectively (all P < 0.05). After propanolol, 1 mg/kg + 0.3 mg/kg/hr, the cardiostimulatory effect of d‐celiprolol was abolished, whereas that of i‐celiprolol was unchanged. Dose‐response curves for heart rate and contractile force stimulation by d‐ and I‐celiprolol were parallel with I‐celiprolol being approximately 100 times more potent than d‐celiprolol and 3 times more potent than racemic celiprolol. These observations suggested that the physiologic effects of celiprolol may be largely mediated via I‐stereoisomer. In additional experiments cardiostimulatory effects of racemic celiprolol, 30 μg/kg, were inhibited by propranolol. Dose‐response curves for celiprolol alone and in the presence of propranolol were parallel. Beta‐blockade shifted the effects 1.5 log units to the right and affected chronotropic and inotropic activities similarly. Biochemical studies of celiprolol showed no significant inhibition of canine kidney sodium potassium ATPase, or of multiple forms of canine cardiac cyclic nucleotide phosphodiesterase. In conclusion, both I‐ and d‐celiprolol are cardioselective beta‐blocking agents with I‐celiprolol being the more potent stereoisomer. Also, the propranolol insensitive cardiac stimulatory activity of celiprolol may illustrate a complex interaction between beta antagonist with and withous ISA rather than a novel positive inotropic mechanism.
Differential effects of anesthetic agents on regional blood flow and central hemodynamic parameters in rats
Authors: Vasthare Usha S. , Irion Glenn L. , Carlsson Christer , Tuma Ronald F.
Published: January 2005

Three commonly used anesthetic agents (pentobarbital, chloralose‐urethane, and inactin) were studied in a rat model. The radiolabeled microsphere technique was used to evaluate rats anesthetized (no reaction to pain stimulus) with the three drugs as compared to awake unanesthetized animals. Of the three anesthetic agents studied, pentobarbital caused the smallest alteration in central hemodynamic parameters. Chloralose‐urethane significantly lowered cardiac output (56%), stroke volume (35%), and minute work (51%). Chloralose‐urethane also significantly increased total peripheral resistance (59%). Inactin at the concentration used in the present study had very little effect on cardiac index, heart rate, stroke volume, and minute work but significantly increased total peripheral resistance and mean arterial pressure. All three anesthetic agents reduced cerebral and skeletal muscle blood flows equally. While pentobarbital and chloralose‐urethane significantly decreased renal blood flow (33%), inactin did not change flow to the kidney. It is concluded that anesthetic agents used in small animal experiments should be chosen carefully so that they do not influence blood flow to the organ being studied.
Baclofen does not block interoceptive discriminative stimulus produced by pentylenetetrazol
Authors: Idemudia Smart O. , Lal Harbans
Published: January 2005

Baclofen was compared with diazepam for ability to block the interoceptive discriminative stimulus produced by the anxiogenic drug pentylenetetrazol (PTZ). Male hooded rats of the Long Evans strain were trained in two‐lever operant chambers to respond for food reward. Presses on one lever were reinforced after intraperitoneal injections of PTZ (20 mg/kg), and on the other lever after saline. After rats had acquired the PTZ discrimination, it was shown that pretreatment with baclofen failed to block the interoceptive stimulus produced by PTZ, whereas pretreatment with diazepam was effective. As baclofen is ineffective in a conflict procedure as well as in antagonizing the PTZ stimulus, but produces a diazepamlike interoceptive discriminative stimulus, it is concluded that elicitation of the diazepam stimulus may not be related to diazepam's anxiolytic efficacy and that diazepam discrimination may be an inappropriate model for studying anxiolytic properties of drugs. Furthermore, the difference between baclofen and diazepam with respect to anxiolytic efficacy is suggested to be related to receptor specificity. The binding of diazepam facilitates GABAA receptor activity, whereas the binding of baclofen facilitates BABAB receptors Hence, it is suggested that modulation of GABAA receptors may be critical in diazepam's blockade of the PTZ stimulus.
Possible memory‐enhancing properties of vinpocetine
Authors: Coleston Donna M. , Hindmarch Ian
Published: January 2005

