Assessment of pimozide's motor and hedonic effects on operant behavior in rats

The present study examined the effects of the neuroleptic pimozide on several measures of motor capacity and reinforcement efficacy in rats trained to respond according to a multiple random interval (RI) food reinforcement schedule (mean interreinforcement intervals of 10, 20, 40, 80, and 160 sec). Pimozide (0.125, 0.25, 0.5, and 1.0 mg/kg) produced a dose-dependent suppression of response rates for all five RI schedules and a dose-dependent increase in response duration. An independent measure of motor activity in photocell activity chambers also was decreased by pimozide in a dose-dependent manner. Photocell activity was significantly correlated with response duration and with the Matching Equation parameter k. Thus, all three measures of motor performance revealed similar decreases in motor capacity at the high dose of pimozide. Reinforcement efficacy also was reduced by the 1.0 mg/kg dose of pimozide as indicated by an increase in the Matching Equation parameter Re. The parameters k and Re were not significantly correlated, suggesting that these two Matching Equation parameters do provide independent measures of motor capacity and reinforcement efficacy, respectively. The present results demonstrate the importance of obtaining measures other than simple response rates in order to assess drug effects on operant behavior.     

Differential sensitivity to the effects of albuterol on locomotor activity and operant behavior

The purpose of the present study was to determine the effects of the beta-2 selective adrenergic agonist albuterol on three behaviors, locomotor activity, behavior maintained under a differential-reinforcement-of-low-rate (DRL) schedule, and behavior maintained under a multiple fixed-interval, fixed-ratio (FI-FR) schedule of reinforcement. Albuterol reduced response rate under the DRL schedule in a manner that resulted in an increase in reinforcement rate. Similarly, albuterol reduced response rate under both components of the multiple FI-FR schedule in a dose-dependent manner. The ED₅₀ values for the effects of albuterol on these two operant behaviors were calculated to be approximately 1 mg/kg and the minimal effective doses were 0.3–1 mg/kg. In addition to affecting operant behavior, albuterol also reduced locomotor activity; the ED₅₀ values and minimal effective doses were 0.05 and 0.03 mg/kg, respectively. The effects of albuterol on DRL behavior, FI-FR behavior and locomotor activity were antagonized by the beta adrenergic antagonist propranolol; this suggests that the behavioral effects of this agonist were mediated, at least in part, by beta adrenergic receptors. The differential sensitivity of locomotor activity and operant behavior to albuterol suggests that the actions of this drug on locomotor activity may be mediated predominantly by peripheral beta adrenergic receptors and that its effects on operant behavior may be mediated by beta adrenergic receptors in the central nervous system.     

Effects of ethanol and NMDA antagonists on operant behavior in ethanol withdrawal seizure-prone and-resistant mice

The acute effects of ethanol (EtOH) on fixed-ratio performance were studied in separate lines of mice selectively bred for differences in severity of handling-induced convulsions following withdrawal from EtOH. Because modulation of N methyl-D-aspartate (NMDA) receptors has been implicated in production of the acute and withdrawal-induced effects of EtOH, we also tested NMDA and three NMDA antagonists. Withdrawal seizure-resistant (WSR2) mice were more sensitive to the response rate-decreasing effects of EtOH than were withdrawal seizure-prone (WSP2) mice. Similar to EtOH, NPC 12626 (a competitive NMDA antagonist) and phencyclidine (a non-competitive NMDA antagonist) decreased responding in WSR2 mice at doses that did not affect responding in WSP2 mice. Although a second non-competitive NMDA antagonist, dizocilpine, produced line differences in the same direction as did PCP, these differences were not statistically significant. In contrast, NMDA produced nearly equipotent dose-dependent response rate decreases in both lines. Combined with the results of previous in vitro studies which showed that the number of NMDA receptors in the hippocampi of WSR2 and WSP2 mice differ, the results of the present study suggest that the interaction of EtOH with NMDA receptors may contribute to differences in the acute effects of ethanol on schedule-controlled behavior in WSP2 and WSR2 mice.     

Interaction between ethanol and caffeine in operant behavior of rats

The interaction between ethanol and caffeine on operant behavior was studied in 24 water-deprived male rats trained in a discrete trial spatial alternation schedule with water as reinforcer. One single drug dose-response experiment or one dose combination of ethanol and caffeine (including the associated control treatments) was run on 4 successive days in 1 week. The four treatments of 1 week were administered to each animal in a distinct order according to the 24 possible permutations. In the single drug weeks, ethanol (0.25, 0.5, 0.75 and 1.0 g/kg IP) or caffeine (5, 10, 20, and 40 mg/kg PO) were administered 15 min before the session. In four interaction experiments all combinations of two doses of ethanol (0.5 and 1.0 g/kg IP) and two doses of caffeine (25 and 50 mg/kg PO) were employed. Ethanol and caffeine alone showed both dose-dependently decreased choice accuracy and increased response latency and passiveness. In combination, caffeine normalized the ethanol-induced alterations in ITI response rate and pause length but potentiated the effects on choice accuracy, latency and number of pauses. The results are interpreted in terms of effects of these drugs on attentional and arousal processes, and the test procedure is proposed as a screening tool for the preclinical assessment of ethanol-drug interactions.     

