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PubMed1977

Effects of pimozide on the acquisition, maintenance, and extinction of an amphetamine-induced taste aversion.

Different groups of rats were pretreated with the dopamine receptor blocker, pimozide (0.25, 0.5, or 1.0 mg/kg), in an attempt to investigate the role of dopaminergic transmission in the acquisition, maintenance, and extinction of a taste aversion produced by d-amphetamine dulphate (1.0 or 2.0 mg/kg). In the first phase of the experiment, all doses of pimozide attenuated but did not block the acquisition of the aversion produced by 1.0 mg/kg but not by 2.0 mg/kg amphetamine. In Phase II, pimozide pretreatment was suspended to allow the attenuated groups to acquire the aversion and then reintroduced in Phase III. In this phase all groups continued to avoid the taste, indicating a failure of pimozide to affect the maintenance of the avoidance response. When amphetamine treatment was suspended in Phase IV, pimozide accelerated the extinction, especially in those groups that had previously received the 1.0 mg/kg dose of amphetamine. These results are discussed with reference to dopaminergic mechanisms in avoidance learning and a pimozide-mediated reduction in the functional strength of amphetamine as an unconditioned stimulus.

Animals↗

PubMed1981

Pimozide attenuates lever pressing for water reinforcement in rats.

Rats were trained to lever-press for water on a schedule of continuous reinforcement, then tested every fourth session on five occasions either under conditions of non-reinforcement or following injections of the dopamine receptor blocker pimozide (0.5 or 1.0 mg/kg) or the injection vehicle. The low dose of pimozide did not significantly attenuate responding until the fifth session. The high dose attenuated responding on all occasions, with residual responding decreasing progressively across repeated drug sessions. Responding in the pimozide conditions was never less than that of the non-reinforced control group. Responding in each condition was strongest in the early minutes of a session. After five sessions, rats were switched from the pimozide condition to the non-reinforced condition (or vice-versa) for one additional test day. Decreased responding continued for rats transferred from non-reinforcement to pimozide though not for rats transferred from pimozide to non-reinforcement. These data suggest a role for brain dopamine in behavior; they reflect the same patterns as have been seen with food reinforcement and with several centrally-acting reinforcers.

Animals↗

PubMed1982

A comparison of the effects of pimozide and nonreinforcement on discriminated operant responding in rats.

Some controversy surrounds the interpretation of the effects of dopamine receptor blocking drugs on conditioned operant responding. To assess the motoric versus the reinforcement-reducing consequences of these compounds, the effects of pimozide (1.0 mg/kg) and nonreinforcement on discriminated operant responding were compared. Rats were trained extensively on a successive discrimination implemented with the use of a multiple schedule. Rats subsequently injected with pimozide showed a significantly greater decrease in responding in the nonreinforced component than control rats showing that pimozide produces a decrease in general level of behavioral arousal. Additionally, pimozide injection resulted in an extinction-like decrease in reinforced responding over three test sessions indicating a reduction in the effects of reinforcement. However, animals treated with pimozide continued to discriminate. Transfer between pimozide and nonreinforcement was not observed probably because of the differential effects of the two procedures on behavioral arousal. Dopaminergic neurons may influence both general behavioral arousal and the effects of reinforcement but not stimulus-stimulus associative learnings.

Animals↗

PubMed1983

Prior training and intermittent retraining attenuate pimozide-induced avoidance deficits.