Critical flicker fusion threshold, choice reaction time, total reaction time, and Sternbergtype memory tasks of digits/words were measured in twelve volunteers after having received vinpocetine or placebo for two days. A significant improvement was recorded in the short‐term memory test following 40 mg of the drug when compared to placebo.
Hoe 288: Indications on the memory‐enhancing effects of a peptidase inhibitor
Authors: Usinger Patricia , Hock Franz J. , Wiemer Gabriele , Gerhards Hermann J. , Henning Rainer , Urbach Hansjörg
Published: January 2005

Several neuropeptides have recently been found to be involved in motivational, memory, and learning processes. Therefore, we tested the hypothesis that the peptidase (EC 3.4.15.1) inhibitor Hoe 288 modulated cognitive functions. Hoe 288 exhibited nootropic effects in uphill avoidance in mice (30 mg/kg orally administered [p.o.]). Scopolamineinduced amnesia in mice and rats was antagonized after subchronic administration for two or three days (1–10 mg/kg p.o. or intraperitoneally [i.p.]) in step‐through avoidance and an eight‐arm‐radial maze, respectively. The resulting bell‐shaped dose‐response curves had a maximum effect at 3 mg/kg. To elucidate the underlying neurochemical effects, ex vivo experiments in rats were performed: acute or repeated administration of Hoe 288 (0.03 – 3 mg/kg i.p.) induced a significant decrease of acetylcholine (ACh) content in certain brain areas that lasted up to 6 hr after treatment. The reduced brain ACh content was most likely due to an enhanced ACh release, as coadministration of the choline uptake inhibitor hemicholinium‐3 (HC‐3) and Hoe 288 potentiated the decrease of ACh induced by HC‐3. Choline acetyltransferase activity in brain increased after acute and subchronic administration of the peptidase inhibitor. Receptor‐mediated effects of ACh were estimated indirectly by its stimulation of guanylate cyclase. Hoe 288 increased cGMP content in a comparable dose range (0.3 – 1 mg/kg i.p.). The converting enzyme inhibitor Hoe 288 was shown to influence acquisition and retention of information in rodents, and the effects on ACh metabolism are in concordance with results obtained with potential nootropics in animal experiments.
Complement peptides and neuronal dysfunction in the central nervous system: Specificity of receptor sites for anaphylatoxin C3a activity in the rat hypothalamus
Authors: Williams Curtis A. , Schupf Nicole , Reilly Christopher L. , Wagner Jolynn
Published: January 2005

The research described centers on the possible activities of complement in neural tissues. Activation of the complement cascade will generate the pharmacologically potent anaphylatoxins C3a and C5a, cleavage peptides of C3 and C5, respectively. Their actions depend on a carboxyterminal arginine, and they are inactivated by a carboxypeptidase in serum, yielding the desarginated derivatives C3ai and C5ai. Using well‐characterized eating and drinking responses to focal chemical stimulation of hypothalamic sites in the rat, we have shown that immune complex formation elicits consummatory behaviors which mimic the responses to norepinephrine (NE) and dopamine (DA). We have also shown these effects to be complement dependent. C5a was found to stimulate eating, similar to the effect of NE, and C3a was found to mimic the effect of DA, potentiating NE‐induced eating or carbachol‐induced drinking. C5a has been shown to act presynaptically to modulate endogenous catecholamine function. In this study 125‐C3a binding to a refined synaptosome preparation reveals a C3a binding site which is completely inhibited by C3ai. We also show that the psychopharmacological action of C3a is also antagonized by C3ai. These studies demonstrate the presence of anaphylatoxin‐sensitive sites in the perisynaptic membrane systems of the rat CNS. They also suggest that the anaphylatoxins could mediate or contribute to the neuropsychiatric disorders often seen in immune complex disease.
Neocortical anomalies in autoimmune mice: A model for the developmental neuropathology seen in the dyslexic brain
Authors: Sherman Gordon F. , Rosen Glenn D. , Galaburda Albert M.
Published: January 2005

