Distinctive behavioral effects of the pyrazoloquinoline CGS 8216 in squirrel monkeys

The behavioral effects of the pyrazoloquinoline CGS 8216 were studied in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. Dose-effect curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the FI schedule. CGS 8216 (0.1-3.0 mg/kg) produced dose-related decreases in the rate of FI responding. In comparison, diazepam (0.1-3.0 mg/kg) had biphasic effects under identical conditions: intermediate doses increased the rate, whereas high doses decreased the rate of FI responding. Pretreatment with the benzodiazepine antagonist Ro 15-1788 (3.0 or 5.6 mg/kg) attenuated the decreases in response rate normally produced by high doses of CGS 8216. The behavioral effects of CGS 8216 were not altered systematically by pretreatment with either diazepam (0.3-3.0 mg/kg) or the alpha 2-adrenergic agonist clonidine (0.01-0.03 mg/kg). The results suggest that CGS 8216 has benzodiazepine inverse agonist effects on schedule-controlled behavior of squirrel monkeys. CGS 8216 can, however, be distinguished from inverse agonists of the beta-carboline type on the basis of its effects in the presence of diazepam or clonidine.     

Pyrazoloquinoline benzodiazepine receptor ligands: effects on schedule-controlled behavior in dogs

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896, and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under both components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.     

Attenuation of the behavioral effects of meperidine and normeperidine by daily administration of diazepam

The effects of meperidine, normeperidine, morphine, pentobarbital and d-methadone were determined on the key-pecking behavior of pigeons responding under a multiple fixed-ratio (FR), fixed-interval (FI) schedule of grain presentation. Dose-effect curves were obtained for each drug alone and during daily administration of 10 mg/kg of diazepam. The daily administration of diazepam had little effect on the behavior itself. Meperidine and normeperidine caused dose-related decreases in both FI and FR responding. The dose-effect curves for these drugs during daily administration of diazepam were shifted to the right compared to the dose-effect curves determined in the absence of daily diazepam. In contrast, the effects of morphine, d-methadone and pentobarbital either were not affected by daily administration of diazepam or were shifted to the left by daily administration of diazepam. These data further support the hypothesis that the behavioral effects of meperidine and normeperidine are due to a proconvulsive action produced by these drugs. In contrast, the effects of morphine, d-methadone and pentobarbital are not due to such a proconvulsive action.     

Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats

To determine what stereoselective differences there may be in the behavioral effects of the isomers of pentobarbital and secobarbital, the effect of each isomer was determined on the spontaneous motor activity (SMA) and multiple fixed-ratio 30, fixed-interval 600-sec (mult FR30 FI600) responding of mice, and on the variable-interval 60-sec (VI60) responding of rats. The S-(-) isomers of pentobarbital and secobarbital decreased SMA at lower doses than those required for the R-(+) isomers. At moderate to high doses of R-(+)-pentobarbital (30-42.5 mg/kg) and low to moderate doses of S-(-)-secobarbital (5.6-17.5 mg/kg) SMA was increased. An increase in SMA following R-(+)-secobarbital was only observed at 30 mg/kg, and no increases were observed with S-(-)-pentobarbital. No potency differences were observed between the isomers of pentobarbital and secobarbital on the responding of mice under the mult FR30 FI600 schedule over a dose range of 1-30 mg/kg. Increases in FI600 responding were only observed following moderate doses of the S-(-) isomer of pentobarbital (5.6-17.5 mg/kg). In rats responding under the VI60 schedule of food presentation, no qualitative stereoselective differences were observed in the behavioral effects of the isomers of pentobarbital (1-13 mg/kg) and secobarbital (1-13 mg/kg), but small differences in potency were observed. Thus, differences in the effects of the isomers were usually restricted to differences in potency, but in some cases differences in efficacy were observed.     

