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PubMed1983

Time course of pimozide effects on brain stimulation reward.

Lever pressing for brain stimulation reward (BSR) was tested at hourly intervals following 0.5 or 1.0 mg/kg of pimozide given intraperitoneally. Response suppression was seen within one or two hours and peak effects occurred 5-8 hours after injection. Recovery approached completion within about 24 hours. Since peak brain levels of pimozide are reached quickly, the time course of peak action suggests a complex mechanism of pimozide action.

Animals↗
PubMed1991

Effects of pimozide on the hedonic properties of sucrose: analysis by the taste reactivity test.

The ability of the neuroleptic agent, pimozide, to modify sucrose palatability was assessed using three 10-min taste reactivity test sessions. Pimozide was found to suppress the ingestive response of tongue protrusions, but enhance the mildly ingestive/neutral response of mouth movements elicited by an intraoral infusion of sucrose solution. Since the pattern of taste reactivity responding shifted from highly ingestive to mildly ingestive/neutral, our results suggest that pimozide pretreatment reduces the palatability of sucrose solution. The temporal pattern of the modification of these taste reactivity responses was predicted by the Anhedonia Hypothesis.

Animals↗
PubMed1978

Effect of pimozide and sulpiride on the release of LH and FSH by pituitary cells in culture.

A culture of dispersed rat anterior pituitary cells was used to test the ability of pimozide and sulpiride to affect the basal gonadotropin release and their effects on the response to Gn-RH. Sulpiride did not alter either the basal or the Gn-RH-induced release of LH, and the lowest dose (500 ng/ml) seemed to potentiate the Gn-RH-induced FSH release. On the other hand, both doses of pimozide (100 ng/ml and 10 microgram/ml) significantly inhibited the release of FSH and LH induced by Gn-RH but did not affect the basal release of the two gonadotropins. From these results it is evident that pimozide, at the doses used, is a powerful inhibitor of the pituitary response to Gn-RH in vitro. Sulpiride on the other hand had no effect on the pituitary response to Gn-RH in vitro, except on FSH release, using the lower dose.

Animals↗
PubMed1984

Influence of pimozide on hypothalamo-pituitary function in children with behavioral disorders.

Hypothalamo-pituitary functions were examined in thirteen children with behavioral disorders (six with hyperkinesia, four with autism, two with tic and one with schizophrenia) before and during treatment with pimozide, an antidopaminergic drug. The mean (+/- S.E.M.) basal serum PRL level (24.5 +/- 4.2 ng/ml) during pimozide treatment was significantly higher than that (12.4 +/- 3.2 ng/ml) before treatment. Hyperresponse of PRL to TSH releasing hormone (TRH) was observed in five (three with hyperkinesia, one with tic and one with autism) of the thirteen patients before treatment and in seven (four with hyperkinesia, two with autism and one with tic) during treatment. Mean TSH response during treatment was not significantly different from that before treatment. However, three of the four autistic children showed hyperresponse of TSH to TRH before treatment, whereas only one also showed a hyperresponse during treatment. The pimozide treatment had no demonstrable influence on GH or cortisol secretion in response to insulin-induced hypoglycemia, or on serum T4 and T3 levels.

Adolescent↗
PubMed1992

Decreased reactivity to sweetness following chronic exposure to mild unpredictable stress or acute administration of pimozide.

Consumption of a palatable wet mash was examined in rats subjected chronically (4-10 weeks) to unpredictable mild stress. Intake of mash containing 0, 10%, or 20% additional sucrose was normal in stressed animals. In control animals, the addition of 30% or 40% sucrose caused a decrease in the quantity of mash consumed, but increased the rate of eating. Both the increase in eating rate and the decrease in intake, at high sucrose concentration, were markedly attenuated in stressed animals (which therefore had higher intakes of very sweet mash and lower rates of eating, relative to control animals). Like chronic mild stress, the dopamine receptor antagonist pimozide (0.2 mg/kg) also increased the intake of a wet mash with 30% added sucrose, while decreasing the rate of consumption. Stressed animals were relatively insensitive to pimozide, though there were significant additive effects on duration of eating (increased) and on postprandial resting (suppressed). The failure of stressed animals to adapt their intake to increases in sweetness, and the similarities between the effects of chronic mild stress and acute pimozide, are compatible with the hypothesis that animals exposed to chronic mild stress are anhedonic.