Developmental ectopias (nests of neurons) in the molecular layer of the cerebral neocortex and associated dysplasias of underlying layers have been seen in two strains of mice (New Zealand Black and BXSB) that spontaneously develop autoimmune disorders. The ectopias are usually unilateral and males are more often affected than females. The emerging situation is comparable to that of male dyslexics who in addition to their language problems show similar developmental brain anomalies. These anomalies are through to have their origin during the last stages of neuronal migration. We believe that maternal autoantibodies passing through the placenta and blood‐brain barrier may damage the important structural components of the cerebral cortex affecting the final positions of migrating neurons. The autoimmune mice are a useful experimental animal model for understanding the development of neuropathology in dyslexics.
α‐Flupenthixyl chloride: Binding profile to dopaminergic, serotonergic, adrenergic, and cholinergic neuro‐receptors
Authors: Murphy Randall B. , Einstein Richard , Schuster David I. , Narula A. P. S. , Meyerson Laurence R.
Published: January 2005

The binding of the putative affinity ligand α‐flupenthixyl chloride (FPT‐Cl), a derivative of the neuroleptic α‐flupenthixol (FPT), to rat striatal dopamine, α1‐adrenergic, and muscarinic cholinergic recognition sites, as well as to serotonin (5‐HT) receptors and to the presynaptic 5‐HT transport complex, was examined in vitro. FPT and FPT‐Cl were relatively potent at inhibiting the binding of [3H]‐flupenthixol and [3H]‐spiroperidol in striatal tissue preparations as well as [3H]/spiroperidol and [3H]‐WB‐4101 in cortex with Ki values in the 10–20 nM range. With the exception of the muscarinic cholinergic sites (3H‐quinuclidinyl‐benzilate [3H‐QNB]), where FPT‐Cl was more potent than FPT, the Ki values for FPT‐Cl were, in general, slightly greater than those for FPT for other neuro‐receptors tested. FPT‐Cl was found to be essentially inactive at 5‐HT binding sites labeled with [3H]‐LSD and at the 5‐HT transport complex labeled with [3H]‐imipramine, with lC50 values for both exceeding 5μM. It is concluded that the transformation of FPT to FPT‐Cl is not severely detrimental to its dopamine receptor binding characteristics, suggesting that in the presence of appropriate antagonists for masking other receptors, FPT‐Cl may represent a useful affinity ligand to label dopamine receptors.
Comparison of the effects of clonidine, rilmenidine, and guanfacine in the holeboard and elevated plus‐maze
Authors: Johnston Amanda L. , Koening‐Berard Elisabeth , Cooper Teresa A. , File Sandra E.
Published: January 2005

The effects of clonidine, rilmenidine, and guanfacine were studied in the holeboard and elevated‐plus maze tests in rats. In the holeboard test, clonidine had a profound effect on locomotor activity, significantly (P < 0.05) reducing this measure at all but one of the doses tested (0.005–0.25 mg/kg). In contrast, rilmenidine and guanfacine only markedly affected locomotor activity at 2.5 mg/kg or higher. The ED50<apos;s for locomotor activity were as follows: clonidine, 0.024 mg/kg; rilmenidine, 1.92 mg/kg; and guanfacine 1.65 mg/kg. All three compounds also caused significant decreases in the number of head dips and time spent head‐dipping. The effects of clonidine (0.005–0.25 mg/kg)and rilmenidine (0.25–10 mg/kg)on the number of head‐dips were significant (P < 0.01) at all doses and were dose dependent. The actions of guanfacine were similar, with all doses (0.125–5 mg/kg) differing significantly (P < 0.05) from the controls, except 1 mg/kg. However, the time spent head‐dipping was only decreased significantly (P < 0.05) by clonidine (0.005–0.25 mg/kg), rilmenidine (1,5, and 10 mg/kg), and guanfacine (0.5–5.0 mg/kg). In the elevated plus‐maze, clonidine had no significant effect on the % number of entries made onto open arms, or the % of time spent on the open arms; rilmenidine reduced the % time spent on the open arms, but this decrease was secondary to the drop in total activity; in contrast, guanfacine reduced both the % number of entries made onto open arms and the % time spent on the open arms, and this was independent of the drop in total arm entries, thus indicating an anxiogenic‐like effect. The results show that all three compounds are sedative (as judged by reductions in locomotor activity in the holeboard), with clonidine being much more potent on this measure. Guanfacine differed from the other two compounds in its apparent anxiogenic‐like effects in the plus maze.
Effects of loperamide‐oxide on fentanyl drug discrimination in rats
Authors: Meert Theo F. , Niemegeers Carlos J. E.
Published: January 2005