Disruption of schedule-controlled behavior by Ro 15-1788 one day after acute treatment with benzodiazepines

The behavioral effects of the benzodiazepine antagonist Ro 15-1788 were studied in squirrel monkeys after acute injections of benzodiazepines. Monkeys responded under a multiple schedule of food presentation with alternating fixed-interval (FI) and fixed-ratio (FR) components. Chlordiazepoxide (10 mg/kg) increased FI responding and had little effect on FR responding 1 h after it was administered; FI responding was still elevated during the session on the following day. When Ro 15-1788 (0.1–3 mg/kg) was administered 1 h after chlordiazepoxide, it antagonized the effects of chlordiazepoxide in a dose-related manner. When Ro 15-1788 was administered 1 day after chlordiazepoxide, however, doses of 1 or 3 mg/kg suppressed both FI and FR responding. Suppression of schedule-controlled responding was also observed when Ro 15-1788 (3 mg/kg) was administered 1 day after diazepam (3 or 5.6 mg/kg) or N-desmethyldiazepam (5.6 mg/kg). The results show that Ro 15-1788 can precipitate disruption of schedule-controlled behavior 1 day after acute treatment with benzodiazepines.Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council; DHEW publication (NIH) 78-23, revised 1978     

Effects of phencyclidine,d-amphetamine and pentobarbital on schedule-controlled behavior in rats

The effects of phencyclidine, d-amphetamine, and pentobarbital on responding maintained under a multiple fixed interval (FI) 3-min fixed-ratio (FR) 30 schedule of food presentation were studied in rats. Phencyclidine (0.32–7.5 mg/kg) had a biphasic effect on overall response rate in both components; response rate increased and then decreased as the dose was increased. The FR was slightly more sensitive to the rate-decreasing effects of phencyclidine than the FI. The effects of d-amphetamine (0.1–7.5 mg/kg) on overall rate were qualitatively similar to those of phencyclidine. The FI tended to be slightly more sensitive than the FR to the rate-increasing effects of d-amphetamine. Pentobarbital (1–18 mg/kg) produced little or no rate-increasing effects in the FR at low doses and decreased FR response rate at higher doses. In the FI, pentobarbital produced small increases in overall rate at intermediate doses while decreasing response rate at higher doses. The FR tended to be more sensitive than the FI to the rate-decreasing effects of pentobarbital. Unlike d-amphetamine and pentobarbital, phencyclidine produced smaller rate-increasing effects when the dose-effect curves were redetermined. Within the FI, the effects of phencyclidine and d-amphetamine on response rate were generally independent of the control rate of responding.     

Ethanol suppression of schedule-controlled responding: interactions with Ro 15-4513, Ro 15-1788 and CGS 8216

Rats (N = 14) were trained to respond under a five seconds differential reinforcement of low rate (DRL 5') schedule and under a fixed ratio 10 (FR10) schedule of reinforcement. Ro 15-1788 did not influence the number of responses in the DRL 5' schedule, but increased responding in the FR10 schedule. Ethanol (ETOH, 1250 mg/kg) and CGS 8216 (5 mg/kg) suppressed responding in both schedules and these effects were not antagonized by Ro 15-1788. The response suppressing effects of ETOH in both schedules were not influenced by CGS 8216. These results indicate that the response suppressing effects of ETOH and CGS 8216 are not mediated by the BDZ receptor. Ro 15-4513 suppressed responding strongly in the FR10 schedule. The response suppressing effects of Ro 15-4513 were additive with the response suppressing effects of ETOH. In rats (N = 11) trained to respond under a variable interval 40 seconds-fixed ratio 10 (VI 40'-FR10) schedule Ro 15-4513 dose-dependently suppressed responding. These results indicate that Ro 15-4513 has sedative effects and is not able to antagonize all the behavioral actions of ETOH.     

Discrimination of pentobarbital doses and drug mixtures under fixed-ratio and fixed-interval reinforcement schedules

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 10mg/kg pentobarbital, and saline, under either fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. When baseline responding stabilized, a higher percentage of responses occurred on the key that produced the reinforcer under the FR schedule than under the FI schedule. After low doses of pentobarbital, responding shifted from the saline key to the 5 mg/kg pentobarbital key; at higher doses of pentobarbital responding shifted to the 10mg/kg pentobarbital key under both schedules. After low doses of ethanol and chlordiazepoxide, responding shifted from the saline key to the 5 mg/kg pentobarbital key, but after high doses of these drugs, responding continued to occur on the 5 mg/kg pentobarbital key under both reinforcement schedules. A 5 mg/kg dose of pentobarbital increased responding on the 10 mg/kg pentobarbital key when it was combined with pentobarbital, ethanol or chlordiazepoxide. Phencyclidine and D-amphetamine produced responding largely on the saline key under both reinforcement schedules. Under the FR schedule, pentobarbital dose-response curves were usually quantal, whereas under the FI schedule the pentobarbital dose-response curves usually were graded.     

