James W. McKearney

Punished behavior: Increases in responding after d-amphetamine

Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30 th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01–0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.

Effects of methamphetamine and chlordiazepoxide on schedule-controlled and adjunctive licking in the rat

The effects of methamphetamine (0.03–1.7 mg/kg) and chlordiazepoxide (3.0–30.0 mg/kg) were studied in a situation in which the same motor response, licking a water-filled tube, served as a schedule-controlled and as an adjunctive behavior. Rats responded under a 3-min fixed-interval (FI) schedule of food presentation in which the required response was a lick on the tube (schedule-controlled); licking also occurred following every food presentation (adjunctive). Adjunctive licking occurred at a high, steady rate, but schedule-controlled licking was emitted at a changing rate over time, characteristic of FI schedules. Both drugs had little effect on overall adjunctive licking, except for decreases at the highest doses, but there were changes in the pattern of adjunctive licking. Methamphetamine produced only decreases in schedule-controlled licking, but chlordiazepoxide produced dose-dependent increases. In general, the magnitude of drug effect on local rates of responding within the FI was related to control rates of responding within the same periods, but there were instances in which the magnitude of effect depended also on whether licking was adjunctive or schedule-controlled.

Stimulant actions of histamine H1 antagonists on operant behavior in the squirrel monkey

Squirrel monkeys were studied under fixed-interval schedules of reinforcement in which the first response (lever press) after a fixed period of time resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. Benztropine mesylate (0.03–1.7 mg/kg), promethazine HCl (0.3–10 mg/kg), and diphenhydramine HCl (0.3–17 mg/kg) all produced marked increases in responding at intermediate doses. The increases in responding were at least as great as those observed with psychomotor stimulants, such as amphetamine, in this species under similar behavioral conditions. Benztropine was most potent and diphenhydramine was least potent in most monkeys and, in some, promethazine and diphenhydramine were about equipotent. The order of potency and the magnitude of potency differences among the drugs suggest that the behavioral effects were due to antagonist actions at histamine H1 receptors, rather than to effects on dopamine uptake or on muscarinic receptors.

Tolerance to suppressive effects of chlordiazepoxide on operant behavior: Lack of cross tolerance to pentobarbital

Pigeons responded under schedules in which either the 60th response (fixed-ratio schedule) or the first response after 3 minutes (fixed-interval schedule) resulted in food delivery. The effects of chlordiazepoxide HCl (1-30 mg/kg) and pentobarbital sodium (1-17 mg/kg) were determined before and during chronic daily exposure to either 10 or 17 mg/kg chlordiazepoxide--doses that markedly suppressed responding when given acutely. After about three weeks of daily injections of chlordiazepoxide, there was at least a three-fold shift to the right of the dose-effect curve for chlordiazepoxide, but not consistent change in the effects of pentobarbital.

Effects of dopamine uptake inhibitors on schedule-controlled behavior in the squirrel monkey.

Squirrel monkeys responded under a multiple fixedinterval (FI) fixed-ratio (FR) schedule of stimulus-shock termination. Benztropine mesylate (0.03–1.7 mg/kg), bupropion HCl (0.3–5.6 mg/kg), mazindol (0.01–0.3 mg/kg), and nomifensine maleate (0.1–1.0 mg/kg) markedly increased responding under the FI schedule, but not under the RR schedule. Mazindol was about three-times more potent than nomifensine and ten-times more potent than bupropion. Benztropine and mazindol were about equal in potency. The order and relative magnitude of potency differences for mazindol, nomifensine, and bupropion are similar to those reported by others for in vitro inhibition of dopamine uptake in rat striatum, but the relative potency of benztropine was greater in these behavioral experiments than expected from its potency in inhibiting dopamine uptake.

Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(l-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3-5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) or pirenperone (0.001-0.1 mg/kg). Quipazine (0.3-5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.