The effects of loperamide and loperamide‐oxide were studied in rats trained to discriminate 0.04 mg/kg, fentanyl from saline. After oral pretreatment with the doses of 0.63, 2.50, 10.0, and 40.0 mg/kg, neither loperamide nor loperamide‐oxide produced any generalization with fentanyl. Both compounds depressed the response rate at 10 and 40 mg/kg. These results indicate that loperamide and loperamide‐oxide produce no fentanyl generalization in rats up to doses at least 250 times their antidiarrheal dose and that both drugs are expected to be devoid of an opiate‐like addiction liability in man.
Graphic assessment of statistical significance and clinical‐biological relevance
Authors: Lewi Paul J.
Published: January 2005

A diagram is presented that evaluates results from clinical and biological studies in which two treatments are compared. In the case of all‐or‐none observations (such as symptoms), the diagram presents the overall rate of occurrence (Prevalence), the difference of the rates of occurrence in the two treatment groups (contrast), and the statistical significance of the result. The prevalence‐contrast (p‐c) diagram can also be applied to other variables (such as scores, temperature, blood pressure, etc.). Accumulation of p‐c diagrams from related studies adds clinical‐biological relevance to statistical significance.
Rimcazole (BW234U) in the maintenance treatment of outpatients with schizophrenia
Authors: Munetz Mark R. , Schulz S. Charles , Bellin Marvin , Harty Irma
Published: January 2005

Rimcazole (BW234U), a substituted carbazole compound, has been reported to be effective in treating acutely ill schizophrenic patients without significant extrapyramidal side effects. A two‐phase study was done to assess the efficacy and safety of rimcazole in the maintenance treatment of schizophrenia. Study I was a double‐blind comparison of rimcazole (50–300 mg daily) with haloperidol (5–30 mg daily) with ten stable schizophrenic outpatients. Three of six patients relapsed on rimcazole, while there were no relapses on haloperidol. One patient dropped out of each group. Extrapyramidal side effects were minimal in the rimcazole group, and two patients with tardive dyskinesia showed marked improvement in AIMS Scores. Study II was an open label trial of rimcazole using a higher maximum dose of 450 mg daily in seven schizophrenic outpatients. Four of the seven patients relapsed, at a mean of 7 weeks, one dropped out, and two patients remained stable. While the drug was generally well tolerated, both of the nonrelapsing patients developed transient elevations in liver transaminases. The small sample size in these studies prevents definitive conclusions to be drawn. There may be subgroups of schizophrenic patients who can be successfully maintained on rimcazole with less morbidity than from standard neuroleptic drugs.
Comments on method and theory in drug discrimination: A potpourri of problems, perplexities, and possibilities
Authors: Holloway Frank A. , Gauvin David V.
Published: January 2005

This paper focuses on how selected training variables may affect the nature of drug discrimination (DD) during generalization tests, specifically addressing the following issues: (1) the production and interpretation of intermediate drug‐lever responding in drug‐saline tasks, (2) how the complexity of the interoceptive stimulus and the nature of the reinforcing event may interact to influence generalization functions, and (3) the ways in which DD history can influence the pattern of generalization results. The analysis of these issues suggests that knowledge of the behavioral factors that are operative in DD tasks may be as critical as knowledge of the pharmacological action of the drugs themselves. First, the issue of quantal vs. continuous response distribution in DD experiments may be partially resolved by attending to how the response class alternates are defined and to whether the reinforcement schedule biases the animal toward an “all‐or‐none”, or maximization, strategy or toward a response mixing or matching strategy. Both strategies appear equivalently to map the drug stimulus dimension. Second, the baseline motivational state defined by the nature of the reinforcing event (e.g., appetitive or aversive) may influence the pattern or profile of drug‐stimuli generalization tests by altering the saliency of one set of effects produced by a given drug over other effects produced by that same drug. In essence, basal conditions can exert selective influence over which stimulus features acquire stimulus control. Finally, the applicability of the paradigms of latent inhibition, overshadowing, and blocking to DD may provide some useful insights into how drug stimuli provide information to the organism.
Methods for planning experimental designs that allow measurement of several concurrent drug effects
Authors: Overton Donald A. , Shen C. Frank
Published: January 2005

