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PubMed1996

Subjective responses to d-amphetamine alone and after pimozide pretreatment in normal, healthy volunteers.

The role of dopamine in d-amphetamine-induced euphoria has not been systematically examined in normal volunteers. Therefore, we examined the effects of the dopamine antagonist, pimozide, on responses to d-amphetamine in healthy volunteers, using a within-subjects, double-blind design. Ten subjects received single oral doses of d-amphetamine (0, 10, 20 mg) 2 hours following pretreatment with pimozide (0, 1, 2 mg). Subjective, behavioral, and physiological effects were assessed predrug and for 3 hours after d-amphetamine administration. d-Amphetamine alone produced prototypic effects on a variety of measures, including euphoria and drug liking. Pimozide did not produce any effects when administered alone and produced inconsistent effects on responses to d-amphetamine. Although higher doses of pimozide may be needed to antagonize the euphorigenic effects of d-amphetamine, these results raise the possibility that the role of dopamine in the subjective effects of stimulants may be more complex than initially appreciated.

Adult↗
PubMed1986

Effects of naloxone and pimozide on initiation and maintenance measures of free feeding.

Latency to initiate and duration of eating of 18 daily 5-pellet meal segments was measured in 22-h food-deprived rats under conditions of pimozide (1 mg/kg, i.p.) and naloxone (2.5, 5.0 and 10.0 mg/kg, i.p.) pretreatment. Neither drug increased latency on the first or second day of testing; pimozide increased mean latency slightly on the third test. Both drugs slowed duration scores dramatically; the slowing was progressive both within and across test sessions in the case of pimozide; it was dose-dependent and progressive within (but not across) sessions in the case of naloxone. In each case, shifts in mean duration scores. In each case, shifts in mean duration score reflected an increase in score variance caused by an increase in the number and extremity of long duration scores. In each case best scores under the drug condition were equal to best scores under control conditions; indeed, very fast latency scores were slightly more frequent under each drug on the first day of testing. Thus each drug decreased the probability of moderate scores but neither drug caused a simple change in the ability to make occasional fast responses. While the effects of the two drugs were similar in some ways, naloxone, unlike pimozide, did not completely suppress feeding.

Animals↗
PubMed1996

Different effects of chronic administration of haloperidol and pimozide on dopamine metabolism in the rat brain.

We investigated the differences between the action of haloperidol and pimozide on dopamine metabolism and on catalepsy in periods up to 6 weeks after cessation of chronic administration of the neuroleptics to male Wistar rats. Dopamine and its metabolites (dihydroxyphenylacetic and homovanillic acids) were measured, using high-performance liquid chromatography (HPLC), in the frontal cortex, nucleus accumbens, and striatum. Both neuroleptics produced similar effects after a single dose: catalepsy and an increase of dopamine metabolism in the brain structures. However, haloperidol and pimozide differed after chronic treatment. In haloperidol-treated rats hypersensitivity of the dopaminergic system developed at the end of 2 weeks' administration, as evidenced by depression of dopamine metabolism. The biochemical changes were accompanied by behavioral hyperactivity that lasted up to 3 weeks. Dopamine metabolism in rats treated with pimozide was normal from 24 h after the end of the treatment, while catalepsy was maintained at the high level for up to 8 days and was observable up to 3 weeks after the last dose. Our results suggest that in contrast to haloperidol, pimozide is not able to produce adaptive changes leading to supersensitivity of the dopaminergic system. This may be the consequence of its potent Ca2+ channel blocking action.

Animals↗
PubMed1986

Pimozide blocks establishment but not expression of cocaine-produced environment-specific conditioning.

