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PubMed1990

A presumptive role for GABA in the stimulatory effects of Des-Gly10, [D-Ala6]-LHRH-ethylamide and pimozide on the gonadotropin release in carp.

To investigate the effect of endogenous gamma-aminobutyric acid (GABA) on the blood maturating gonadotropin (GtH) levels, or to study its interaction with pimozide (dopamine antagonist) and a luteinizing hormone-releasing hormone analog (LHRH-a), sexually mature male and female carps were treated with drugs that may either inhibit GABA biosynthesis or GABA degradation. In females the irreversible inhibitor of GABA-transaminase, gamma-vinyl GABA (GVG), which was to increase the endogenous GABA-ergic tone, had no influence on GtH release. On the other hand, the increased GtH response to the combination of pimozide (PIM) and LHRH-a was clearly enhanced by the administration of 3-mercaptopropionic acid (MPA), an inhibitor of the rate limiting enzyme of GABA-biosynthesis. In males the GABA-ergic compound, valproic acid (DPA) decreased LHRH-a stimulated GtH levels. In male carps that received PIM to diminish the dopaminergic inhibition of GtH release, the spermiating response to LHRH-a was increased by administration of MPA. These data suggest that GABA interacts with the action of dopamine and the gonadotropin releasing hormone (GnRH) on the release of GtH.

3-Mercaptopropionic Acid↗
PubMed1986

Failure of pimozide and metergoline to antagonize the RDS-127-induced facilitation of ejaculatory behavior.

Metergoline, a serotonin-receptor antagonist, when administered in either an ascorbic acid or ethanol containing vehicle was without effect on male rat copulatory behavior (3 mg/kg, 90 minutes pretest). When initially dissolved in several drops of acetic acid, however, the same dose of metergoline dramatically suppressed male rat sexual behavior. Thus, one-half of the treated rats failed to intromit and ejaculate, and those displaying the behaviors exhibited elongated intercopulatory and postejaculatory intervals. The administration of the putative dopamine-receptor agonist RDS-127 (2-N,N-di-n-propylamino-4,7-dimethoxyindane; 3 mg/kg, six minutes pretest) induced seminal emission ex copula and drastically reduced intromission frequency and ejaculation latency in copula, as well as effecting lesser reductions in the intercopulatory and postejaculatory intervals in two sequential copulatory series. RDS-127-induced seminal emission was effectively antagonized by pretreatment with the dopamine-receptor antagonist pimozide (250 micrograms/kg, two hours pretest), but not by pretreatment with metergoline. In contrast to seminal emission ex copula, pimozide pretreatment failed to antagonize the RDS-127 facilitation of ejaculatory behavior in copula. Metergoline pretreatment also failed to antagonize the RDS-127-induced facilitation of ejaculatory behavior in copula. However, RDS-127 prevented the suppressive effects of metergoline treatment, suggesting that RDS-127 has some agonistic action at serotonergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hedonic reactivity to sucrose in rats: modification by pimozide.

Reward summation functions (RSFs) are an important way to dissociate and quantify hedonic and motor effects of neuroleptics. Previously used only with brain stimulation reinforcement, we demonstrate they will also work using sucrose solution reinforcement. Eighteen male rats were trained to lever press on a CRF schedule for 0.01 ml sucrose solution reinforcers of varying concentration (0.025, 0.05, 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.7, 2.3 M). Making the lever harder to press caused an increase in the asymptote of the function, demonstrating a motor effect. Quinine added to the solutions (0.05%) caused the function to shift right, demonstrating an hedonic effect. Rats injected with 0.2 mg/kg pimozide, a dopamine antagonist, then tested four hours later, showed a right shift in the function with no change in asymptote. Thus, at this dose pimozide affects hedonic and not motor substrates of the CNS. These data demonstrate the generalizability of the RSF method to reinforcers other than brain self-stimulation.

Animals↗
PubMed1989

Neuroleptic-induced emotional defecation: effects of pimozide and apomorphine.