Pharmacokinetic determinants of cocaine's differential effects on locomotor and operant behavior.

Dose-response, effect-time and concentration-effect relations of intravenous cocaine (1-4 mg/kg) were investigated on contingency-controlled [fixed-ratio (FR) 70 performance] and unconditioned (locomotor activity) behaviors. Cocaine dose-response curves exhibited decreasing rates of response under the FR 70 schedule but increasing locomotor activity in a dose-related fashion. Effect-time profiles confirmed that these changes were time-dependent and provided additional clarity by mirroring the biexponential decay of cocaine concentrations with time. The duration of action of cocaine was comparatively shorter on locomotor activity than on FR performance. We integrated effect-time profiles of the two behaviors with concentration-time profiles simulated from our previously published pharmacokinetic parameters to derive cocaine's pharmacodynamic parameters. Classical inhibitory Emax and sigmoidal Emax models were used to describe cocaine's effects on FR performance and locomotor activity, respectively. Simultaneous pharmacokinetic-pharmacodynamic modeling reveals evidence of acute tolerance to cocaine in locomotor activity, as indicated by decreasing potency with dose, but not in contingency-controlled behavior.     

Time-response effects of pimozide on operant behavior and schedule-induced polydipsia

Previous research has indicated that the administration of specific doses of pimozide results in the suppression of the acquisition of schedule-induced polydipsia in rats while not affecting operant behavior. The purpose of this study was to determine if these results were due to a specific action of pimozide on schedule-induced polydipsia or if they were due to an insufficient presession time of drug administration. Pimozide at 1.0 mg/kg was administered to three groups of rats at either 30, 60 or 120 minutes presession with control subjects receiving administration of the drug vehicle also at these times. The results of the study were that both operant behavior and the acquisition of schedule-induced polydipsia were affected in a nondifferential and time-dependent manner by pimozide. It was also found that pimozide caused an alteration in the temporal pattern of both schedule-induced polydipsia and operant responding. This latter result appears to have been caused by a disruption in sensorimotor integration due to the dopamine blocking properties of pimozide.     

Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior

Rationale and objectives  The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, α-conotoxin MII (αCtxMII, α₃β₂*, β₃*, α₆*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-β-erythroidine (DHβE, α₄β₂*), and methyllycaconitine (MLA, α₇*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats. Methods  The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. αCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHβE, and MLA were administered systemically. Results  αCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHβE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation. Conclusions  Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR α₃β₂*, β₃, and/or α₆* receptor subunits might be of therapeutic value for the treatment of alcoholism.     

Effects of GBR 12909, a selective dopamine uptake inhibitor, on motor activity and operant behavior in the rat

GBR 12909, an aryl 1,4-dialkylpiperazine derivative, is a potent and selective inhibitor of the presynaptic dopamine uptake complex. The behavioral effects of this compound were studied in rats using several different paradigms. GBR 12909 (1, 10, 20 mg/kg i.p.) elicited a dose-dependent, long-lasting behavioral activation characterized by locomotion, rearing, sniffing and stereotypies at the highest dose. A second experiment investigated the consequences of subchronic treatment (one injection every 2 days for 14 days) with a high dose (20 mg/kg) of GBR 12909. Evidence was obtained for sensitization to GBR 12909, indicated by progressively more intense stereotypy induced by the high dose of GBR 12909, and also by an enhanced locomotor response to subthreshold doses of the drug, which lasted up to 7 weeks following the end of subchronic treatment. In a test of fixed-interval responding for food reward, GBR 12909 strongly enhanced lever pressing and lowered quarter-life. Low rates of responding were affected more than high rates. GBR 12909 also potentiated responding for a conditioned reinforcer (a stimulus which had previously been paired with food), suggesting that the rewarding impact of the stimulus was increased. It is concluded that the behavioral profile of GBR 12909 is similar to other dopamine-enhancing psychostimulants, and the sensitization may involve long-term changes in the dopamine uptake site.     

