Comparative studies on the anti-punishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller-Seifter and Vogel conflict procedures.

The studies presented here compared the responsiveness to clinically effective anxiolytics of two major conflict procedures in rat (i.e. the Geller-Seifter and Vogel procedures) and of the newly introduced pigeon conflict procedure. The compounds studied were the prototypical benzodiazepine chlordiazepoxide and the non-benzodiazepine anxiolytics buspirone and ritanserin. Chlordiazepoxide produced reliable anti-punishment effects in all three procedures, but only the pigeon conflict procedure also revealed statistically significant effects on punished responding with buspirone and ritanserin. The data thus constitute the first confirmation of findings from another laboratory that these two non-benzodiazepine compounds exert robust disinhibitory effects on punished behavior in the pigeon. Further, the quantification of drug effects on punished and on unpunished responding in the pigeon. Further, the allowed the effects of the three compounds to be differentiated. The pigeon conflict procedure may be unique among available animal models of anxiety in combining the following two features. Firstly, the procedure allows the behavioral response to be highly defined and permits the experimenter to control rigidly the stimulus events which act in a conflicting manner to increase and decrease response frequency. Secondly, [??084] behavior in this procedure is responsive to benzodiazepines, but also to anxiolytic drugs the effects of which are not mediated by benzodiazepine receptors. It is proposed that the pigeon conflict procedure be used in extensive parametric studies, in an effort to examine the independent variables which may perhaps explain the widely varying and often paradoxical effects that drugs can produce in available animal models of anxiety.

Effects of trialkyltins on the schedule-controlled behavior of the pigeon.

Male White Carneaux pigeons trained to respond for food under a multiple fixed-ratio fixed-interval schedule of reinforcement were given single injections of trimethyltin (TMT), or triethyltin (TET). A dose of 0.3 mg/kg TMT produced no effect on behavior, while a 1.0 mg/kg dose was a threshold dose and 1.75 mg/kg produced behavioral changes that persisted for months in some birds. TMT produced effects on responding under the multiple schedule at approximately the same doses that produce neuronal damage in the hippocampus and the brain stem of the pigeon. Higher doses given to untrained birds produced signs of extensive neurological damage. A dose of 1.0 mg/kg of TET decreased rates of responding under both schedule components three hours after administration, but behavior usually had recovered by the next day. Doses of 3.0 and 5.6 mg/kg had similar effects, but responding did not recover for several days. Some birds showed significant rate increases, especially under the fixed-interval component several days to several weeks after TET administration. Doses greater than 10 mg/kg TET were lethal. Dose-effect curves for the effects of d-amphetamine, chlorpromazine and morphine on responding under the multiple schedule were determined for some birds before and one month after 1.0 and 1.5 mg/kg of TMT. TMT shifted the dose-effect curve for d-amphetamine to the right, but it did not produce systematic changes in the dose-effect curves for morphine and chlorpromazine.

Reinstatement of responding maintained by cocaine or thiamylal.

Rhesus monkeys were trained to self-administer one of two reference drugs, either cocaine or thiamylal. The lowest dose of cocaine or thiamylal which maintained responding was determined. Responding extinguished when saline was substituted for a reference drug. Then the effects of a variety of other drugs on saline self-administration were determined. In the cocaine-trained monkeys, the i.m. administration of d-methylamphetamine, cocaine, morphine or codeine during a session reinstated responding for saline infusions; in contrast, naloxone, chlorpromazine, dimethyltryptamine, diazepam and secobarbital did not. Naloxone blocked responding produced by the i.m. administration of morphine. In the thiamylal-trained monkeys, the administration of secobarbital (i.m.), pentobarbital (p.o.), butabarbital (p.o.) and phenobarbital (p.o.) reinstated responding for saline. The onset of behavioral responding was related to the pharmacokinetic properties of the drugs, with phenobarbital greater than pentobarbital = butabarbital. In contrast, cocaine and d-amphetamine i.m. failed to reinstate the responding in monkeys which had been trained to self-administer thiamylal. These data support the hypothesis that drugs producing responding at a rate significantly greater than that produced by vehicle controls share reinforcing properties with the reference drug.

Tolerance to d-amphetamine and lack of cross-tolerance to other drugs in rats under a multiple schedule of food presentation.

Rats were trained under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Dose-response curves for d-amphetamine, pentobarbital, chlordiazepoxide, ethanol, morphine, phencyclidine and delta 9-tetrahydrocannabinol were determined. At low doses, pentobarbital and chlordiazepoxide produced small increases in response rates, whereas other drugs had no effect. At high doses, all drugs produced decreases in both fixed-ratio and fixed-interval rates of responding. With the exception of ethanol, all drugs produced decreases in fixed-ratio rates at lower doses than those which decreased fixed-interval rates. After the initial dose-response determinations, all animals received a single daily dose of d-amphetamine (10 mg/kg) after the behavioral session for 112 d-amphetamine (10 mg/kg) after the behavioral session for 112 consecutive days. Chronic postsession treatment with d-amphetamine produced a progressive decrease in rate of responding. Dose-response curves for all the drugs were redetermined after 2 weeks of chronic d-amphetamine treatment. During chronic d-amphetamine treatment, there was tolerance to the rate-decreasing effects of d-amphetamine. No cross-tolerance was observed for the other drugs tested.

Effects of chronic delta 9-tetrahydrocannabinol administration on schedule-controlled behavior of pigeons: cross-tolerance to pentobarbital and barbital.

Pigeons responding under a variable-interval (VI) 75-s schedule of food presentation were used to study cross-tolerance from delta 9-tetrahydrocannabinol (delta 9-THC) to pentobarbital and barbital. After initial dose-effect functions for pentobarbital and barbital were determined, the birds received delta 9-THC injections for 6 weeks. This chronic administration regimen resulted in a greater than 100-fold tolerance to delta 9-THC. Redetermination of the pentobarbital and barbital dose-effect functions during the chronic delta 9-THC regimen revealed statistically significant shifts to the right for the pentobarbital (0.191 log unit) and barbital (0.078 log unit) dose-effect curves. All six birds showed tolerance to pentobarbital, while four of the six showed tolerance to barbital. Blood barbital levels before and after chronic delta 9-THC was more prolonged and of much greater magnitude than the cross-tolerance to pentobarbital or barbital. The results demonstrate that cross-tolerance can develop from delta 9-THC to a barbiturate that normally undergoes little metabolism.

Evaluation of narcotic and narcotic antagonist interactions in primates.

Multiple and single drug interactions were studied in morphine-dependent monkeys whose dependency was maintained by self-infusion. Naloxone, naltrexone, and cyclazocine precipitated abstinence syndrome which the animals generally controlled with increased morphine intake. Methadone and L-alpha-acetylmethadol (LAAM) initially reduced, then increased, the morphine intake. Multiple interactions were studied using ethanol, seconal, diazepam, amphetamine, and diphenylhydantoin.