Animals↗
PubMed1992

Pimozide prevents the development of conditioned place preferences induced by rewarding locus coeruleus stimulation.

Electrical stimulation in the vicinity of the cell bodies of the locus coeruleus (LC) has been shown to support self-stimulation behaviors in rats. In the present study, a Conditioned Place Test, sensitive to both rewarding and aversive qualities of brain stimulation, was employed to determine (a) whether rewarding locus coeruleus stimulation would result in place preferences and (b) if so, whether dopamine receptor antagonism would affect the development of such place preferences. Animals were pretreated with pimozide (0.0, 0.5 or 1.0 mg/kg) prior to exposure to two distinctive environments only one of which was paired with locus coeruleus stimulation. Rats that received vehicle injections prior to stimulation/place pairings developed strong preferences for the stimulation-paired environment while those animals pretreated with 0.5 mg/kg pimozide showed no reliable shift in preference from baseline performance. Additionally, animals injected with the 1.0 mg/kg dose of pimozide exhibited mild place aversions to the stimulation-paired environment. It is hypothesized that dopamine neurotransmission is important for the rewarding effects of locus coeruleus stimulation without which such stimulation appears to be aversive.

Animals↗
PubMed1997

Sensitive assay for pimozide in human plasma using high-performance liquid chromatography with fluorescence detection: application to pharmacokinetic studies.

A method is described for the measurement of pimozide in human plasma using HPLC with fluorescence detection. The method is specific and sensitive in the range of concentrations seen in human plasma after conventional dosing (1-15 ng/ml) with a limit of quantification of 1 ng/ml. The calibration curves are linear for concentrations between 1 and 50 ng/ml. Within-day and inter-day coefficients of variation are less than 7.4% and 15.5%, respectively, at three concentrations of pimozide (2, 10 and 20 ng/ml). Intra-day and inter-day bias are less than 18.5% and 12.5%, respectively. A pharmacokinetic study conducted in a healthy volunteer administered 6 mg of pimozide orally demonstrates the utility of this method.

Antipsychotic Agents↗
PubMed1981

Effects of trifluoperazine and pimozide on stimulus-secretion coupling in pancreatic B-cells. Suggestion for a role of calmodulin?

The possible involvement of calmodulin in insulin release was evaluated by studying the effects on intact islets of trifluoperazine and pimozide, two antipsychotic agents known to bind strongly to calmodulin in cell-free systems. Trifluoperazine (10-100mum) produced a dose- and time-dependent inhibition of the two phases of glucose-stimulated insulin release. The effect was not reversible by simple washing of the drug, but could be prevented by cytochalasin B or theophylline. Trifluoperazine also inhibited the release induced by glyceraldehyde, oxoisocaproate, tolbutamide or barium, but not that stimulated by 10mm-theophylline or 1mm-3-isobutyl-1-methylxanthine. Pimozide (0.5-10mum) also produced a dose-dependent inhibition of insulin release triggered by glucose, leucine or barium, but did not affect the release induced by methylxanthines. Glucose utilization by islet cells was not modified by trifluoperazine (25mum), which slightly increased cyclic AMP concentration in islets incubated without glucose. The drug did not prevent the increase in cyclic AMP concentration observed after 10min of glucose stimulation, but suppressed it after 60min. Basal or glucose-stimulated Ca(2+) influx (5min) was unaffected by 25mum-trifluoperazine, whereas Ca(2+)net uptake (60min) was inhibited by 20%. Glucose-stimulated Ca(2+) uptake was almost unaffected by pimozide. In a Ca(2+)-free medium, trifluoperazine decreased Ca(2+) efflux from the islets and did not prevent the further decrease by glucose; in the presence of Ca(2+), the drug again decreased Ca(2+) efflux and inhibited the stimulation normally produced by glucose. In the absence of glucose, trifluoperazine lowered the rate of Rb(+) efflux from the islets, decreased Rb(+) influx (10min), but did not affect Rb(+) net uptake (60min). It did not interfere with the ability of glucose to decrease Rb(+) efflux rate further and to increase Rb(+) net uptake. The results show thus that trifluoperazine does not alter the initial key events of the stimulus-secretion coupling. Its inhibition of insulin release suggests a role of calmodulin at late stages of the secretory process.