Lorazepam and pentobarbital discrimination: interactions with CGS 8216 and caffeine

Baboons and rats were trained under a two-lever, food-reinforced drug discrimination procedure. The training drug was either lorazepam (1.0 mg/kg) or pentobarbital (5.6 mg/kg in baboons, 10.0 mg/kg in rats). Under test conditions, a range of training drug doses occasioned 100% drug lever responding. CGS 8216 (3.2-10.0 mg/kg) combined with lorazepam produced a complete shift to the no-drug lever in both species; this shift was surmountable with higher doses of lorazepam. CGS 8216 (32.0 mg/kg) combined with pentobarbital produced a statistically significant decrease in drug-lever responding in rats, and in baboons CGS 8216 initially, but not subsequently, produced a complete shift to the no-drug lever. Caffeine (0.32-10.0 mg/kg) combined with lorazepam inconsistently decreased drug-lever responding across multiple determinations in baboons and significantly decreased drug lever responding in rats. Caffeine combined with pentobarbital also yielded an inconsistent decrease in drug lever responding in baboons but there was no effect in rats. Thus the most reliable and complete antagonism across species was obtained with the CGS 8216/lorazepam combinations.     

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.     

Discriminative stimulus properties of CL218872 and chlordiazepoxide in the rat

Rats were trained to discriminate either CL218872 (5 mg/kg PO) or chlordiazepoxide (5 mg/kg PO) from vehicle in a 2-lever discrimination task on an FR20 schedule. The discriminative cues produced by these two drugs generalised to a range of benzodiazepine receptor agonists and partial agonists. Nitrazepam, diazepam, RU32698 and RU32514 were less potent in substituting for the CL218872 cue than the chloridiazepoxide cue. Zopiclone, RU31719 and RU43028 substituted for both cues with similar potency, whilst zolpidem and CL218872 were clearly more potent in substituting for the CL218872 cue. Chlordiazepoxide substituted only partially for the CL218872 cue, even at doses which decreased the rate of responding. CGS9896 substituted partially for both cues, but was less effective with the CL218872 cue. RU39419 substituted for the chlordiazepoxide cue, but antagonised the CL218872 cue. CGS8216 and FG7142 antagonised both cues. The contributions of benzodiazepine receptor subtypes or partial agonism to the generation of the CL218872 cue is discussed.     

Pentobarbital discrimination and generalization to other drugs under multiple fixed-ratio fixed-interval schedules

Pigeons were trained to discriminate 5mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18s (mult FR40 FI18), mult FR10 FI18s, mult FR10 FI180s and mult FR90 FI10s. After responding stabilized under each multiple schedule, generalization curves were determined for pentobarbital, amobarbital, diazepam, phencyclidine and d-amphetamine. Pentobarbital generated dose-dependent increases in responding under all schedule components; however, there was more responding on the drug key after low doses of pentobarbital under FI components than under FR components, except for the FR90 component of the mult FR90 FI10 schedule. This tendency for more responding on the drug key after low doses of pentobarbital under FI components than under FR components generally was observed for low doses of all of the drugs. Examination of data from individual subjects revealed that there was a greater tendency for birds to distribute responding on both keys (mixed responding) under FI components than under FR components, where responding after each dose was confined largely to one of the two response keys. Analysis of local rates of responding within the FI component of the schedules showed that responding under the FI components developed the typical FI scallop at all FI-component durations. These data suggest that FI schedules with values between 10 and 180s generate similar dose-effect curves with higher rates of responding on the drug key after low doses of drugs than under FR schedules with low response requirements; however, under schedules with higher FR requirements, the dose-effect curves for some drugs begin to look more like those under FI schedules.     

Behavioral studies with the beta-carboline FG 7142 combined with related drugs in monkeys

The beta-carboline FG 7142 was studied alone and in combination with Ro 15-1788, CGS 8216 and lorazepam in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. FG 7142 (0.3-5.6 mg/kg i.v.) produced dose-related decreases in the rate of FI responding, effects opposite to those of moderate doses of lorazepam (0.03-0.3 mg/kg i.v.). Pretreatment with low doses of Ro 15-1788 (0.1 and 0.3 mg/kg i.v.) shifted the dose-response curve of FG 7142 progressively to the right indicating pharmacological antagonism at benzodiazepine recognition sites. In comparison, pretreatment with the pyrazoloquinoline CGS 8216 (0.1-1.0 mg/kg i.v.), which alone decreased responding, did not alter the effects of FG 7142 in a systematic manner. Combinations of behaviorally active doses of FG 7142 and lorazepam had primarily additive effects: the opposing actions of one drug tended to cancel the other's effect on responding. These results show that the reduction in behavior by FG 7142 is modified predictably by Ro 15-1788 but not by CGS 8216, and behaviorally active doses of both FG 7142 and lorazepam may be needed for their mutual antagonism.     