Two experiments were conducted to examine the effects of pimozide on cocaine-produced conditioning to a specific environmental context. On 8 treatment days, 12 rats were injected with cocaine (10 mg/kg i.p.) and 12 with saline prior to placement for 60 min into a test chamber outfitted with infrared emitters and detectors. Following each treatment session the saline group received cocaine in their home-cages and the cocaine group received saline. Cocaine produced a significant increase in vertical activity on treatment days. On test days all rats received saline. Significantly greater vertical activity was observed in the group previously receiving cocaine in the test environment. All rats then received 8 more treatment sessions. On saline test days, pimozide (0.4 mg/kg i.p.) pretreatment failed to antagonize expression of the conditioned effect. In experiment 2, pimozide was given prior to treatment and no evidence of conditioning was seen on saline test days. Thus, pimozide blocked the establishment but not the expression of cocaine-produced environment-specific conditioning. These results suggest that during conditioning, the effects of cocaine on dopaminergic neurons may have produced a change that subsequently influenced behaviour even when dopaminergic systems were blocked.

Animals↗
PubMed1992

Pimozide mitigates excessive running in the activity-stress paradigm.

The present study investigated the role of dopamine in the maintenance of behaviors observed in the activity-stress paradigm. In Experiment 1, several doses (0, 0.125, 0.25, 0.50, and 1.0 mg/kg) of the dopamine D2-receptor blocker, pimozide, were administered to rats maintained on an ad lib feeding schedule. Results indicated that 0.25 mg/kg pimozide did not disrupt running activity when compared to control animals. In Experiment 2, injections of either 0, 0.25, or 0.50 mg/kg pimozide were given every 12 hours to rats subjected to the activity-stress paradigm. Although 0.25 mg/kg pimozide had no effect on dark-phase activity, it significantly suppressed light-phase activity and subsequently increased the number of survivors in the paradigm. It was concluded that dopamine plays a role in maintaining high running levels in the activity-stress paradigm.

Animals↗
PubMed1982

Establishment of secondary reinforcement in sign tracking and place preference tests following pimozide treatment.

The effects of pimozide (1.0 mg/kg), a DA receptor blocker, on the capacity of environmental stimuli to acquire secondary reinforcing properties was investigated using two different paradigms. In the first experiment rats pretreated with either pimozide or its vehicle, were exposed to light-food pairings. When tested under drug-free extinction conditions, these animals approached the light cue significantly more frequently than did control animals who never had the cue associated with food during training. No differences in approach behavior were observed between the pimozide and vehicle groups that received the light-food pairings. The second experiment employed a place preference paradigm where animals were confined in distinctive compartments under reinforced (S+) or nonreinforced (S-) conditions. Pimozide and vehicle treated animals, when tested drug-free and given unrestricted access to both chambers under extinction conditions, spent comparable amounts of time in the S+ chamber relative to vehicle subjects that had never received food in either chamber. The results from these two studies indicate that an animal's ability to code relevant environmental information and to use this encoded information to guide and direct food seeking behavior is relatively independent of dopaminergic activity. The results also have significance for any theory which assumes that dopamine mediates reward processes.

Animals↗
PubMed1982

Effects of reinforcement-blocking doses of pimozide on neural systems driven by rewarding stimulation of the MFB: a 14C-2-deoxyglucose analysis.

An analysis by means of 14C-2-deoxyglucose autoradiography of the neural systems unilaterally activated by the reinforcing stimulation used in the two accompanying papers revealed strong and reliable effects in the nucleus of the diagonal band of Broca, in the medial forebrain bundle (MFB) and/or the fornix throughout the diencephalon, and in the part of the anterior ventral tegmentum where the dopaminergic projection to the lateral habenula originates. The terminal fields of the dopaminergic forebrain projections were not affected, but there was bilateral suppression of lateral habenular activity. A second experiment found that the same systems are still activated by (automatically administered) reinforcing stimulation in rats treated with reinforcement blocking doses of pimozide. The only clear effect of pimozide was to reverse the bilateral suppressive effect of the stimulation on lateral habenular activity. Animals treated with pimozide show greatly elevated activity in the lateral habenula, whether or not they receive reinforcing stimulation. The results suggest that pimozide's effect on reinforcement is mediated by the circuitry interconnecting the lateral habenula with the nucleus of the diagonal band of Broca and/or the anterior ventral tegmentum.

Animals↗
PubMed1983

Alteration of exploration and the response to food associated cues after treatment with pimozide.