Psychoactive drugs concurrently produce a variety of effects on the formation and retrieval of memories and on performance of learned responses. Experimental designs used in psychopharmacology are usually arranged so that some drug effects do not occur or do not influence the dependent variables of interest and so that the strength and statistical significance of the remaining effects can be concurrently determined. Moderately complex designs are often required to allow the simultaneous evaluation of the several drug effects expected to occur in a preparation. In general, the inclusion of more experimental conditions in a design will allow concurrent measurement of more drug effects, but it is often less than obvious exactly which effects can be measured by any given design. Multiple linear regression provides a method for determining which effects can be measured with certain types of designs and hence provides a method for selecting designs adequate to deal with the drug effects anticipated in any particular experiment. This paper presents illustrative examples of the use of multiple linear regression to evaluate the utility of selected experimental designs. It also describes some new experimental designs more adequate than those previously employed for the study of state‐dependent learning and concurrently occurring drug effects.
Drug discrimination in pentylenetetrazol‐trained baboons: Generalization to buspirone and β‐carboline‐3‐carboxylic acid ethyl ester but not lorazepam or pentobarbital
Authors: Ator Nancy A. , Cook J. M. , Griffiths R. R.
Published: January 2005

Pentylenetetrazol (PTZ) has been characterized as producing anxiogenic effects in humans and rats, and PTZ drug discrimination procedures in rats have been used to categorize drug effects as anxiogenic. In the present study, baboons trained to discriminate a subconvulsant dose of PTZ from the no‐drug condition showed dose‐dependent generalization to PTZ and to β‐carboline‐3‐carboxylic acid ethyl esther [β‐CCE; a benzodiazepine (BZ)‐receptor inverse agonist] but no generalization to the BZ‐receptor antagonist Ro 15‐1788 (flumazenil). Ro‐1788 produced surmountable antagonism of the β‐CCE discriminative stimulus. The novel anxiolytic buspirone also occasioned 100% drug lever responding in the PTZ‐trained baboons, although lorazepam and pentobarbital did not. Results with the 5HT ligand 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) were mixed. Lorazepam but not buspirone antagonized PTZ. Observations of baboons after PTZ, buspirone, and β‐CCE at doses occasioning PTZ lever responding showed that tremors and agitation occurred after buspirone but not after β‐CCE or PTZ.
CGS 9896 blocks the pentylenetetrazol‐like effect of withdrawal from chronic ethanol
Authors: Harris Cynthia M. , Elkhayat Ibrahim S. , Benjamin Dan , Bhadra Samiran , Lal Harbans
Published: January 2005

Termination of chronic ethanol produces a withdrawal syndrome characterized not only by physical signs but also by subjective symptoms. One such subjective effect is an interoceptive discriminative stimulus similar to that of the anxiogenic drug pentylenetetrazol (PTZ). In the present study, the pyrazoloquinoline CGS 9896, a nonsedating anxiolytic of low abuse liability, was tested for its ability to reduce the PTZ‐like stimulus effect of ethanol withdrawal. Rats were trained with food reward in a two‐lever choice task to discriminate between PTZ, 20 mg/kg, and saline. Training was then suspended, and the rats were given ethanol for 4–6 days in a nutritionally complete liquid diet (dose consumed 11–13 g/kg/day). At selected times after a final dose of ethanol (3 g/kg), given by gavage, they were tested for lever selection. In contrast to their saline‐lever selection in tests with saline prior to chronic ethanol, rats selected the PTZ lever in tests with saline during withdrawal. Although CGS 9896 transiently impaired performance of the lever‐selection task, it decreased the percentage of rats selecting the PTZ lever during withdrawal. Blockade by CGS 9896 of the PTZ‐like withdrawal stimulus was dose‐dependent over the range 5–20 mg/kg and was more effective after orally than after intraperitoneally administered CGS 9896. These data suggest that CGS 9896 may ameliorate some of the unpleasant subjective sequelae of ethanol withdrawal and may be of clinical value in the treatment of alcoholism.
Discrimination between oral amobarbital and diazepam effects in rats
Authors: Henteleff Harvey B. , Barry Herbert
Published: January 2005