Neuroleptics, such as haloperidol, have been found to produce dysphoria, anxiety and akathisia in humans. In animals, these effects have rarely been reported since the decreased movement produced by these drugs can confound the study of many behavioral indices of emotionality. In fact, most investigators have found a decrease in emotional defecation in rats given neuroleptics in novel environments, supporting their action as a major tranquilizer. We have found, however, that in rats a profound increase in emotional defecation can result from haloperidol administration in well habituated environments, such as the homecage. In male rats, defecation was measured for a one hour test period following various doses of the neuroleptic, pimozide, and the dopamine receptor agonist, apomorphine. Apomorphine and pimozide (a dopamine receptor antagonist) were both found to increase levels of fecal boli excretions. In addition, when apomorphine was combined with haloperidol, defecation levels were also increased suggesting that this phenomenon is not directly mediated by dopamine receptors. It is suggested that this drug-induced defecation is a consequence of the agent's interaction with the affective state of the animal, creating a dysphoric or anxious state in the animal.

Animals↗
PubMed1976

Time dependent action of pimozide on deprivation-induced water intake: evidence for a direct drug effect.

Time-response curves were established for the effect of 3 doses of pimozide, a potent and specific dopamine receptor blocker, on deprivation-induced drinking in rats. Injections occurred once every 3 days at intervals of 2, 4, 8, and 16 hr prior to the daily 15 min drinking period. Pimozide produced a significant attenuation in the amount of water normally consumed (on nondrug days) whose degree varied with the proximity of the injection to the drinking period. Only the 2 higher doses (0.5 and 1.0 mg/kg) produced a significant dose dependent effect which was strongest at the 2 hr interval and which gradually weakened by the 8th post injection hr. The relevance of these findings for a direct versus an indirect action of the drug on water intake is discussed.

Animals↗
PubMed1978

Effect of pimozide on the improvement in learning produced by self-stimulation and by water reinforcement.

When rats self-stimulate immediately after the training trial of an appetitive task their performance on a retention test is improved the next day. In the present study, this improvement was blocked by pretraining injections of pimozide, a dopaminergic blocker. In a second experiment, injections of pimozide retarded learning on the same task when the learning was reinforced by drinking water, but had no effect on learning which occurred in the absence of a reinforcer. The data made the hypotheses that the animal's behavior was a result of an action of primozide on sensory or motor mechanisms, or that the drug produced state-dependent effects, highly unlikely. We concluded that neural systems involving dopamine mediate an effect of reinforcing events on behavior.

Animals↗
PubMed1979

Pimozide-induced extinction in rats: stimulus control of responding rules out motor deficit.

Rats stopped responding for electrical stimulation of the brain following pretreatment with the dopamine antagonist pimozide, as well as following truncation of brain stimulation trains. In either case the extinguished responding was temporarily reinstated on presentation of a light if the light had previously signalled reward but not if the light had had no such significance. These results indicate that pimozide reduces self-stimulation by abolishing the rewarding effect of brain stimulation rather than by interfering with motor ability.

Animals↗
PubMed1980

The use of conditioned defensive burying to test the effects of pimozide on associative learning.

Rats shocked by a wire-wrapped prod mounted on the wall of the experimental chamber buried the prod with available bedding material when they were tested 24 hr later. Injection of the neuroleptic, pimozide (1.0 mg/kg) before conditioning and again before testing disrupted this conditioned defensive burying; however, a concomitant reduction in general activity suggested that this deficit in conditioned burying may have reflected a general motor impairment instead of a learning deficit. The observation that rats conditioned under the influence of pimozide but tested 24 hr later while undrugged did not display deficits in conditioned burying confirmed this view. Thus, neuroleptics appear to disrupt learned behavior by interfering with the performance of conditioned responses rather than by disrupting associative learning per se.

Animals↗
PubMed1982

Does pimozide block the reinforcing effect of brain stimulation?

The neuroleptic pimozide produces an extinction-like decline in the runway and Skinner box performance of rats rewarded with electrical stimulation of the medial forebrain bundle (MFB) in the lateral and posterior hypothalamus. The required dose is an order of magnitude less than the dose that incapacitates. The extinction-like decline is seen even when the drug treated rats run and receive brain stimulation in a running wheel prior to runway testing. The decline is also task-specific: after extinguishing in the Skinner box, rats readily perform in the runway, but soon show extinction in this task, too. The characteristics of pimozide's effects on rewarded behavior imply that the drug, whatever other effects it may have, does block the reinforcing effect of the brain stimulation reward.

Animals↗
PubMed1983

Acute and chronic effects of estrogen treatment on pimozide-induced catalepsy in the rat.