A series of experiments assessed the effects of pimozide on spontaneous alternation in a Y- and 8-arm radial maze, and on approach to food or cues that had previously been associated with food. Mice treated with pimozide (0.2, 0.4 and 0.8 mg/kg) displayed a dose dependent reduction of alternation performance, without engendering a perseverative tendency and apparently without affecting the course of habituation. When food deprived mice entered an arm of the maze that was baited with a food pellet they consumed the food and remained in the vicinity of the food cup. Moreover, upon retesting in the non-drug state mice still exhibited a preference for cues that had been associated with food. It seems that although pimozide at the doses tested produced a haphazard pattern of exploration, the drug did not alter the rewarding value of secondary reinforcers. Contrary to an anhedonic hypothesis, it is suggested that higher doses of pimozide may actually increase, rather than decrease, the saliency of biologically significant stimuli.

Animals↗
PubMed1990

Pimozide prevents the response-reinstating effects of water reinforcement in rats.

Thirsty animals were trained to traverse a straight runway once each day for a reward consisting of 100 licks from a water-filled drinking tube. Once running speeds had stabilized, single daily extinction trials were initiated during which no water reinforcement was provided in the goal box. Extinction trials continued until running had slowed to levels approximately half of that observed during reinforced trials. A single treatment trial was then conducted in which some animals found water in the goal box and others continued to find an empty water bottle. Those subjects that were reinforced on treatment day subsequently demonstrated a reinstatement of their operant running response on the very next trial (i.e., 24 hr later). However, pretreatment with 1.0 mg/kg (but not 0.5 mg/kg) of the dopamine antagonist drug, pimozide, attenuated this response-reinstating effect of water-reinforcement. This action of pimozide was not likely a consequence of some residual sedative or motor incapacitation since a) the test day was conducted 24 hr after the treatment day by which time the pharmacological actions of the drug had greatly subsided; b) a Motor Control group administered pimozide after the reinforced trial exhibited normal response-reinstatement 24 hr later on Test Day; and c) on treatment day, pimozide did not reliably attenuate running times, latency to initiate drinking, nor the rate of licking behavior. Together, these data suggest that dopamine receptor antagonism can produce an attenuation in the reinforcing efficacy of water.

Animals↗
PubMed1990

Pimozide enhances the aversiveness of quinine solution.

The taste reactivity test was employed to assess the effect of pimozide pretreatment on rats' hedonic responsiveness to palatable and unpalatable tastants. Pimozide selectively enhanced the aversiveness of unconditionally unpalatable quinine solution (Experiment 1) and produced the greatest enhancement of aversion at the highest concentration of quinine (0.1%) solution tested (Experiment 3). Pimozide also enhanced the aversiveness of a conditionally unpalatable lithium-paired solution, but only when the dose of pimozide was relatively high and the strength of the baseline aversion was relatively low (Experiment 2). These results are discussed in light of the anhedonia and the sensorimotor deficit hypotheses of neuroleptic effects on reinforced responding.

Animals↗
PubMed1994

Differential sensitivity of operant behaviors to changes in the concentration of a sucrose reinforcer: effects of pimozide.

The sensitivity of operant response rates to changes in a sucrose reinforcer was examined in well-trained animals maintained on a variable ratio (VR) or variable interval (VI) schedule (experiment 1). Although VR performance showed greater resistance to small reductions in the concentration of the sucrose reinforcer than VI performance, VR performance was more sensitive to large reductions in the sucrose concentration. Despite this differential sensitivity only the smallest dose of pimozide (0.125 mg/kg) differentially affected these behaviors by reducing VI rates without affecting VR rates. These and other results support the view that low doses of pimozide reduce the hedonic impact of the reinforcer. The results also indicate that the attenuation of operant responding by higher doses (0.25, 0.5, and 1.0 mg/kg) cannot be solely a result of the blunting of reward. Experiment 2 demonstrated that when rats drink in daily, brief one-bottle tests they show greater resistance to reductions in the sucrose concentration than when they lever-press for sucrose, and require a higher dose of pimozide (2.0 mg/kg) to attenuate consumption. Together the results of both experiments suggest that the greater the resistance to reductions in the reinforcement value, the greater the dose of pimozide necessary to attenuate performance. We discuss the importance of attaining a more complete understanding of the factors in control of operant performance in order to better assess the effects of neuroleptics on reward.