Changes in the rate-increasing effects of d-amphetamine and pentobarbital by response consequences

Keypecking in one group of pigeons was maintained under schedules in which food was presented only when a specified number of responses was followed by a 30-s pause without a response. d-Amphetamine and pentobarbital increased low rates of responding (and, thus, decreased food presentation) only after initial injections or when, during drug sessions, responses during the 30-s period did not reset the period. When responses during the pause-interval postponed food delivery, the rate-increasing effects of both drugs diminished over succeeding administrations. Thus, immediate effects of response consequences were as influential as the actual presence of a drug in determining the reproducibility of the behavioral effects of that drug. In a second experiment, keypecking in another group of pigeons was maintained under a 10-min fixed-interval schedule of food presentation but suppressed by a 100-response fixed-ratio schedule of shock delivery (punishment). d-Amphetamine and pentobarbital increased low rates of punished responding when shock delivery was eliminated during drug sessions. Pentobarbital, but not d-amphetamine, also increased punished responding when shock delivery was present. Rate-increasing effects of these drugs were determined by not only predrug patterns of responding but also effects of reinforcers and punishers that occurred during exposure to the drug.

Relative potencies of histamine H1 antagonists as behavioral stimulants in the squirrel monkey

Although histamine H 1 antagonists are among the most widely taken drugs, generally under little or no medical supervision, their behavioral effects in experimental animals have not been studied extensively. In the rat, the H 1 antagonists, chlorpheniramine and diphenhydramine, have been shown to increase locomotor activity and responding maintained by electrical brain stimulation (Wauqnier and Niemegeers 1981 ; Niemegeers et al. 1982). In the squirrel monkey, diphenhydramine increases responding that has been suppressed by response-produced injections of histamine, but decreases responding under fixed-ratio schedules of food presentation (Goldberg 1980). A report from this laboratory (McKearney 1982) showed that several drugs with H 1 antagonist actions (benztropine, diphenhydramine, promethazine) produce marked increases in responding of squirrel monkeys studied under fixed-interval (FI) schedules of food delivery or of stimulus-shock termination. More recently, it has been reported that behavior of squirrel monkeys can be maintained by response-produced IV infusions of diphenhydramine (Bergman and Spealman 1984). Since publication of the 1982 paper, experiments on the behavioral effects of several other H 1 antagonists have continued. Without exception, these drugs markedly increase responding under FI schedules. The present report is a brief summary of these findings.

Methamphetamine effects on responding under a multiple schedule of shock presentation.

Abstract Squirrel monkeys responded under a multiple 3-min variable-interval (VI) 10-response fixed-ratio (FR) schedule of response-dependent electric shock presentation. Methamphetamine (0.01-0.17 mg/kg) produced dose-dependent increases in relatively low rates of responding whether these occurred during the FR or the VI component of the schedule. In the one monkey with a relatively high control rate of responding during the VI component, methamphetamine only produced decreases in responding. Responding during the FR component was increased by methamphetamine, even in the monkey whose responding appeared to be suppressed during this component. Previous experiments have shown only further decreases after amphetamines in responding suppressed by response-dependent shock. The present experiments indicate that, in addition to the frequency and intensity of the electric shock and to the schedule maintaining the reference behavior, the nature of the event maintaining the reference behavior can be important in determining the effects of amphetamines. The effects of methamphetamine depend not only on the intensive and temporal characteristics of the ongoing schedule-controlled behavior itself, but also on the past and present context in which the behavior occurs.

Tolerance to behavioral effects of clonidine after chronic administration of morphine

Male rats (Buffalo strain) were studied under a procedure in which each 30th lick of a drinking tube resulted in the delivery of 0.01 ml water. The effects of clonidine HC1 (0.003-0.3 mg/kg, IP) were determined before, during and after exposure to conditions in which a morphine sulfate solution (0.5 mg/ml in 0.4% saccharin) was the only source of fluid. After either 10 or 80 days exposure to the chronic morphine regimen, rats were maintained under a repetitive cycle in which the morphine was available for 3 days and then removed for 4 days. The subjects consumed an average of 100 mg/kg/day morphine during the times it was available. The effects of clonidine were redetermined once weekly, on the 4th day after removal of the morphine solution. The effects of clonidine were also determined after morphine was removed for more prolonged periods (18-67 days). Chronic exposure to the morphine solution resulted in a 4- to 5-fold shift to the right in the dose-effect curve for clonidine (decreased responding). ED50 values returned to pre-morphine levels when rats were tested at longer post-morphine times (e.g., 18 days). Under the conditions of this experiment, chronic exposure to morphine produced marked cross-tolerance to the behavioral effects of clonidine.