The effects of acute (3 days) and chronic (3 weeks) estrogen treatment on pimozide-induced catalepsy in ovariectomized female rats is described. Bar and grid tests were used to evaluate the cataleptic response to a 4 mg/kg dose of pimozide. Bar data showed that acute estrogen treatment (10 microgram/kg/day) significantly potentiated catalepsy when rats were tested 24 hours after the hormone but not if a dose-test interval of 48 hours was used. In the chronic phase catalepsy was significantly increased in both hormone treated groups (24 and 48 hours after estrogen). The grid data showed a qualitatively similar trend but did not reach significance in either the acute or chronic test phase. The difference between the two test phases may arise from the operation of independent factors in each case: the acute phase effect resulting from a central action of estrogen while the chronic data might be more typical of a metabolic effect. These, and other, possibilities are discussed.

Animals↗
PubMed1984

Pimozide and amphetamine have opposing effects on the reward summation function.

The reward summation function is the plot of self-stimulation performance as a function of the number of pulses in a train of fixed duration. It has previously been shown that drugs that impair performance compress this curve but do not shift it laterally; whereas when the reinforcing efficacy is reduced by reducing current intensity, the curve shifts laterally. The amount of the shift is a measure of the magnitude of a drug's effect upon reinforcing efficacy. We report here that pimozide shifts the curve to the right in a dose-dependent manner, indicating an impairment of reinforcing efficacy, while amphetamine shifts it to the left, indicating an enhancement of reinforcing efficacy. When the two drugs are given together their effects on the reward summation function cancel out. These results are consistent with the hypothesis that pimozide and amphetamine exert their effects on reinforcing efficacy via one and the same set of dopaminergic synapses.

Amphetamine↗
PubMed1985

Relative effectiveness of pimozide, haloperidol and trifluoperazine on self-stimulation rate-intensity functions.

Rats were trained to lever press for 60 Hz sine wave stimulation of the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. Rate intensity functions were determined by stepping down the current intensity by 0.05 log10 units every five min. Haloperidol shifted the function approximately one step to the right at 0.08 mg/kg, with lower doses producing no effect. Pimozide shifted the curve in a dose-dependent manner over the range of 0.06 to 0.24 mg/kg; 0.12 mg/kg produced an approximate one-step shift. Trifluoperazine also produced dose related shifts to the right over the range of 0.08 to 0.32 mg/kg; this agent, unlike the others, appeared to shift the curve down as well as to the right. Less than a one-step shift was produced by 0.08 mg/kg; more than a one-step shift was produced by 0.16 mg/kg. On a molar basis, the order of potency for displacing the curves to the right was haloperidol, pimozide and trifluoperazine. While this order of potency is not predicted from simple in vitro binding affinities for the D2 receptor, this may be due to differences in the penetration of these agents to central D2 receptors in vivo.

Animals↗
PubMed1985

Differential effects of pimozide on response-rate and choice accuracy in a self-stimulation paradigm in mice.

Intracranial self-stimulation (ICSS) from the dopamine (DA) A9 cell grouping was evaluated in mice following pimozide administration in both a one hole head dipping task and a two hole discrimination paradigm. While pimozide reliably decreased response rates, choice accuracy in the discrimination paradigm was unaffected by the drug treatment. The data were taken to suggest that neuroleptics influence response rate owing to motoric disturbances, without influencing the effectiveness of cues that previously had been associated with primary reinforcement.

Animals↗
PubMed1986

Effects of pimozide on emitted force, duration and rate of operant response maintained at low and high levels of required force.

The behavioral effects of pimozide (0.25, 0.5, and 1.0 mg/kg) were assessed in two separate experiments in which session mean peak force, maximum peak force, and response duration served as the dependent variables complementing operant response rate. In the first experiment, two groups of water-deprived rats were trained on a continuous reinforcement (CRF) schedule for reaching out and pressing downward on a force transducer with peak forces of at least 4 g (low-force group) or 40 g (high-force group). In the second experiment a pull-type response topography and fixed ratio 20 were used, and force requirements were 4 g for the low-force group and 100 g for the high-force condition. Under these conditions pimozide decreased response rate and increased response duration irrespective of response topography, required force, or schedule of reinforcement. Neither mean peak force nor maximum peak force were significantly decreased by the drug, and in the low-force CRF condition a small but significant dose-related rise in mean peak force was observed. It was hypothesized that neuroleptics exert their motor-impairing effects primarily in the temporal domain of behavior but do not appreciably affect the force dimension of performance capacity. And these temporal domain effects may be reflected in differences in the kinetic requirements for the overall behavior and not just the response itself. Additionally, the possibility that some of the observed effects could be accounted for by "anhedonia" was addressed.