Amobarbital (40 mg/kg) and diazepam (8 mg/kg) were orally intubated in 8 male and 8 female rats 60 min before the 10‐min discrimination sessions. Presses on different levers, depending on the drug given, were reinforced by food pellets on a 10‐sec fixed interval schedule. Within 27 sessions, divided between the 2 drugs, the rats made reliably more than 50% of their presses on the reinforced lever prior to the first food pellets of the session. Additional training sessions included higher doses of both drugs (60–120 mg/kg amobarbital; 12–32 mg/kg diazepam). The amobarbital choice predominated after the high amobarbital doses (80–120 mg/kg) but was close to 50% after all diazepam doses. Response rates were decreased by the highest doses of amobarbital but not diazepam. In a subgroup of 7 high‐dose discriminators, the reinforced lever was predominantly chosen after high doses of either drug. In a subgroup of 7 high‐dose nondiscriminators, the high diazepam doses induced a majority of amobarbital choices but the high amobarbital doses induced a greater preponderance of amobarbital choices. The discriminative performance by both subgroups indicated qualitatively different effects of the 2 drugs in spite of their similar sedative effects. A low response rate by both subgroups after a lower dose of both drugs and in nondrug tests indicated that both drug effects were distinctively different from the nondrug condition.
Generalization of cocaine to the isomers of 3,4‐Methylenedioxyamphetamine and 3,4‐methylenedioxyamethamphetamine: Effects of training dose
Authors: Broadbent Julie , Michael Elizabeth K. , Appel James B.
Published: January 2005

MDA and MDMA are popular recreational drugs which have considerable abuse potential and may be neurotoxic. Because these compounds have sometimes been reported to have behavioral effects that resemble those of d‐amphetamine, the stimulus properties of all of the enantiomers of both MDA and MDMA were analyzed in animals trained to discriminate another abused stimulant, cocaine, from saline. Since the extent of generalization of any drug depends on training dose, separate groups of rats were trained to detect 3.5, 10.0, or 20.0 mg/kg of this compound. The results indicate that all of these doses of cocaine maintain discrimination behavior reliably and consistently and that the three cues are qualitatively similar. Among all the individual enantiomers of MDA and MDMA, only d‐MDA mimicked cocaine; however, this effect occurred consistently only in the group trained to detect the lowest dose (3.5 mg/kg).
Interaction of haloperidol and risperidone (R 64 766) with amphetamine‐induced motility changes in rats
Authors: Megens Anton A. H. P. , Awouters Frans H. L. , Niemegeers Carlos J. E.
Published: January 2005

The interaction of the new antipsychotic risperidone (RIS) and haloperidol (HAL) with amphetamine (AMP) was studied in rats using an activity meter which measured horizontal, vertical, and stationary components of motility. All three components increased markedly and progressively after AMP doses between 0.63 and 5.00 mg/kg (hyperactivity dose range). At still higher doses of 10.0 to 80.0 mg/kg, stationary movements (reflecting stereotypy) further increased, whereas horizontal activity was much reduced and vertical activity virtually abolished. Both HAL and RIS were potent AMP antagonists. Doses on the order of 0.02 to 0.04 mg/kg significantly reduced hyperactivity and reversed stereotypy to a motility pattern equivalent to that of a lower AMP dose. Both compounds were able to restore normal motility at any dose level of AMP stimulation. At the lowest dose of AMP (0.63 mg/kg), the required normalization doses were comparable for HAL (0.022–0.046 mg/kg) and RIS (0.034–0.16 mg/kg). In order to normalize motility induced by higher AMP doses up to 5.00 mg/kg, however, a relatively small dose increment of HAL (to 0.045–0.071 mg/kg), but a large dose increment of RIS (to 0.50–0.96 mg/kg) was required. In other words, the dose‐normalization curves of RIS and HAL diverged at low doses of AMP (0.63–5.0 mg/kg). At higher doses of AMP (10–80 mg/kg), however, this difference disappeared, and the slopes of the dose‐normalization curves became comparable for the two antagonists. It is suggested from these experiments that RIS and HAL are equipotent in controlling a low level of dopaminergic overactivity by partially occupying dopamine‐D2 receptors. Higher levels of functional dopamine antagonism up to saturation of the D2 receptors require a much higher dose of RIS than of HAL. Therefore, the risk of dopaminergic overblockade (and induction of EPS) is considered to be much smaller with RIS than with HAL.
Dopamine receptor agonist activity of U‐66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties
Authors: von Voigtlander Philip F. , Althaus John S. , Ochoa Marlene Camacho , Neff Gary L.
Published: January 2005

Investigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, and d‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be therapeutically useful.
Blockade of peripheral α2‐adrenoceptors by L‐659,066 enhances glucose tolerance and insulin release in mice
Authors: Goldman M. E. , Pettibone D. J. , Reagan J. E. , Clineschmidt B. V. , Baldwin J. J. , Huff J. R.
Published: January 2005

The purpose of this study was to compare the effects of a peripherally selective (L‐659,066) vs. a centrally and peripherally active (L‐657,743; MK‐912) α2‐adrenergic antagonist on murine plasma glucose and insulin levels following fasting or administration of hyperglycemic agents (α2‐adrenergic agonists, glucose). The intravenous administration of L‐657,743 or L‐659,066 alone did not cause major alterations in plasma glucose or insulin levels. Pretreatment of mice with either of these agents, however, at selective α2‐adrenoceptor blocking doses (0.3–3 mg/kg) prevented the elevations of plasma glucose levels induced by the α2‐adrenoceptor agonists clonidine or 3,4‐dihydroxyphenylimino‐2‐imidazoline (DPl). Prazosin, an α1‐adrenergic antagonist, did not alter clonidine‐induced elevations of plasma glucose levels. Pretreatment of fasted mice with L‐657,743 or L‐659,066 (1 mg/kg) 5 min before receiving intravenous glucose resulted in higher plasma insulin levels and improved glucose tolerance compared to saline‐pretreated animals. Moreover, both α2‐adrenergic antagonists enhanced the acute insulin response to glucose. These findings indicate that, under conditions of hyperglycemia, insulin release is enhanced by the blockade of peripheral α2‐adrenoceptors α2‐Adrenoceptor antagonists, such as L‐657,743 or the peripherally selective agent L‐659,066, may prove effective in treating noninsulin‐dependent diabetes mellitus.
Pharmacology of receptors for excitatory amino acids
Authors: McLennan H.
Published: January 2005

The pharmacological evidence for the existence of three distinct neuronal receptors for the excitatory amino acids is reviewed. Although most or all central neurones respond to the eponymous agonists N‐methyl‐D‐aspartate (NMDA), quisqualate, and kainate, and the blockade of their effects is reasonably consistent throughout the neuraxis, subtle regional variations are detected when other agonists are tested. Thus, the tryptophan metabolite quinolinate is completely NMDA‐mimetic in the hippocampus and neocortex but is almost inactive in the spinal cord. L‐Homocysteate resembles NMDA in the cord and striatum but is quisqualate‐like in the hippocampus. There is good evidence for the involvement of amino acids in the mediation of excitatory synaptic events; however, the regional differences in the actions of the endogenous agonists make positive identification of the chemical species active at a particular synaptic site, at best, rather tentative.
Pharmacological regulation of the phencyclidine‐binding site associated with the N‐methyl‐D‐Aspartate receptor‐operated ion channel
Authors: Johnson Kenneth M. , Snell Lawrence D. , Sacaan Aida I. , Jones Susan M.
Published: January 2005

The ion channel operated by N‐methyl‐D‐aspartate (NMDA) receptor agonists is modified by several positive and negative effectors. A variety of chemical structures are known to antagonize the effects of NMDA agonists by preferentially binding with high affinity to the open state of the ion channel. Binding of two of these noncompetitive antagonists has been study extensively in recent months as a probe of NMDA receptor function. It has been found that NMDA agonists and antagonists increase and decrease, respectively, the binding of 3H‐TCP or 3H‐MK‐801 by altering the affinity of the putative phencyclidine (PCP) receptor localized within the ion channel. This affinity change is presumed to be correlated with the conformational change associated with channel opening. This model is also discussed in relationship to one in which binding is increased under nonequilibrium conditions because of a simple increased accessibility to the channel binding site. The modulatory effects of glycine, other amino acids, certain polyamines, and divalent cations on 3H‐TCP and/or 3H‐MK‐801 binding are discussed in relation to their effects on NMDA function in more intact, physiological preparations. It is concluded that the complexity of NMDA receptor regulation provides many possibilities for pharmacological intervention, and that the use of noncompetitive antagonists to probe NMDA receptor function could play a key role in drug development.
N‐methyl‐D‐aspartate receptors, synaptic plasticity, and Alzheimer's disease
Authors: Cotman C. W. , Monaghan D. T. , Geddes J. W.
Published: January 2005

