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Rationale: Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs., Objective: The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident-intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive-compulsive disorder and in a model for evaluating sexual dysfunction., Results: WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar-Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT(2C/2B) receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model., Conclusions: Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Saline-key responding occurred following administration of the D1 agonist SKF-38393, the D1 antagonist SCH-23390, the alpha 2 receptor agonist clonidine, the alpha 1 antagonist prazosin, a nonselective beta-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D2/D3 agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3-1.0 mg/kg), whereas much lower doses (0.003-1.0 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT3 antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT1A and DA D1 and D2 receptors.

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.

CL 284,846, N-[3-(3-cyanopyrazolo[1, 5-a]pyrimidin-7-yl)phenyl)]-N- ethylacetamide, is a novel non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesired side effects. In an effort to further characterize its pharmacological activity, CL 284,846 (3.0 mg/kg, IP, 30 min pretreatment) was established as a discriminative stimulus (DS) in rats (n = 7). CL 284,846 (0.3-10.0 mg/kg) showed a dose-related increase in drug-appropriate responding up to the training dose and a dose-related decrease in response rate. The benzodiazepine agonist triazolam (0.1-1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3-3.0 mg/kg) and the triazolopyridazine CL 218,872 (1.0-3.0 mg/kg) substituted for CL 284,846 in all rats, whereas the imidazopyridines zolpidem (3.0-10.0 mg/kg) and alpidem (10.0-30.0 mg/kg), the benzodiazepine partial agonist bretazenil (0.03-10.0 mg/kg) and the novel putative anxiolytic CL 273,547 (10.0-56.0 mg/kg) substituted in most, but not all, rats. Ro 17-1812, bretazenil, and CL 218,872 had no effect on response rate while the other drugs showed a concomitant decrease in rate. The 5-HT1A agonist buspirone (1.0-10.0 mg/kg) and the barbiturate pentobarbital (3.0-17.0 mg/kg) failed to substitute for CL 284,846 up to rate-decreasing doses. The benzodiazepine antagonist flumazenil (3.0-10.0 mg/kg) blocked the DS effects of CL 284,846 in most rats with no effect on response rate. Taken together, these results suggest that the DS effects of CL 284,846 are mediated via benzodiazepine receptors; however, the DS profile of CL 284,846 remains distinct from both benzodiazepine and non-benzodiazepine sedative-hypnotic drugs.

The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1-3.0 mg/kg) and chlordiazepoxide (3.0-30 mg/kg) increased punished responding at doses that had little effect on unpunished responding; d-amphetamine (0.3-5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding.(ABSTRACT TRUNCATED AT 250 WORDS)

The ability of selective 5-HT3 receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT3 receptor antagonists that are substituted tropines, ICS 205-930 (0.1-0.56 mg/kg) and MDL 72222 (3.0-17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT3 receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25-40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56-1.7 mg/kg), which is also a 5-HT3 receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT2 receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT3 mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT3 receptor antagonists influence their ability to block this action of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of three amphetamine analogs were assessed in pigeons key pecking under a multiple 3-min fixed-interval (FI), 30 response fixed-ratio (FR) schedule of food presentation. At doses between 0.1 and 10.0 mg/kg, (+-) 3,4-methylenedioxyamphetamine (MDA), (+-) 3,4-methylenedioxymethamphetamine (MDMA), and (+-)-N-ethyl-3,4-methylenedioxyamphetamine (MDE) either had no effect or decreased response rates in both components of the multiple schedule in a dose-dependent manner. MDA was at least 1 log unit more potent than the other two compounds. Metergoline (0.1-1.0 mg/kg), a serotonin (5-HT) antagonist with comparable affinity for the 5-HT1 and 5-HT2 receptor subtypes, blocked the rate-decreasing effects of 3.0 mg/kg MDA in both components of the multiple schedule, but did not affect the MDMA dose-response curve. The 5-HT2 receptor antagonist ketanserin (0.1-3.0 mg/kg) also restored FI and FR responding that was decreased by 3.0 mg/kg MDA, but had no effect on responding suppressed by MDMA. The noradrenergic alpha-1 antagonist prazosin (0.3-3.0 mg/kg) blocked the behavioral effects of 3.0 mg/kg MDMA at doses that did not attenuate MDA's rate-decreasing effects. These results indicate that although MDA and MDMA are structurally similar and have similar behavioral effects, their actions appear to be mediated through different neurotransmitter systems.

Responding of two squirrel monkeys with a previous avoidance history was developed and maintained under a multiple fixed-interval 10-min schedule of food and electric shock presentation. Under this schedule the first response after 10 min produced either food or shock depending on the prevailing stimulus condition. Subsequently, responding maintained by food was suppressed when each 30th response produced shock (punishment). Presentation of the same intensity electric shock (10 mA) under the fixed-interval schedule in the other component continued to maintain high positively-accelerated rates of responding. Although increases in punished responding do not usually occur with d-amphetamine, under these conditions, where responding was both maintained and suppressed by the same consequent event, d-amphetamine markedly increased punished responding. Responding maintained by the presentation of shock was also increased by d-amphetamine. The effects of d-amphetamine on punished responding can depend on specific features of the situation in which behavior is studied.

Two principal oblique factors are identified in the Bass Social Acquiescence Scale, a measure previously shown to correlate positively with placebo response and negatively with anxiolytic drug response. The two factors appeared very similar in separate analyses of data from samples of 941 psychiatric outpatients and 1,837 college students. Also, results are presented which indicate that one factor, tentatively labeled "traditionalism", accounted for the empirically observed relationships to placebo and drug response in two clinical trials.