Although the effects of neuroleptics on avoidance behavior have been studied extensively, no studies have systematically investigated the possible relationship between these effects and prior training. This paper reports the effects of prior training and intermittent retraining on pimozide-induced avoidance deficits. Experiment 1 investigated the effects of pimozide (0.5 or 1.0 mg/kg IP) on one-way avoidance responding in groups of rats (n = 15 or 16) that had received 0, 2, 3, or 10 prior sessions of training (10 trials per session). All trained groups were more resistant to the disruptive effects of the drug than the groups receiving no prior training but the 2, 3, and 10 session pretrained groups did not differ significantly from one another. However, the avoidance responding of the pretrained groups eventually was impaired across the 15 sessions of testing under the drug condition; this effect was shown not to be attributable to an accumulation of the drug with repeated dosing. Experiment 2 showed that periodic retraining in the absence of pimozide reversed the cumulative session-to-session disruptive effects of the low and high dose of pimozide on avoidance responding, a finding not previously reported. The results suggest that dopaminergic systems play a role in the acquisition and maintenance of operant response learning. Avoidance learning fails to occur if training is conducted in untrained, pimozide-treated animals. Pretrained animals, when injected with pimozide, can maintain avoidance responding for several sessions but lose this ability in the continued absence of normal dopamine function; however, intermittent retraining can prevent this eventual loss of avoidance responding.

Animals↗

PubMed1985

Pimozide decreases the positive reinforcing effect of sham fed sucrose in the rat.

Rats with chronic gastric cannulas were intraperitoneally injected with the dopamine receptor antagonist pimozide (0.25 mg/kg) before sham feeding 5, 10, 20, or 40% (w/v) sucrose solutions. Amount of sham intake after control injections increased as a function of sucrose concentration. At each concentration, the rate of sham feeding was greatest during the initial 3 min of sham feeding and subsequently decelerated. Pimozide inhibited sham feeding rate, and the temporal pattern of decreases in sham feeding rate after pimozide were similar to those produced by decreasing the concentration of sucrose sham fed. These data extend previous reports of the inhibitory effect of pimozide on ingestion of sweet fluids by eliminating the possibility that the effect was the result of pimozide facilitating postingestional inhibitory mechanisms. Further, pimozide did not appear to produce fatigue or sedation, or to reduce the rats' motor capacity to sham feed. Therefore, these data are consistent with the hypothesis that central dopaminergic synaptic activity mediates the reinforcing effects of sweet taste that drive sham feeding.

Animals↗

PubMed1989

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.

Animals↗

PubMed2005

Validation of the tremulous jaw movement model for assessment of the motor effects of typical and atypical antipychotics: effects of pimozide (Orap) in rats.

Drug-induced tremulous jaw movements (TJMs) in rats have been used as a model of parkinsonian tremor. Previous studies demonstrated that the typical antipsychotic haloperidol induced TJMs after acute or subchronic administration, while atypical antipsychotics did not. Moreover, it has been suggested that the relative potency for suppression of tacrine-induced TJMs relative to the suppression of lever pressing can be used to discriminate between typical and atypical antipsychotics. In order to validate this model with additional drugs, the present studies assessed the effects of the typical antipsychotic pimozide. In the first series of experiments, the effects of acute pimozide on tacrine-induced TJMs and lever pressing were examined. As with haloperidol, pimozide failed to suppress tacrine-induced TJMs, even at doses considerably higher than those that suppressed lever pressing. In the second group of experiments, rats were given single daily injections of pimozide (0.125-1.0 mg/kg) or tartaric acid vehicle for 13 days, and were observed for TJMs on days 1, 7, and 13. Pimozide induced TJMs in a dose-related manner on all days. The jaw movements occurred largely in the 3-7 Hz frequency range characteristic of parkinsonian tremor. These data support the hypothesis that typical antipsychotics can induce TJMs in rats, and demonstrate that chronic administration of typical antipsychotics is not necessary for induction of TJMs. TJMs induced by acute or subchronic pimozide may be related to early-onset motor syndromes such as drug-induced parkinsonism.

Animals↗

PubMed2000

High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic pimozide.

Pimozide is an antipsychotic agent also used to treat facial tics. Pimozide can cause acquired long QT syndrome and ventricular arrhythmias. To elucidate the mechanism behind these clinical findings, we examined the effects of pimozide on the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene; rapid component of delayed rectifier), Kv1.5 (ultra-rapid delayed rectifier) and KvLQT1/minK (slow component of delayed rectifier). Using patch clamp electrophysiology, we found that pimozide was a potent inhibitor of HERG displaying an IC(50) value of 18 nM. In contrast, pimozide (10 microM) was a weak inhibitor of KvLQT1/minK and Kv1.5. We conclude that pimozide is a specific, high affinity antagonist of HERG, and that this interaction leads to prolongation of cardiac repolarization.