Pentobarbital, diazepam and phencyclidine disrupt delayed matching performance: interactions with picrotoxin in pigeons and squirrel monkeys

The ability of picrotoxin to antagonize selectively the effects of pentobarbital was investigated in pigeons and squirrel monkeys responding under a titrating matching-to-sample schedule of reinforcement. Under the titrating matching-to-sample baseline, the length of the delay changed as a function of the animal's matching accuracy. Picrotoxin (0.03-1mg/kg) failed to alter significantly the matching accuracy of pigeons; however, rate of responding was markedly suppressed at a dose of 1mg/kg. In squirrel monkeys responding under a similar schedule, picrotoxin (0.001-0.3mg/kg) was without significant effect. Selected doses of picrotoxin in both pigeons (0.3 and 0.56mg/kg) and squirrel monkeys (0.1 and 0.3mg/kg) failed to shift the pentobarbital or diazepam dose-response curve for mean delay length to the right. However, in both species, picrotoxin shifted the dose-response curve for pentobarbital on rate of responding to the right. No such shift was observed for the effect of diazepam on rate of responding. In both species, the combination of picrotoxin and phencyclidine shifted the dose-response curves for phencyclidine on rate of responding, but not mean delay, downward and to the left, in an apparent additive manner. Thus, picrotoxin failed to produce a significant pharmacological antagonism of the effects of pentobarbital, diazepam or phencyclidine on matching accuracy. This failure to observe an antagonism of the effects of pentobarbital on matching accuracy, at doses of picrotoxin that antagonized the effects of pentobarbital on rate of responding, suggests that the effects of pentobarbital on matching accuracy and rate of responding are mediated by different receptor sites.     

Behavioral effects of arecoline in rats

Summary Effects of arecoline (0.25–4 mg/kg) were studied on several behavioral schedules in rats. It usually decreased the responses, especially at high doses, in schedules including spontaneous motor activity, FR (water and food) and FI (food) reinforcement, DRL and shock avoidance. Slight enhancement of responses was observed at low doses in spontaneous activity, FR (food) reinforcement, FI reinforcement and shock avoidance. Arecoline methiodide had negligible and insignificant effects.The depressant effect of arecoline (2 mg/kg) in the spontaneous activity schedule could be antagonized by scopolamine (0.25 and 0.1 mg/kg), but not by methylscopolamine (0.5 mg/kg) and mecamylamine (2 mg/kg). On the other hand, arecoline induced behavioral depression under FR water and food reinforcement could neither be antagonized by scopolamine (0.025–0.1 mg/kg) that itself caused depression, nor by mecamylamine (2 mg/kg).Supported by a Grant No. U100472 from the U. S. Public Health Service.     

Behavioral effects of caffeine, (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse

The effects of caffeine (1–100 mg/kg, IP), (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA) (0.01–1 mg/kg, IP), and of the two drugs in combination were studied in mice responding under a mult FR30 FI600 s schedule of food presentation. The lowest dose of caffeine, 1 mg/kg, had no effect on responding under either component of the mult schedule. Intermediate doses of caffeine (3 and 10 mg/kg) slightly increased responding under the FI component, while higher doses decreased responding. Caffeine only decreased responding, at doses above 30 mg/kg, under the FR component. PIA decreased responding under both components of the mult schedule in a dose-dependent, and similar, manner. In most cases, the rate-increasing effect of caffeine on FI responding was diminished when combined with a rate-decreasing dose of PIA. However, when 0.01 mg/kg PIA, a dose that had no effect alone, was combined with 3 mg/kg caffeine, the increase in rate exceeded that of caffeine alone. Rate-deceasing effects of PIA were antagonized by caffeine; with larger doses of PIA, larger doses of caffeine were required for antagonism. Thus, while the rate-increasing effects of caffeine can be either enhanced or diminished, when combined with different doses of PIA, the rate-decreasing effects of PIA are clearly antagonized by caffeine in a dose-dependent manner.     