Animals↗
PubMed1981

The effect of TRH, cyproheptadine and pimozide on the growth hormone response to intramuscular glucagon.

Glucagon-induced growth hormone (GH) secretion was studied in healthy subjects under basal conditions (n = 18), and when treated with TRH (n = 10), cyproheptadine (n = 8) and pimozide (n = 6). With glucagon alone, the mean serum GH level significantly increased at 150 minutes and at 180 minutes. TRH administered as a bolus injection completely suppressed the GH response to glucagon. Cyproheptadine pretreatment resulted in a substantial suppression of the GH response to glucagon. A significant difference between basal and post-cyproheptadine GH levels was observed at 150 minutes after glucagon. Pimozide pretreatment was followed by a reduction of GH response to glucagon, but the difference between control and pimozide-treated groups was not significant. In conclusion, it is proposed that glucagon-induced GH secretion is at least partly mediated via serotoninergic mechanisms while significant dopaminergic involvement does not seem probable. It is further suggested that TRH plays a substantial inhibitory role in glucagon-stimulated SH secretion.

Adult↗
PubMed1977

Effect of pimozide on levodopa-induced growth hormone release in man.

Serum growth hormone (GH) behaviour after levodopa administration was measured in twelve healthy subjects both in basal conditions and after a 4 day course of pimozide (4 mg daily), a specific blocker of dopamine (DA) receptors. In addition, fasting plasma GH was measured on the first, second and third day of treatment. No significant difference was found between GH response to levodopa in basal conditions and after pimozide; moreover, fasting GH was uninfluenced by pimozide.

Adult↗
PubMed1990

Conditioned drug effects of pimozide, haloperidol and chlorpromazine on methamphetamine-induced behavior.

The separate effects of pimozide, haloperidol and chlorpromazine on conditioned behavioral responses and whether there is a difference when the drug is administered accompanied by a sound stimulus were examined in rats. The results showed a similar degree of inhibition could be obtained by saline plus sound as that by pimozide alone. The pimozide with sound group showed a higher inhibition rate than that of the other two groups of rats. In the haloperidol with sound group, a stronger inhibition appeared and furthermore when the injection was discontinued, conditioned abnormal behavior that had been inhibited began to recover. The chlorpromazine group was similar to the haloperidol group. This means that repeated saline injections accompanied by sound and each drug individually inhibits conditioned abnormal behavior and that each drug combined with sound causes the strongest inhibition. The findings obtained suggested that the antipsychotics examined could have conditioned drug effects.

Animals↗
PubMed1975

Pimozide in the treatment of monosymptomatic hypochondriacal psychosis.

An account is given of six cases treated with pimozide. Four of there cases fall into the diagnostic category of monosymptomatic hypochondriacal psychosis, a group with a traditionally poor prognosis. Three out of the four have responded favourably to pimozide, while the fourth showed a partial improvement. A fifth case also showed a marked degree of improvement despite a possibility of early cerebral arteriopathy. The one case which showed no improvement was suspected all along of having a personality disorder rather than a psychotic illness, and this was subsequently confirmed. It is suggested that pimozide: a) may be an effective treatment for monosymptomatic hypochondriacal psychoses whatever their aetiology; and b) may differentiate rapidly between cases of monosymptomatic hypochondriacal psychoses and dysmorphophobias due to neurotically determined factors.

Adult↗
PubMed1978

Neuroleptic-induced "anhedonia" in rats: pimozide blocks reward quality of food.

The dopamine receptor blocker pimozide attenuated lever-pressing and running for food reward in hungry rats. In each case the characteristic behavior of pimozide-treated rats was the same as that of undrugged rats when reward was simply withheld. Drug-induced performance difficulties were ruled out by the presence of periods of normal responding in drug-treated animals. Pimozide appears to selectively blunt the rewarding impact of food and other hedonic stimuli.