Animals↗

PubMed1997

High dose pimozide does not block amphetamine-induced euphoria in normal volunteers.

Studies with laboratory animals have shown that dopamine antagonists block the rewarding and interoceptive effects of amphetamine. However, studies using dopamine antagonists with humans have not consistently shown blockade of amphetamine-induced euphoria. The unexpected results in humans may relate to the low doses of dopamine antagonists tested. The purpose of this study was to evaluate the effects of a relatively high acute dose (8 mg) of the dopamine receptor antagonist, pimozide, on responses to d-amphetamine (10 and 20 mg) in normal volunteers. Male and female volunteers (N = 12) attended six sessions on which they received pimozide or placebo (7:30 am) followed by d-amphetamine or placebo (9:30 am). Subjective, physiological and behavioral measures were obtained at baseline (7:15 am) and hourly over a 5 h period. d-Amphetamine and pimozide, when administered alone, produced significant and opposite effects on ratings of Elation and Vigor, as well as on psychomotor performance and physiological measures. However, there were few significant interactions between pimozide and d-amphetamine. Thus, pimozide failed to consistently antagonize the effects of d-amphetamine, even at doses of pimozide that had behavioral and physiological effects when administered alone. Possible reasons for lack of robust dopamine antagonism of amphetamine-induced euphoria in humans are discussed.

Adult↗

PubMed1997

Pimozide does not shift palatability: separation of anhedonia from sensorimotor suppression by taste reactivity.

Several "taste reactivity" studies of dopamine and reward have concluded that pimozide suppresses the hedonic reaction patterns normally elicited by sucrose but enhances aversive reaction patterns elicited by quinine. However, other taste reactivity studies have failed to find hedonic/aversive shifts in reaction patterns after dopamine antagonists or dopamine lesions. The divergent conclusions have come from two different laboratories. To resolve the controversy regarding dopamine blockade and palatability, the present study joined the two laboratories to investigate the effect of pimozide on taste reactivity patterns elicited by sucrose and quinine. The results replicated many (but not all) of the earlier findings and identified procedural factors responsible for different outcomes. Overall, the results provide evidence for sensorimotor effects of pimozide on taste reactivity but not for a hedonic shift in palatability. Pimozide suppressed both hedonic and aversive reaction patterns in a gradual sensorimotor fashion when the eliciting taste stimulus was repeated or continued for several minutes. The general suppression typically did not alter the initial reaction to a taste but emerged only after an oral infusion of sucrose or quinine continued for several minutes or trials. Aversive reactions were never enhanced. The balance between hedonic and aversive reaction patterns was not shifted by pimozide. We conclude that pimozide produces a sensorimotor impairment of taste reactivity patterns but does not shift taste palatability toward anhedonia or aversion.

Animals↗

PubMed1983

Precocious induction of luteal activation and termination of delayed implantation in mink with the dopamine antagonist pimozide.

The effects of the dopamine antagonist pimozide on the preimplantation delay phase of mink gestation were investigated in field and laboratory trials. Three doses of 0.1 mg pimozide in acetic acid administered on the 7th, 9th and 11th days after mating abbreviated gestation in Pastel kit female mink to a mean (+/- SEM) of 45.5 +/- 0.5 days, 10 days less than that observed in mink treated with vehicle only (55.6 +/- 0.6 days). In laboratory trials, four doses of 0.1 mg pimozide on the 7th, 9th, 11th and 13th day after mating resulted in embryo implantation at a mean of 25 +/- 4.3 days after mating while vehicle-treated control animals had mean preimplantation delay of 37 +/- 3.1 days. Luteal activation in the pimozide-treated group, as indicated by a rapid increase in circulating progesterone, began within 2 days after the first pimozide injection. No increase was observed in vehicle-treated mink until 6 or more days after the initiation of injections or 13 days after mating. It was concluded that pimozide, presumably by permitting endogenous secretion of prolactin, can induce precocious luteal activation and embryo implantation in the mink.

