Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.     

Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response

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. Changeover responses were increased only moderately by the anxiolytic drugs when the punishment schedule was added to a 3-min variable-interval schedule and the alternate schedule was a 1-min variable-interval schedule without punishment; the amount of time spent in the punishment component, however, increased two-fold at the higher doses of chlordiazepoxide. When these conditions were reversed and punishment was added to the variable-interval 1-min schedule, time spent in the punishment component increased and changeover responses out of the punishment component decreased, particularly following chlordiazepoxide. Anxiolytic drugs appear to attenuate the aversiveness of stimuli correlated with punishment, but the degree of attenuation is controlled by other conditions prevailing in the presence of those stimuli.     

Effects of chlordiazepoxide on comparable rates of punished and unpunished responding

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.     

Effects of opiate antagonists and putative κ agonists on unpunished and punished operant behavior in the rat

The effects of naloxone and diprenorphine, opiate antagonists with different receptor-binding properties, and the putative -receptor agonists, ketocyclazocine and ethyl-ketocyclazocine (EKC), were studied on food-reinforced responding in rats. Behavior was maintained under a multiple-component 1-min variable-interval schedule in which 12-min periods of unpunished responding alternated with 4-min periods in which each response was punished by a brief electric footshock. Daily sessions were 1 h. Naloxone (0.01–10 mg/kg) decreased unpunished responding only slightly; punished responding was decreased significantly to 66% of control by 10 mg/kg. Diprenorphine (0.01–10 mg/kg) did not affect unpublished responding and increased punished responding dose-dependently to as much as 190% of control. EKC (0.01–1.0 mg/kg) decreased unpunished and punished responding dose-dependently and comparably, whereas ketocyclazocine (0.01–1.0 mg/kg)decreased unpublished responding but did not significantly affect punished responding. Diprenorphine was more potent than naloxone in blocking the decreases in responding produced by the agonists. Differences in the behavioral effects of naloxone and diprenorphine appear to reflect the different receptor-binding properties of the two opiate antagonists.     

Interaction of buspirone and dopaminergic agents on punished behavior of pigeons

The non-benzodiazepine anxiolytic buspirone was studied alone and in combination with either haloperidol or apomorphine. Drug effects were evaluated under a baseline of punished and unpunished keypeck responses of pigeons; every 30th response produced food (no punishment) in the presence of a white keylight and, when the keylight was red in alternate 3 min periods, every 30th response produced both food and a brief electric shock (punishment). Buspirone (0.03-3 mg/kg, IM) increased the low rates of punished responding to a maximum of 1000% of control at doses of 0.1-1 mg/kg. Unpunished responding was only marginally affected at lower doses and dose-dependent decreases were obtained from 1 to 10 mg/kg. Although less potent, chlordiazepoxide (1-100 mg/kg IM) produced effects which were similar to those of buspirone, a finding which contrasts with the greater efficacy of benzodiazepines for increasing punished behavior in mammals. Dose-effect functions for buspirone were unchanged by haloperidol administration (0.01 and 0.03 mg/kg, IM, 5 min prior) or by concurrent treatment with a behaviorally-ineffective dose of apomorphine (0.003 mg/kg, IM). Rate-decreasing doses of apomorphine (0.01-0.1 mg/kg) reversed the increases in punished responding produced by lower doses of buspirone (0.03 and 0.1 mg/kg) and the apomorphine-induced decreases in unpunished responding were antagonized by buspirone at doses which had little affect when given alone. The ability of buspirone to reverse the rate-decreasing effects of apomorphine on unpunished responding suggests that buspirone does exhibit dopaminergic antagonist properties in vivo. However, effects of buspirone on punished responding of pigeons do not appear to be due to dopaminergic mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli

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.     

Anticonflict effects of the 5-HT1A compound flesinoxan

The new phenylpiperazine derivative flesinoxan, a potent and selective serotonin(1A) (5-HT(1A)) agonist, was examined under a procedure that has proved to be a reliable and sensitive method for detecting novel anxiolytic drugs believed to produce their effects at the 5-HT( 1A) receptor subtype. Key pecking by pigeons was maintained by the presentation of food following every 30th response in the presence of a white keylight; during an alternate component, correlated with a red keylight, every 30th response produced food and electric shock which suppressed responding (punishment). Flesinoxan doses from 0.001 to 0.3 mg/ kg, intramuscularly, produced significant increases in punished responding at doses that did not affect unpunished responding. Doses of flesinoxan between 1.0 and 3.0 mg/kg also increased punished responding but produced decreases in responding that was not punished. In a second study flesinoxan substituted for the 5-HT(1A) anxiolytic buspirone under a drug discrimination procedure, providing further evidence that the behavioural effects offlesinoxan are mediated by 5-HT(1A) mechanisms. Based on these findings, it would appear that flesinoxan should be a useful compound in the clinical management of anxiety.     