Identical overall rates and patterns of key pecking by pigeons were maintained under a multiple fixed-interval schedule of food presentation. In one component, every thirtieth response produced an electric shock (punishment) whereas during the other component the response that produced food had to be preceded by a pause of a minimum (10 or 11 s) duration. Although chlordiazepoxide (1.0--17.0 mg/kg) increased both punished and unpunished responding, greater increases were uniformly obtained with punished responding.

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.

The serotonin agonist quipazine maleate (1-10 mg/kg, IM) and the serotonin precursor l-5-hydroxytryptophan (5HTP, 3-30 mg/kg, IM) produced dose-dependent decreases in responding (lever-pressing) of squirrel monkeys maintained under a fixed-ratio 30 schedule of food presentation. The classical serotonin antagonist methysergide antagonized the behavioral effects of both quipazine and 5HTP. The behavioral effects of quipazine but not 5HTP were antagonized by the selective serotonin-2 receptor antagonist ketanserin. These results suggest that decreases in food-maintained responding may be produced independently by stimulation of either serotonin-1 or serotonin-2 receptor subtypes.

Ethanol, pentobarbital, and chlordiazepoxide were administered to squirrel monkeys responding under a multiple schedule comprised of two fixed-ratio 100-response schedules (FR 100). Under one FR schedule, the one-hundredth response produced food. Under the other schedule, the one-hundredth response terminated the prevailing stimuli and accompanying schedule of electric shock presentation (stimulus-shock termination). Comparable high response rates were maintained under the two schedules. Each drug produced dose-related decreases in response rates. With all three drugs the effects on all aspects of performance were quantitatively similar for both stimulus-shock termination and food-maintained responding.

Lever pressing by squirrel monkeys was maintained under second-order schedules of either food presentation or IM cocaine injection. Under one second-order schedule, every tenth response produced a brief (1-s) visual stimulus and the first brief stimulus presented after 30 min had elapsed was followed either by ten 300 mg food pellets or by a 3.0 mg IM injection of cocaine. Under another second-order schedule, the first response after 3 min produced the brief stimulus and the tenth brief stimulus was followed either by food or by cocaine. The two types of second-order schedules generated distinctly different patterns of responding. Furthermore, the temporal distribution of responding maintained by food presentation or cocaine injection sometimes differed slightly under the same schedule. Food presentation or cocaine injection occurred only at the end of each daily session, thereby allowing assessment of the effects of presession administration of cocaine, chlorpromazine (CPZ), and chlordiazepoxide (CDP) on responding at times when the direct effects of consequent cocaine injections were minimal or absent. Presession treatment with suitable doses of cocaine increased low rates of food- or cocaine-maintained responding under both types of second-order schedules, whereas CPZ only decreased responding. CDP increased responding in some monkeys, whereas in other monkeys it had little or no effect. Individual differences in the effects of CDP were not related to the schedule of reinforcement, the maintaining event, or the control rate of responding. Thus, the behavioral effects of cocaine, CDP, and CPZ were largely independent of whether responding was maintained by food or by cocaine.

The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001-0.03 mg/kg), haloperidol (0.001-0.01 mg/kg), molindone (0.001-0.03 mg/kg) and thiothixene (0.001-0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01-1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule.

Morphine administration typically decreases responding of squirrel monkeys trained to avoid electric shock. However, the rate-decreasing effects of morphine on avoidance responding were reversed after either concurrent or prior exposure to a condition in which responding was maintained by shock presentation. These findings demonstrate that behavioral experience can play a significant role in determining the behavioral effects of drugs and that specific types of environmental conditions can completely reverse the usual effects those drugs have on behavior.

A lever-lifting response by Dutch Belted and New Zealand White rabbits was maintained in water-deprived animals by 0.26% saccharin solution and in food-deprived animals by food pellets under a multiple 3-min fixed-interval (FI) 30-response fixed-ratio (FR) schedule. Rabbits responding for the saccharin solution had food freely available during the session and in the home cage, whereas those responding for pellets had water continuously available during the session as well as in the home cage. Under nondrug conditions the FR and FI schedules controlled different rates and patterns of responding in the rabbit that were characteristic of those found with other species. In addition, eating or drinking occurred during the initial portion of the FI under the saccharin solution and initial food presentation schedules, respectively. Doses of d-amphetamine (0.1--10.0 mg/kg) increased responding under the FI and FR schedules of food delivery, but increased only FI responding maintained by the saccharin solution. Doses of 3.0--10.0 mg/kg d-amphetamine produced extremely high (300--800% of control) rates of stereotyped perseverative level responding. Schedule-related eating or drinking were unaffected or decreased at doses of d-amphetamine that increased schedule-controlled responding. Chlorpromazine (0.03--0.3 mg/kg) increased FI responding maintained both by saccharin and food, whereas FR responding generally was unaffected at these dose levels; eating but not drinking was increased with chlorpromazine. Since the behavioral effects of drugs such as amphetamine and chlorpromazine differ somewhat in the rabbit from those found with other typically studied nonhuman mammals, further studies with the rabbit may yield useful information for comparative behavioral pharmacology.

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1-3.0 mg/kg), cocaine (1.0-3.0 mg/kg) and bupropion (1.0-30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056-0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha 1 antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha 1 receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.

The effects of thyrotropin-releasing hormone (TRH) and an enzyme-resistant analogue, MK-771, were compared on punished responding of squirrel monkeys maintained either by food presentation or stimulus-shock termination. Both TRH and MK-771 (1.0-30 mg/kg IM) produced dose-related decreases in punished responding maintained by food presentation and dose-related increases in punished responding maintained by shock termination. TRH was more potent than MK-771 in altering punished response rates maintained by either event.