Tolerance to ethanol's disruptive effects on operant behavior in rats

The effects of pre-session and post-session daily ethanol injections on the development and loss of tolerance to ethanol's effects on fixed ratio operant performance in rats was assessed using a cumulative dosing procedure. Daily pre-session ethanol administration produced a greater decrease in ethanol sensitivity than did daily post-session ethanol. Both tolerance effects persisted for at least 1 month after the chronic injection phase. No changes in ethanol sensitivity were apparent in the saline control group and no changes in estimated blood ethanol levels were found after the chronic treatments. The post-session ethanol groups displayed a performance decrement during the initial segment of the chronic injection period, but improved significantly across the chronic phase. These data suggest that some delayed effect of ethanol initially impaired performance but that tolerance to this ethanol effect also occurred and probably contributed to the decline in ethanol sensitivity seen in these groups. Compensatory learning as the mechanism for tolerance development in the pre-session and post-session ethanol groups was supported by the finding of no change in ethanol sensitivity in rats exposed to comparable daily ethanol without any concurrent operant task on which the direct, immediate, or indirect, delayed ethanol effects could operate.     

Cholinergic mediation of motor effects of ethanol in rats.

The role of cholinergic neurons in the motor depressant effects of ethanol was examined. Choline chloride pretreatment (30-90 mg/kg i.p.) potentiated the hypomotility produced by 2 g/kg of ethanol. Physostigmine pretreatment (0.2 mg/kg i.p.) also enhanced the motor depression produced by ethanol. Conversely, in animals pretreated with scopolamine (0.25 and 0.5 mg/kg) the depressant effect of ethanol was less. The potentiation produced by choline was not associated with changes in levels of ethanol in blood. It is concluded that cholinergic neurons are involved in the motor activity changes produced by ethanol. Such a mechanism may operate in conjunction with the dopaminergic neuronal system.     

Differential effects of phencyclidine and MDA on complex operant behavior in monkeys

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. With increasing doses of phencyclidine the overall response rate in each schedule component decreased, the percent errors in each component increased, and there was less within-session error reduction (acquisition) in the learning component. MDA (3,4-methylenedioxyamphetamine), a hallucinogen that is self-administered in nonhuman primates, was similar to phencyclidine in producing dose-related rate-decreasing effects in both schedule components. Unlike phencyclidine, however, MDA had little or no effect on accuracy in either learning or performance.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

Differential interaction of cholecystokinin with morphine and phencyclidine: effects on operant behavior in pigeons.

To extend previous operant research in rats with morphine and cholecystokinin (CCK), these two substances were given alone and in combination to pigeons. In one component of a multiple schedule, responding of pigeons (key pecking) was reinforced under a fixed-ratio (FR 50) schedule of food presentation. In the other component, responding had no programmed consequence (timeout). Each session consisted of four 10-min timeout components alternating with four 5-min FR components. In Experiment 1, cumulative dose-effect curves for morphine were obtained by giving an IM injection before each of four FR components; successive injections increased the cumulative dose by 1/4 log-unit steps. In general, as the cumulative dose of morphine increased, the overall response rate in each FR component decreased. Dose-dependent decreases in response rate also occurred when single noncumulative doses of CCK were administered alone 20 min prior to the start of the session. This effect of CCK alone diminished as the session progressed. When CCK was given as a pretreatment before cumulative doses of morphine, the morphine dose-effect curve for response rate shifted to the left. At intermediate doses of CCK, the "potentiation" was so complete that two of three subjects failed to respond during any of the four FR components (i.e., the dose-effect curve for morphine had shifted approximately 1 log-unit to the left). In order to evaluate the pharmacological specificity of this effect, cumulative doses of phencyclidine were administered in combination with CCK (Experiment 2). Unlike the interaction between morphine and CCK, the interaction between phencyclidine and CCK was reciprocal.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the effects of opiate antagonists on operant and ingestive behavior

Previous studies have found that naloxone and other opiate antagonists will decrease the food and water intake of experimental animals. The present study investigated the possibility that these effects may be due to a generalized action of opiate antagonists to block an endogenous reward system. A direct comparison was made between the effects of naloxone and naltrexone on FR responding maintained by small quantities of milk and on the consumption of milk when it was freely available. Both drugs reduced milk consumption at all doses (0.3–30 mg/kg) but produced only small decreases in FR response rates at the highest doses. These results do not support the view that the actions of opiate antagonists on eating and drinking represent an inhibitory action on central reward mechanisms.     

Isodirectional conditioning effects of d-amphetamine and pentobarbital on schedule-controlled operant behavior in pigeons

Pigeons were trained to peck a key on a multi FR30-FI3' schedule. Presession injections of d-amphetamine (2 mg/kg) and pentobarbital (7.5 mg/kg, 10 mg/kg) were paired with presentation of a red light on the ceiling of the operant chamber. After the five pairings separated by two saline sessions in which a white light was lit, the red light was presented without drug injection. The red light came to cause an isodirectional (drug-like) effect on operant behavior. When the red light was paired with drug injections and operant behavior was prevented from occurring, the light did not acquire isodirectional conditioned effect. Thus, responding in the presence of the drug effect is necessary to establish the conditioning.     