Animals↗
PubMed1983

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

Animals with a history of receiving daily injections of +-amphetamine in a specific environment showed a placebo effect (enhanced activity) when injected with saline and placed there; control animals with similar but dissociated drug histories and experience with the test chamber failed to show the effect. The dopamine receptor blocker pimozide antagonized the establishment of conditioning. However, the same dose of pimozide, when given to previously conditioned animals on the placebo test day, failed to antagonize the expression of conditioned activity. Thus, during conditioning dopaminergic neurons mediated a change that subsequently influenced behavior even when dopaminergic systems were blocked. Although schizophrenia may be related to hyperfunctioning of dopamine, neuroleptic drugs, which block dopamine receptors on their first administration, do not have therapeutic effects for a number of days. The results of the pimozide experiments may resolve this paradox.

Animals↗
PubMed1986

Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette's syndrome.

During the last seven years 65 patients with Gilles de la Tourette's syndrome have been treated. Pimozide was used as the preferred drug because of our experience of treating other hyperkinesias which indicated fewer side-effects than with haloperidol. Of the 65 patients with Gilles de la Tourette's syndrome, 59 were treated with pimozide alone or in combination with tetrabenazine or clonidine. The dose ranges of pimozide were 0.5-9 mg per day. Eighty-one percent experienced a good clinical response without side-effects. The side-effects seen in our patients were sedation, gain in weight, depression, pseudoparkinsonism and akathisia; acute dystonic reactions, blurred vision, slurred speech and xerostomia did not occur. No cases of tardive dyskinesia were seen.

Adolescent↗
PubMed1980

Effects of apomorphine and pimozide on temperature regulation during exercise in the rat.

The purpose of this study was to determine the effects of a specific dopamine receptor agonist (apomorphine) and antagonist (pimozide) on thermoregulation when the heat loss pathway was activated by the stress of exercise. Apomorphine or its control vehicle (0.9% wt/vol saline) was injected systemically (0.5, 1.0, 1.5 mg/kg ip) or within the preoptic-anterior hypothalamus (5, 10, 20 micrograms) immediately before the start of treadmill exercise at 21.5 m/min. Colonic, tailskin, and ambient temperatures were recorded each minute. Oxygen consumption was calculated from on-line measurements of percent O2 and CO2. Pimozide injected systemically (0.5 mg/kg ip) had no effect on resting colonic temperature, but caused a significant (P less than 0.05) hyperthermia during treadmill exercise compared to saline controls. Central and systemic injections of apomorphine caused a dose-dependent hypothermia that was blocked by pretreatment with pimozide. Oxygen uptake values during exercise following the central injection of apomorphine were virtually identical to those following the injection of saline, but colonic temperature was significantly (P less than 0.05) lower than saline controls, indicating that the hypothermia observed was not due to a reduction in metabolic rate. These data indicate that dopamine receptors in the preoptic-anterior hypothalamus of the rat participate in the mediation of heat dissipation when the animal is challenged with a heat stress.

Animals↗
PubMed1978

A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette's syndrome.

In a double-blind placebo-controlled study, both pimozide and haloperidol significantly decreased tic frequency in nine patients with Gilles de la Tourette's syndrome. These findings are consistent with the catecholamine hypothesis of tic generation. Pimozide was associated with significantly fewer complaints of lethargy. Follow-up 4-20 months later showed that six of seven patients receiving pimozide and one of two receiving haloperidol had had greater than 75% improvement in symptoms.

Adolescent↗
PubMedDate not supplied

Successful treatment with pimozide of Capgras syndrome in an elderly male.

A case of Capgras syndrome in a 67-year-old man who failed to improve on haloperidol, but responded to pimozide, is described. The patient's paranoid delusions abated with 8 mg per day of pimozide. We believe pimozide's established benefit in the treatment of delusional disorders warrants its consideration in alleviating other delusions, including "the delusion of doubles."

Capgras Syndrome↗