Schedule control of quantal and graded dose-effect curves in a drug-drug-saline discrimination

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 5 mg/kg morphine, and saline when responding was maintained under fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. After the discrimination was established, other drugs were substituted for the training drugs. After low doses of pentobarbital and chlordiazepoxide, responding shifted from the saline key to the pentobarbital key under both FR and FI schedules. After low doses of morphine and methadone, responding shifted from the saline key to the morphine key under both reinforcement schedules. After all doses of d-amphetamine, responding occurred largely on the saline key under both schedules. Responding also was confined largely to the saline key after phencyclidine administration under the FR schedule, but under the FI schedule, responding shifted from the saline key to the pentobarbital key at high doses of phencyclidine. When responding was maintained under the FR schedule, the dose-response curves for drugs that generalized to the training drugs were quantal in shape, while under the FI schedule, the dose-response curves for drugs that generalized to the training drugs were graded. These data extend observations that FR schedules generate quantal dose-response curves, and FI schedules generate graded dose-response curves to complex three-key drug discriminations.     

Interactions between the effects of methamphetamine and pentobarbital on operant behavior in the pigeon

Summary This study investigated the effects of methamphetamine and pentobarbital on the performance of pigeons trained to peck a key on two alternating schedules of food reinforcement. In the presence of a blue key-light, every 31st response was reinforced (FR 31); in the presence of a red key-light, a single response was reinforced when 5 min had elapsed (FI 5). In control studies, methamphetamine (1–3 mg/kg, i.m.) alone decreased rates of responding on FR 31, but increased rates of responding on FI 5. Pentobarbital (1–10 mg/kg, i.m.) alone increased rates of responding on both FI 5 and FR 31; maximal effects occurred at 10 mg/kg. Combinations of methamphetamine and pentobarbital produced FR 31 response rates between those produced by the individual drugs. In contrast, the combination markedly increased FI 5 response rates. The maximal increase in FI 5 response rates occurred with the combination of 1 mg/kg of methamphetamine and 10 mg/kg of pentobarbital, and it was greater than the sum of the maximal increases produced by either drug alone. Thus, combined doses of methamphetamine and pentobarbital can either antagonize or enhance the effects of the individual drugs on operant behavior; the type of interaction that occurs is dependent upon the schedule of reinforcement.This work was supported in part by grants MH-02094, MH-07658, 2 TI-GM-95, and K 3-MH-22,589 from the National Institutes of Health, U.S. Public Health Service. A preliminary report was presented at the annual meeting of the Federation of American Societies for Experimental Biology, Chicago, Illinois, April 1964. We are indebted to Mrs. Catherine Jackson and Mrs. Suzanne Ledecky-Janecek for expert technical assistance.     

Drug effects on an effortful operant: pentobarbital and amphetamine

The behavioral effects of amphetamine and pentobarbital depend upon the conditions maintaining behavior. For example, amphetamine usually decreases the rate of operant behavior maintained by fixed ratio schedules while pentobarbital either increases it or leaves it unaffected. However, when considerable exertion is required, as in situations that require endurance, amphetamine tends to enhance performance while barbiturates degrade it. These differences complicate predictions of the effects of these two drugs on effortful operants. The present experiment was designed to characterize effortful responding behaviorally and pharmacologically. Cebus monkeys were trained to operate a lever by flexing their arms and extending their legs; this response exerted a force approximating their body weight. This operant was maintained by a multiple fixed ratio fixed interval (Mult FR FI) schedule. The two schedules maintained dramatically different response patterns. The FR schedule maintained vigorous, high rate responding characterized by a narrow IRT distribution centered at 0.5 sec. The FI schedule maintained very low overall rates of responding characterized by a variable IRT distribution with a median of 1.5 to 2 sec. Despite very low rates of responding during the FI component, no consistent rate increases appeared after amphetamine, and 0.3 mg/kg eliminated responding altogether. Pentobarbital increased overall rate but also shifted the interresponse time (IRT) distribution toward longer IRTs. The increase in overall rate arose from an earlier onset of responding during the FI component and occurred simultaneously with response slowing. The present studies do not support suggestions of a generalized enhancement of effortful performance by amphetamine or a generalized degradation by pentobarbital.     

Effects of chlorpromazine and d-amphetamine on schedule-controlled and schedule-related behavior of rabbits

A lever-lifting response by Dutch Belted and New Zealand White rabbits was maintained in water-deprived animals by 0.25% 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 inital 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 lever 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.