Prazosin attenuates the effects of cocaine on motor activity but not on schedule-controlled behavior in the rat.

The spontaneous motor activity of rats was measured following administration of cocaine alone and in combination with the centrally acting alpha 1-antagonist prazosin. Cocaine alone (18-42 mg/kg) increased motor activity in a dose-related manner. At doses of 1 and 1.8 mg/kg, prazosin attenuated the increases in motor activity produced by cocaine. In rats responding under a fixed-ratio discrimination procedure, cocaine (10-32 mg/kg) produced dose-dependent increases in percent errors and decreases in overall response rate. Across a range of doses (0.32-3.2 mg/kg), prazosin failed to antagonize the effects of cocaine on responding under the discrimination procedure. Rather, the combined effects were frequently greater than those obtained with cocaine alone. The data suggest that in rats activation of alpha 1-adrenergic systems may mediate the effects of cocaine on motor activity but not on schedule-controlled behavior.     

The effects of acetylmethadol on motor activity and schedule-controlled responding.

The effects of levo-alpha-acetylmethadol (LAAM) on locomotor activity and operant behavior were examined in rats. LAAM increased locomotor activity when given intraperitoneally (IP) at doses of 1 mg/kg and 3 mg/kg, but 10 mg/kg produced a slight decrease in motor activity over the 10-hour period. The largest increases and decreases in locomotor activity occurred 6--8 hours after administration of the drug. Other rats were trained to lever press for food pellets under a fixed-interval 90-second, fixed-ratio 10-response multiple schedule. LAAM only decreased rates of responding under the multiple schedule. Marked decreases in rates of responding under both components of the schedule occurred with LAAM was administered IP either 3 or 6 hours before the session at doses of 3 mg/kg and 10 mg/kg. The rate- decreasing effects of LAAM became greater the longer the interval between administration of the drug and initiation of the session.     

The effects of N,N-dimethyltryptamine on operant behavior in squirrel monkeys

Five squirrel monkeys were trained to stable levels of performance on fixed ratio schedules of food reinforcement. N,N-dimethyltryptamine (DMT) was then injected intramuscularly prior to fixed ratio testing and the behavioral effects observed. The determination of dose-response relationships with doses of 0.0, 5.4 and 10.8 moles/kg indicated that latencies to initiate responding were an increasing function of the dose, while overall response rates, as measured from the first to the last response of the session were unaffected. When a dose of DMT which initially disrupted operant behavior was administered once daily for 36 to 38 consecutive days, tolerance was not observed to occur.This research was supported by Department of Justice Contract No. J-69-10 from the Drug Control Division, Office of Scientific Support, Bureau of Narcotics and Dangerous Drugs. Basic support of the Yerkes facility was provided by Grant RR-00165 of the Division of Research Resources, NIH. The research described in this report involved animals maintained in animal care facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care.     

Comparative effects of amphetamine, scopolamine, chlordiazepoxide, and diphenylhydantoin on operant and extinction behavior with brain stimulation and food reward

The effects of amphetamine, scopolamine, chlordiazepoxide and diphenylhydantoin have been investigated on operant behavior for brain and food reward, and during extinction with both rewards. The aim was to obtain evidence for a possible mode of action of these facilitatory compounds on self-stimulation behavior. The first 3 drugs increased responding for brain reinforcement, but diphenylhydantoin did not when the reward was a shock in the posterior lateral hypothalamus. Only amphetamine produced striking resistance to extinction of self-stimulation behavior. The facilitation of self-stimulation observed with chlordiazepoxide was independent of the rate of self-stimulation; it was rate-dependent with amphetamine and scopolamine. Operant behavior with food reward was facilitated with amphetamine although consumption of food was depressed. Chlordiazepoxide had no effect on operant behavior for food reward but increased food consumption; scopolamine and diphenylhydantoin depressed responding. During extinction with food reward, amphetamine caused long-lasting resistance to extinction; scopolamine had similar but transient effects; chlordiazepoxide had no effect, and diphenylhydantoin decreased resistance to extinction. The significance of these results are discussed in relation to the concept of arousal: the effects of the drugs seem to depend on their adding to or subtracting from the state of behavioral excitation of the animal induced either by self-stimulation or by hunger. It is concluded that the facilitation of moderate self-stimulators by amphetamine and scopolamine was due at least partially to their action on gross behavioral activity, that of chlordiazepoxide was not.