Animals↗
PubMed1986

The effects of pimozide on the reinforcing efficacy of central grey stimulation in the rat.

The present report describes the effects of the neuroleptic pimozide on the reinforcing efficacy of central grey stimulation. Six adult rats were implanted with a monopolar moveable stimulating electrode in the pontine central grey. Each bar-press in an operant chamber delivered a 0.3-s train of cathodal rectangular pulses of constant duration (0.1 ms) and intensity (from 180 to 440 microA depending on the subject) and of variable frequency. The function relating the rate of bar-pressing to the logarithm of the number of pulses per train (rate-frequency function) was recorded following administration of vehicle and increasing doses of pimozide (from 0.15 to 0.5 mg/kg). Pimozide produced a dose-dependent parallel shift of the rising segment of the rate-frequency function towards higher pulse numbers in 4 subjects, indicating that the drug reduced the reinforcing efficacy of the stimulation. In two subjects, the shift was accompanied by a decrease in slope of the rising segment. Depending on the subject, the greatest shift observed varied from 0.087 to 0.489 log units. Further attempt to increase the magnitude of shift with higher doses resulted in complete abolition of self-stimulation. The fact that pimozide reduced the value of reward in an area containing only marginal amounts of dopaminergic cells adds support to the hypothesis that dopamine modulates reward indirectly. The fact that the shift could not be increased with higher doses was interpreted as an indication that dopaminergic neurons are involved in a gate-like synaptic arrangement in which a limited decrease in dopaminergic activity is sufficient to obliterate the transmission in the reward pathway or the conversion of the signal into a reinforcing effect.

Animals↗
PubMed2001

Pimozide, like extinction, devalues stimuli associated with sucrose taking.

Conditioned stimuli (CS) can be devalued by exposure to those stimuli in the absence of primary reward. We tested the hypothesis that dopamine (DA) mediates the control of behavior by conditioned appetitive stimuli. Long-Evans rats were trained to respond for sucrose under a heterogeneous chain schedule in which seeking responses (lever press) turned on a houselight [variable interval (VI)-120 s]; taking responses (wheel turn or chain pull) in the presence of the houselight were reinforced [fixed ratio (FR)-1] by a sucrose pellet. When responding on this schedule was stable, the levers were retracted and subjects had access to the sucrose-taking manipulandum only. Sucrose-taking responses were either extinguished or reinforced under the influence of the DA antagonist, pimozide. Control groups were also reinforced for sucrose-taking responses but received no injection or a vehicle injection prior to each session. Responses of extinction and pimozide-treated groups declined over sessions. Sucrose-seeking responses were measured in a later test when subjects had no access to the sucrose-taking manipulandum or to the reinforcer. Both extinction and pimozide manipulations reduced seeking responses, relative to the respective control groups. Pimozide injections in the home cage had no effect. These data support the idea that DA mediates the conditioned reinforcing properties provided by access to the taking link of the chain.

Animals↗
PubMed1998

Effects of pimozide on the psychopathology of delusional disorder.

1. The effects of pimozide on the psychopathology of delusional disorder were studied. 2. After six weeks, pimozide (2-12 mg/day) administration had no effect on the Brief Psychiatric Rating Scale, or in the psychological, social and occupational functioning, as measured by the Global Assessment of Functioning Scale. 3. When the different dimensions of the delusional experience were looked upon, no modifications were observed in any of them after six weeks of pimozide treatment. 4. These data failed to support the therapeutic role of pimozide in the treatment of delusional disorder and may suggest, when compared to other disorders with prominent delusions such as schizophrenia, a different neurobiology for the illness.

Adult↗
PubMed2003

Pimozide injections into the Nucleus accumbens disrupt maternal behaviour in lactating rats.