Interactions of metergoline with diazepam,quipazine, and hallucinogenic drugs on a conflict behavior in the rat

The effects of diazepam quipazine, lysergic acid diethylamide (LSD), and 2,5-dimethoxy-4-methylamphetamine (DOM) were examined on a conditioned suppression paradigm. Food-deprived rats were trained to drink a liquid diet from a tube. Subsequently, intermittent 7-s tones were presented during the daily 10-min sessions, the tube being electrified during the last 5 s of each tone. The subject gradually learned to suppress contact with the tube during the tone periods to a low stable level (punished responding) and consumed stable volumes of the liquid diet during the silent periods (unpunished responding). Treatment with diazepam caused large increases (1,000% of control) in punished responding. The hallucinogens produced only modest increases (200–300%), while quipazine did not significantly increase punished responding. Metergoline pretreatment (0.1–2.0 mg/kg, 180 min) had no effect on punished responding itself, and there was no significant alteration of the diazepam dose-response pattern. The weak increase in punished responding by LSD was antagonized by metergoline, but the interaction between metergoline and DOM was variable and inconsistent. Diazepam, quipazine, LSD, and DOM caused dose-dependent decreases in unpunished responding (fluid intake). Metergoline alone decreased unpunished responding only at 2.0 mg/kg. Metergoline pretreatment (1.0 mg/kg) only slightly antagonized the LSD effect on unpunished behavior, but shifted the dose-response curves of DOM and quipazine for decrease in fluid intake to the right approximately eight fold. On the contrary, the dose-response curve of diazepam to decrease fluid intake was shifted to the left by metergoline pretreatment. These data suggest that altered activity of brain serotonin (5-HT) neurons is not responsible for the dramatic increase in punished responding by diazepam. The hallucinogens, quipazine, and diazepam all produce a decrease in unpunished responding, but they appear to do so by different neuropharmacological mechanisms. In addition, there may be at least slight differences in the mechanism by which LSD produces its effects as compared with that of quipazine and DOM.     

Anticonflict effects of 5HT(1A) agonists in pigeons are dependent on the level of response suppression

Anxiety is a phenomenon that has many different manifestations. In order to test whether or not agents targeted to treat anxiety may have the properties necessary to treat differing types of anxiety, we have studied a 8-OH DPAT, buspirone, LY228729, chlordiazepoxide and pentobarbital on three different punished responding procedures in pigeons. Procedure one was a fairly standard multiple FR30 FR30 punished responding model where responding into he punished component was suppressed by electric shock to 7-10% of responding in the unpunished component. Procedure two was similar except that responding during the punished component was suppressed more severely to 1-3% of control, using increased levels of shock. Procedure three was a VI30 schedule as the unpunished component, with concomitant FR5 shock in a second component, and concomitant FR20 shock in the third component. 5HT(1A) agonists, 8-OH DPAT, buspirone and LY228729 produced the typical large increases in punished responding in procedure one, were substantially less effective when shock levels were increased in procedure two, and produced differential results which were likely due to the schedule in procedure three. The more traditional anxiolytics, chlordiazepoxide and pentobarbital, were consistently effective across all three punished responding procedures. These results would seem to indicate that 5HT(1A) agonists may not be as broadly efficacious as traditional anxiolytics, and that the state or severity of anxiety may be an important variable to predict efficacy for 5HT(1A) agonists.     

Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs

 The effects of conventional and novel atypical antipsychotic drugs were compared to clozapine in squirrel monkeys that discriminated IM injections of clozapine (1.0 mg/kg) from saline in a two-lever drug discrimination procedure. Clozapine (0.03–3.0 mg/kg) produced dose-related increases in responding on the clozapine-associated lever with full substitution at the training dose in all monkeys. Dose-related increases in responding on the clozapine-associated lever and full substitution also were observed with structural analogues of clozapine including perlapine and fluperlapine (0.1–3.0 mg/kg), seroquel (0.1–5.6 mg/kg), and JL 5, JL 8 and JL 18 (0.1–3.0 mg/kg). Other clozapine analogues, including olanzapine, amoxapine, loxapine and clothiapine, and conventional antipsychotic drugs, including phenothiazines such as chlorpromazine and thioridazine, produced some clozapine-associated responding up to the highest doses that could be studied, but did not substitute for clozapine. Olanzapine did produce full clozapine-lever responding following pretreatment with the dopamine D₂-receptor agonist (+)-PHNO (0.003–0.01 mg/kg). Putatively atypical antipsychotics that are structurally unrelated to clozapine including risperidone (0.003–0.1 mg/kg), sertindole (0.03–1.0 mg/kg) and remoxipride (0.1–5.6 mg/kg) similarly failed to substitute for clozapine up to the highest doses. The present results indicate that some, but not all, structural analogs of clozapine have clozapine-like discriminative-stimulus effects and that novel antipsychotic drugs which purportedly have clozapine-like clinical efficacy may not produce its interoceptive stimulus effects. Received: 2 November 1996 / Final version: 13 January 1997     

Discriminative and reinforcing effects of brotizolam in rhesus monkeys

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N=3/group) were trained to discriminate pentobarbital (10 mg/kg, IG) ord-amphetamine (0.56–1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6–10 mg/kg), diazepam (1.0–1.7 mg/kg), and brotizolam (0.3–1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. Ind-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01–0.3 mg/kg/injection) and diazepam (0.003–0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001–0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.     

Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats

Rationale The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.Objectives The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.Methods Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.Results Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED₅₀=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED₅₀=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose–response curve for CLZ-appropriate responding to the left. The 5-HT_2A/2C antagonist ritanserin and the H₁ histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The ₁ adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.Conclusions The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.     

Effects of clozapine,haloperidol and thiothixene on schedule-controlled responding and schedule-induced eating and drinking of rabbits

Lever-lift responding by Dutch Belted rabbits was maintained either by the presentation of 0.25% saccharin solution or food pellets under a multiple fixed-interval 3-minute (FI), 30-response fixed-ratio (FR) schedule. Rabbits responding under the schedule of saccharin presentation were water deprived and had food available continuously. During experimental sessions these rabbits ate during the initial portion of many intervals. With rabbits responding under the food-presentation schedule, water was available continuously; these rabbits drank during the initial portion of the interval. Clozapine (0.1–1.0 mg/kg), haloperidol (0.003–0.03 mg/kg) and thiothixine (0.003–0.03 mg/kg) all increased responding under the FI schedules to a maximum of approximately 200 percent of control and generally did not affect or decreased responding under the FR schedules. These effects occurred under schedules where either food or saccharin maintained responding. Higher doses (1–3 mg/kg clozapine and 0.1 mg/kg haloperidol or thiothixine) decreased responding under all schedules. Doses of these drugs that increased responding also increased the amount of eating and drinking that occurred during the experimental session. Although clozapine, a novel antipsychotic compound, typically affects operant performances differently than other antipsychotic drugs, its effects on conditioned rabbit behavior appear similar to those of other antipsychotics. Further, although antipsychotic drugs generally decrease performances in several mammalian species, effects of these agents in the rabbit are similar to those found with humans and chimpanzees. The similarity of antipsychotic drug effects in the rabbit to those found in the human and chimpanzee, together with the comparable effects obtained even with “atypical” compounds, plus the development of schedule-induced eating and drinking suggest that the rabbit may be a very useful addition to research in behavioral pharmacology.     

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (−)S 20500

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT_1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.     

Effects of thyrotropin-releasing hormone (TRH) and a TRH analogue,MK-771, on punished responding of squirrel monkeys

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.     

Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans

 Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30^food:FR30^food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons. Received: 22 May 1998 / Final version: 4 August 1998     

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.     

Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam

This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1–18 mg/kg), cyproheptadine (1–18 mg/kg), metergoline (0,25–2.0 mg/kg) and cinanserin (10–100 mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3–100 g/kg) administered 1,10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6–30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25–2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25–1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.     

Effects of apomorphine on punished and unpunished responding in the rat

Apomorphine has been reported to increase shock-suppressed drinking, which suggests that it might have antianxiety activity. Because some drugs that increase shock-suppressed drinking are not active in other punishment procedures, the effects of apomorphine on punished and unpunished responding maintained by a multiple fixed-interval, fixed-interval schedule of food presentation were studied in rats. At doses from 3.125 to 100 micrograms/kg, apomorphine failed to increase punished or unpunished responding. In contrast, pentobarbital produced large increases in punished responding maintained by a fixed-interval schedule of food presentation.