Animals↗

PubMed2004

Tic reduction with risperidone versus pimozide in a randomized, double-blind, crossover trial.

OBJECTIVE: To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. METHOD: This was a randomized, double-blind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourette's or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. RESULTS: Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGTSS: baseline 43.3 +/- 17.5, pimozide 34.2 +/- 14.2, risperidone 25.2 +/- 13.6; p =.05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. CONCLUSIONS: In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain.

Adolescent↗

PubMed1985

Pimozide: use in Tourette's syndrome.

The orphan drug pimozide was recently approved for marketing in the U.S. for the treatment of Tourette's syndrome (TS). TS is characterized by recurrent, involuntary motor movements and vocal tics, and is believed to be due to neurochemical dysfunction. Pimozide's receptor selectivity differs from that of haloperidol, the standard agent used for TS. Clinical trials with pimozide demonstrate a positive response for many patients, although superiority over haloperidol has not been demonstrated in general. Pimozide causes annoying side effects in a large percentage of patients and may cause severe side effects (e.g., tardive dyskinesia, cardiovascular toxicity) with prolonged use and/or at higher doses. The long half-life of pimozide allows for once-daily dosing. Pimozide should be reserved for treatment of patients with TS who have not responded to haloperidol or who cannot tolerate haloperidol's adverse effects.

Formularies as Topic↗

PubMed1981

Inhibition of gonadotropin-releasing hormone-stimulated luteinizing hormone release by pimozide: evidence for a site of action after calcium mobilization.

In the present work, we show that pimozide is a noncompetitive antagonist of gonadotropin-releasing hormone (GnRH)-stimulated LH release from pituitary cell cultures. For several other neurotropic agents, the concentration needed to inhibit 50% of LH release in response to GnRH correlates well with the ability to inhibit enzyme activation by calmodulin in vitro. Pimozide does not alter the affinity or amount of releasing hormone binding by the GnRH receptor. The additional observation that pimozide inhibits Ca2+ ionophore (A23187 and ionomycin)-stimulated LH release suggests that the locus of pimozide action is after Ca2+ mobilization. Pimozide is known to bind and inactivate the Ca2+-calmodulin complex, and as Ca2+ is a second messenger for GnRH, it is possible that calmodulin is the target of pimozide in this system.

Animals↗

PubMed1983

No acute effect of pimozide on the plasma GH levels in acromegaly.

In 34 acromegalic patients either untreated or inadequately treated by surgery and/or radiotherapy the plasma GH levels and plasma Prl levels were determined during 8 h after the acute administration of the dopamine agonist bromocriptine and during 150 min after the administration of the dopamine antagonist pimozide. A 50% or more suppression of the basal GH levels was arbitrarily defined as a positive response. Seventeen patients displayed a positive response to bromocriptine, 17 patients displayed a negative response to bromocriptine. Plasma Prl levels were elevated in 6 of 17 bromocriptine responders and in 2 of 17 bromocriptine nonresponders. There was no difference in the plasma GH response to pimozide administration in the patients with a positive or a negative GH response to bromocriptine. With one exception there was in no patient a positive GH response to pimozide. In further experiments the plasma GH response to pimozide was measured during 11 h in 6 bromocriptine sensitive and 6 bromocriptine insensitive patients. Again no difference was found between bromocriptine responders and non-responders. There was also no difference in the Prl response to bromocriptine or pimozide between GH responders and GH non-responders. The Prl response to pimozide was blunted in comparison to a control group. The present study does not not lend support to the idea that there is a fundamental difference in the degree of hypothalamic dopaminergic control of GH or Prl secretion between bromocriptine sensitive and bromocriptine insensitive patients with acromegaly.