In rodents ongoing maternal behaviour requires activation of dopamine receptors. Therefore, it is possible that some motor components of maternal behaviour might be mediated by concurrent dopaminergic stimulation. It has been previously demonstrated that peripheral injections of some antipsychotic drugs such as pimozide have disruptive effects on maternal behaviour. The present experiments were designed to verify the effects of pharmacological blockade of limbic dopamine receptors on ongoing maternal behaviour in lactating rats. The hypothesis that central injections of the drug pimozide would have an effect on maternal behaviour was tested. We investigated the effects of central bilateral intra-accumbens microinjections of the dopamine D2 receptor antagonist pimozide (1.5 and 3.0 microg) on maternal behaviour. Animals treated with 3.0 microg of pimozide showed significantly longer latencies for all parameters of maternal behaviour compared to controls. These results suggest that dopamine receptors in the nucleus accumbens play a role in ongoing maternal behaviour.

Animals↗
PubMed2006

Bait-delivered pimozide causes precocious embryo implantation in mink: a fertility control option for the exotic stoat?

Stoats (Mustela erminea), an exotic pest in New Zealand, threaten the conservation of several ground-nesting bird species and broad-scale methods for their control are sought. Females are seasonally monestrous, show a 9-month period of obligatory diapause and usually do not breed more than once in their lives. A bait-delivered agent that terminates diapause and results in a non-viable embryo may have a significant impact on their reproductive success. Prolactin (PRL) is hypothesised to be the only gonadotrophin required for renewal of luteal activity and blastocyst implantation in some mustelids. We investigated the effects of bait-delivered dopamine (DA) antagonists (which stimulate the release of PRL) using a mink model (Mustela vison), a species that maintains a short period of diapause. A bait dose of 0.8 mg kg(-1) of pimozide was more effective in elevating PRL levels than equivalent doses of fluphenazine, sulpiride (P < 0.01) or haloperidol (P < 0.05). Bait doses of 1.6 mg kg(-1) pimozide given at Days 0, 3, 9 and 11 after mating caused a significant reduction in the length of pregnancy compared with a positive control and placebo (46 days v. 51 days), indicating early termination of diapause (P < 0.01). Pimozide doses caused higher elevations in PRL concentration relative to the oral placebo by Day 12, but mean PRL levels fell below all other groups by Day 18. A borderline significant increase in progesterone (P4) secretion compared with the oral placebo was detected at Day 18. These results suggest that bait-delivered pimozide can elevate PRL outside of the normal breeding season and doses of 1.6 mg kg(-1) are effective in terminating embryonic diapause in mink. The implications and limitations of these data are discussed with reference to the use of bait-delivered DA antagonists as a possible means to affect the reproductive success of wild stoats.

Animals↗
PubMed1995

Case report: reversible QT prolongation with torsades de pointes in a patient with pimozide intoxication.

Pimozide is a diphenylpiperidine neuroleptic with well characterized cardiovascular side effects including QT prolongation. So far, life-threatening cardiac arrhythmias, in particular torsades de pointes, have not been described in patients treated with pimozide. The authors describe a patient in whom torsades de pointes developed after the ingestion of 800 mg pimozide as a suicide attempt. After intravenous treatment with lidocaine and magnesium, the patient recovered completely and the QT interval had normalized 5 days after the intoxication. Potential mechanisms leading to torsades de pointes in patients treated with pimozide are discussed.

Electrocardiography↗
PubMed1993

Clinical uses of pimozide.

One of the more difficult psychopharmacologic aspects of current clinical psychiatry is finding a neuroleptic drug that adequately treats delusional states. Furthermore, many chronic schizophrenics remain resistant to standard antipsychotic medication, and clozapine is effective in only 30% to 50% of refractory cases. In addition, clozapine has several serious side effects and is expensive. We have determined that pimozide is clearly effective in Tourette's syndrome, maintenance schizophrenia, and some delusional disorders. We further demonstrate that the drug is likely to be effective in the treatment of the negative symptoms of schizophrenia and other delusional states. In addition, we suggest that a trial of pimozide may be indicated before giving clozapine to treatment-resistant schizophrenic patients. The side effect that probably most limits pimozide's current use is the possible production of ECG abnormalities. This side effect does not seem to be a realistic clinical concern, however, if the patients are properly screened and the pimozide dose is maintained at or below 20 mg/day.

Clinical Protocols↗