The NMDA (N‐methyl‐D‐aspartate) excitatory amino acid receptor mediates a potent excitatory response in many regions of the CNS and plays a key role in excitotoxicity and synaptic plasticity. Results from radioligand‐binding studies indicate that NMDA agonists and antagonists preferentially bind to differing populations of NMDA receptors. The distribution of NMDA receptors as labeled by the agonist L‐[3H]glutamate differs from that obtained with the radiolabeled antagonist [3H]3‐((±2‐carboxypiperazine‐4‐yl)‐propyl‐1‐phosphonic acid ([3H]CPP)). In addition, NMDA agonists and antagonists display complementary regional variations in their ability to displace L‐[3H]glutamate binding. At least some of the differences between agonist and antagonist‐binding properties can be accounted for by suggesting that glycine converts the NMDA receptor from an antagonist‐preferring state into an agonist‐preferring state. Since NMDA and other excitatory amino acid receptor functions are necessary for synaptic function, certain forms of synaptic plasticity, and learning, we have evaluated their status in Alzheimer's disease (AD). Using radioligand‐binding techniques, we find that NMDA receptors are generally preserved in the course of AD pathology in the human hippocampus in spite of partial cell loss. Kainate receptors, on the other hand, display a radistribution within the hippocampus. This redistribution corresponds to an apparent synaptic reorganization owing to the loss of input from the entorhinal cortex. The response of both the NMDA and kainate receptor systems may be adaptive plastic responses that attempt to maintain hippocampal function that is compromised by AD. However, these mechanisms may also render the hippocampus more vulnerable to damage following excessive neuronal activation.
Neurochemical effects of pyritinol and their relevance for the treatment of brain function deficits in old age
Authors: Seyfried Christoph A.
Published: January 2005

This article reviews the neurochemical results obtained in rats treated with pyritinol, a drug used clinically in the treatment of brain function deficits in old age. Pyritinol can be characterized as an indirectly acting cholinergic drug in the CNS, although its precise mechanism and its primary site of action remains to be elucidated. Direct interactions with muscarinic receptors and influences on catecholaminergic or indolaminergic systems are unlikely. Other actions of pyritinol, i.e., increases in cerebral glucose utilization in rats and cerebral blood flow in man might be secondary to its activating actions on cholinergic neurons. Since pyritinol is reported to significantly improve memory and cognitive functions in patients, the results are considered as evidence that neurochemical measurements of cholinergic functions in animals provide useful and relevant information for these indications although, similar to other cholinergic drugs, the magnitude of its therapeutic effect remains limited.
Discriminative stimulus properties of the non‐sedative anxiolytic benzodiazepine receptor ligand RU 32698
Authors: Gardner Colin R.
Published: January 2005

Gardner, C.R.: Discriminative stimulus properties of the non‐sedative anxiolytic benzodi‐ azepine receptor ligand RU 32698. Drug Dev. Res. 18:ll–18, 1989.

Rats were trained to discriminate RU 32698 (10 mg/kg p.o.) from vehicle using a fixed‐ratio 20 drug discrimination procedure. The characteristics of this cue were compared with that evoked by training rats to discriminate a low dose of chlordiazepoxide (CDZP, 5 mg/kg p.o.) from vehicle. Both cues were antagonized by the benzodiazepine inverse agonist FG 7142, and by the weak inverse agonist CGS 8216. Each training drug substituted for the cue induced by the other. Several benzodiazepine receptor ligands substituted for both cues at similar doses (zopiclone, zolpidem, ZK 91296, RU 43028), although there was a tendency for only partial generalization with ligands with only weak agonist activity (RU 39419, CGS 9896, RU 32514). CL 218872 partially substituted for the RU 32698 cue. Tracazolate partially substituted for both cues but buspirone showed little or no substitution for either cue. Thus, RU 32698 induces a cue via an action at benzodiazepine receptors. The RU 32698 cue is sensitive to low levels of agonism at benzodiazepine receptors and should be useful in the discovery of non‐sedative anxiolytic agents.