Animals↗
PubMed1987

Some effects of pimozide on nondeprived rats' lever pressing maintained by a sucrose reward in an anhedonia paradigm.

The present work examined the generalizability of the anhedonia phenomenon (extinction-like responding with repeated neuroleptic treatment) by examining the effects of pimozide (PIM) on nondeprived rats lever pressing for a sucrose solution reward (32%) in an eight day dosing regime. The procedures used replicated the essential features of a previous study (Gramling et al. [10]) wherein the effects of PIM on rats licking directly a sucrose solution were assessed. Thirty nondeprived rats were trained to lever press on a CRF schedule for a 32% sucrose solution reward and then assigned to one of five treatment groups (N = 6). The treatment conditions included a no-reward group (EXT; vehicle injections), two pimozide (PIM) with reward conditions (either PIM 0.25 mg/kg + RWD or PIM 0.5 mg/kg + RWD), and a vehicle control group (RWD; vehicle injections). These four groups each received their respective injections and operant exposure for eight consecutive days. The fifth group was a home cage (HC) control condition wherein the rats were injected with 0.5 mg/kg PIM each test day but did not receive operant exposure until the fourth test day. The PIM treated rats exhibited a significant curvilinear pattern of responding on the rate measure across eight days of testing, whereas rats in the no-reward condition exhibited a significant downward linear trend across eight days of testing. Within-session analysis revealed that rats in the EXT group responded at significantly higher rates during the first five minutes of testing on the first test day compared to rats in the PIM 0.5 + RWD condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Reward summation and the effects of pimozide, clonidine, and amphetamine on fixed-interval responding for brain stimulation.

Two models of reward summation were examined in 16 rats lever pressing for intracranial stimulation under fixed-interval (FI) reinforcement. The first model examined rate-frequency functions and the second model traded off frequency and train duration. The second model was selected to assess the effects of three drugs on reward summation. Both clonidine and pimozide inhibited FI self-stimulation, but pimozide's effect could not be distinguished from a performance deficit. Two amphetamine isomers facilitated self-stimulation in a manner suggesting enhanced reinforcement. The dextro isomer was four times more effective than the levo isomer to facilitate self-stimulation. This study shows that the combination of the FI schedule with a reward-summation model is well suited for evaluating the effects of drugs on self-stimulation. The advantages of this model are that inter-reinforcement intervals are separated, which minimizes priming and stimulation aftereffects, and more responding does not increase stimulation availability, thus eliminating rate-dependency effects.

Amphetamine↗
PubMed1992

Effects of diurnal phase and pimozide on cholecystokinin-elicited hypoactivity in the hamster.

Locomotor activity in golden Syrian hamsters was measured following IP injections of cholecystokinin (CCK; 25 micrograms/kg) and pimozide (0.5 mg/kg), the dopamine receptor antagonist. In addition, animals were tested during either the dark or light phase of the diurnal cycle in either dark or light running wheel environments. Results indicated that CCK-elicited hypoactivity was blocked by pimozide and that the effect of CCK was evident only among animals tested during the light phase of the daily cycle. Ambient lighting conditions in the test environment did not modify the drug effects. Independently of any drug effect, locomotor activity was affected by diurnal phase and ambient lighting in the test environment. Animals were more active when tested during the dark phase than during the light phase and locomotor activity was higher under dark than under light ambient conditions. It is concluded that diurnal phase modulates CCK's effect on hamster locomotion and that CCK's effect on locomotion is mediated, in part, by dopaminergic mechanisms.

Animals↗
PubMed1993

Nicotine and brain-stimulation reward: interactions with morphine, amphetamine and pimozide.

Using a rate-independent discrete trial method of determining thresholds for rewarding electrical intracranial stimulation in rats, we evaluated the pharmacological interaction of nicotine plus morphine, d-amphetamine, or the D2 receptor antagonist, pimozide. Both morphine and amphetamine shifted the dose-response curve for nicotine down and to the left, indicating increased efficacy and potency, respectively. Pimozide at doses that have no effect on performance and only minimal effect on brain-stimulation reward blocked the effect of nicotine. These data suggest that the same dopaminergic substrate that supports the positive reinforcing effects of other drugs of abuse also supports nicotine reward.

Amphetamine↗