Acromegaly↗

PubMed1976

Pimozide: a review of its pharmacological properties and therapeutic uses in psychiatry.

Pimozide 1-(1-[4,4-bis(4-fluorophenyl)butyl]-4-peperidinyl)-2-benzimidazolone, is the first of a new series of psychotropic drugs, the kiphenylbutylpiperidines. It is advocated for once-daily use as maintenance therapy in chronic schizophrenia and for the treatment of psychic and functional disorders induced by personality traits. Published data suggest that in chronic schizophrenia, pimozide 4 to 6mg daily is indistinguishable from maintenance doses of chlorpromazine, fluphenazine, flupenthixol, perphenazine, or thioidazine. Patient groups have usually been to small to allow statistically significant differences to be apparent, but in some trials pimozide was significantly superior to trifluoperzine and to haloperidol. On present evidence, pimozide has no place in the hyperactive, aggressive type of patient or in treating the acute phase of schizophrenia, probably because of its relative lack of sedative properties compared with many antipsychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide are low, but suitably designed controlled studies are needed to determine whether its use leads to a reduction in the requirement for antiparkinsonian medication. In anxious patients, pimozide seems to offer no advantages over currently available anxiolytic agents, either in terms of efficacy or incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven.

Adult↗

PubMed1990

Antipsychotic pimozide is a potent Ca2+ channel blocker in heart.

The diphenylbutylpiperidine (DPBP) antipsychotic pimozide was identified as a potent new Ca2+ channel antagonist in heart. In whole-cell patch-clamp experiments, pimozide blocked Ca2+ current through L type channels of rat ventricular myocytes, in a voltage-dependent manner. At holding potentials positive to -40 mV, approximately 90% of current was blocked by 200 nM pimozide. Nearly half of this block, 48 +/- 5% (mean +/- SE, n = 5), was relieved by 5-min hyperpolarization to -100 mV. In quin2-loaded myocytes, pimozide blocked 50 mM KCl-induced increases in intracellular Ca2+ concentration [( Ca2+]i) half maximally at a concentration of 75 +/- 15 nM (n = 5). Two other DPBPs, penfluridol and fluspirilene, also blocked the KCl-induced response at similar concentrations. The contractile force of cardiac tissue was also depressed by pimozide. One micromolar pimozide reduced twitch tension in rat papillary muscles by an average of 36 +/- 8% (n = 3). These results demonstrate that the DPBPs comprise a potent new class of Ca2+ antagonists in heart, which will be useful in studying cardiac Ca2+ channels. They also suggest that these agents may have therapeutic value outside the field of psychiatry.

Aminoquinolines↗

PubMed1980

Enhanced sensitivity to pentobarbital in haloperidol or pimozide treated mice and rats.

The influence of intraperitoneal administration of two neuroleptic drugs, haloperidol and pimozide (2.5 and 5.0 mg/kg) on pentobarbital induced narcosis, hypothermia and lethality were investigated in mice and rats. Haloperidol and pimozide administered 10 min prior to pentobarbital sodium (60 mg/kg) injection in rats increased significantly the onset time and duration of sleep. Both neuroleptic drugs also enhanced the intensity of hypothermic response to pentobarbital (50 mg/kg). Similar enhancement of narcosis and hypothermia to pentobarbital (75 mg/kg) was observed in haloperidol and pimozide pretreated mice. Pimozide pretreatment decreased the LD50 value of pentobarbital in mice. Brain and plasma levels of pentobarbital in haloperidol and pimozide treated rats on awakening were lower than in the corresponding saline treated rats. Brain and plasma levels determined at identical time interval in saline and neuroleptic treated rats showed similar results. These data indicate that disposition of pentobarbital cannot explain its enhanced pharmacological effects in haloperidol or pimozide treated animals but the brain sensitivity to pentobarbital is altered. These studies suggest an interaction between pentobarbital and neuroleptic drugs which may have clinical relevance.

Animals↗