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PubMed1980

Characterisation of adjustments to the structure of feeding behaviour following pharmacological treatment: effects of amphetamine and fenfluramine and the antagonism produced by pimozide and methergoline.

An observational procedure for examining the micro-structure of eating has been employed to establish the characteristic behaviour patterns displayed after various pharmacological manipulations. Using a double dissociation design it was shown that amphetamine and fenfluramine gave rise to quite distinctive readjustments to the structure of feeding behaviour. Amphetamine anorexia was characterised by a long initial delay, following which feeding was typified by infrequent short bursts of rapid eating. These effects were antagonised by the dopamine receptor blocking agent, pimozide. Fenfluramine exerted a more restricted pattern of action characterised by a marked slowing of the rate of eating. This effect was countered by the serotonin receptor blocking agent methergoline. These data throw light on the way in which pharmacological agents may impede food consumption and upon the neurochemical systems believed to be involved in the expression of feeding behaviour.

Amphetamine↗
PubMed1981

The effects of pimozide during pairing on the transfer of classical conditioning to an operant discrimination.

Transfer of classical conditioning to operant learning was demonstrated by showing enhanced acquisition of an operant discrimination in a group of rats (n = 6) previously exposed to pairings of the discriminative stimulus with food as compared to control animals (n = 6). A group (n = 6) that received the classical conditioning sessions while under the influence of the neuroleptic, pimozide (1.0 mg/kg, IP) also showed enhanced acquisition of the discrimination when tested while undrugged but their performance was intermediate between that of the other groups for the first seven sessions. For the remaining sessions, the two groups that had received classical conditioning did not differ from each other and both groups discriminated better than the controls. These data may indicate a role for dopaminergic neurons in the mechanism by which the effects of classical conditioning influence operant responding.

Animals↗
PubMed1981

Pimozide attenuates acquisition of lever-pressing for food in rats.

Pimozide pretreatment produced a dose-dependent attenuation of acquisition of a lever-pressing habit motivated by food reward in hungry rats. No evidence of learning was seen in animals treated at 1.0 mg/kg, minimal learning was seen at 0.5 mg/kg, and retarded learning which ultimately did reach normal asymptote was seen at 0.25 mg/kg. Thus primozide attenuates the response acquisition function as well as the previously studied response maintenance function of food reward.

Animals↗
PubMed1983

Comparative effects of estradiol stereoisomers on pimozide-induced catalepsy, locomotor activity and body-weight in the rat.

The effects of 17-alpha and 17-beta estradiol were compared at three dose levels on locomotor activity, pimozide-induced catalepsy, and changes in body weight. At 10 micrograms/kg/day they increased locomotor activity to a similar degree but at 5 and 1 microgram/kg/day the beta form was mor effective. However the alpha isomer failed to potentiate catalepsy, or reduce body weight, even at the highest dose whereas 17-beta estradiol did both. From these and other results it is suggested that estradiol might act on intracellular receptors and not by changing catecholamine metabolism.

Animals↗
PubMed1984

Pimozide blocks the open-field hyperactivity produced by lesions of the ventral noradrenergic bundle in rats.

Selective, bilateral, radiofrequency destruction of the ventral noradrenergic bundle resulted in a substantial fall in hypothalamic but not cortical levels of noradrenaline. Ventral bundle-lesioned rats displayed, as compared to sham-operated animals, a pronounced enhancement of ambulation in both peripheral and central squares together with a reduction in immobility and an enhancement of rearing upon introduction into a novel open-field space. Grooming behaviour was not, in contrast, significantly modified. Pretreatment with the dopamine receptor antagonist, pimozide, strongly decreased this hyperactivity without significantly altering the behaviour of sham animals. These data suggest that the ventral bundle plays a role in the control of open-field locomotor behaviour and that this action may be exerted via an interaction with a dopaminergic network.

Animals↗
PubMed1986

Some effects of pimozide and of shifts in sucrose concentration on lick rate, duration, and interlick interval.

Multiple dependent measures were employed to characterize the licking behavior of rats exposed to shifts in reward magnitude or injected with pimozide (PIM). Nondeprived rats licked either a 32% (n = 14) or 4% (n = 15) sucrose solution in daily 10 min sessions. Rats in the 32% condition were then down-shifted to either a 16% (n = 7) 4% (n = 7) sucrose solution. Rats in the 4% condition were up-shifted to either 16% (n = 7) or 32% (n = 8) sucrose solution. The response profiles generated by those rats shifted to a lower reward magnitude were contrasted with either rats shifted from a 32% sucrose solution to a no-reward (plain tap water) condition, or with rats maintained on a 32% sucrose solution and administered the neuroleptic PIM (0.5 mg/kg or 1.0 mg/kg). Rats down-shifted from a 32% to 4% sucrose solution generated response profiles more similar to rats shifted to plain tap water than rats maintained on a 32% sucrose solution and administered PIM. These results suggested that PIM treatment is not functionally equivalent to either a shift to no-reward or to a shift to reduced reward conditions.

Animals↗
PubMed1989

Force-proportional reinforcement: pimozide does not reduce rats' emission of higher forces for sweeter rewards.

A two-step force-proportional reinforcement procedure was used to assess the efficacy of a sucrose reward under neuroleptic challenge. The force-proportional reinforcement method entails an increase in the quality of reward contingent upon higher force-emission. This paradigm was conceived as a rate-free means of addressing the putative anhedonic effects of dopaminergic receptor-blocking agents. Results failed to support the anhedonia interpretation of neuroleptic-induced response decrements: Pimozide did not diminish the ability of a high-concentration sucrose solution to maintain elevated response forces. Alternatives to the anhedonia interpretation were discussed with emphasis on the drug's motor effects in the temporal domain.

Animals↗
PubMed1994

Differential effects of clozapine and pimozide on fixed-ratio responding during repeated dosing.

Previous research has shown that the differential development of tolerance to the disruption of operant responding produced by repeated dosing with pimozide (PMZ) or clozapine (CLZ) can distinguish these two drugs. In the present study, the effects of PMZ (1 mg/kg) and CLZ (10 mg/kg) on response rate and response duration in rats lever pressing for food reward under a fixed-ratio 30 (FR-30) operant schedule were examined. PMZ suppressed response rates across all 10 days of drug dosing; CLZ produced an initial response rate decrease, with partial recovery (50%) occurring within the 10 day period. Similarly, PMZ produced an increase in response duration that persisted into the postdrug vehicle-injection period, while CLZ did not significantly change response duration. The prolonged suppression of FR responding produced by PMZ is similar to the lack of tolerance to this drug in other types of operant schedules. In contrast, CLZ's effects on response rate are schedule dependent. These results suggest that changes in response duration with repeated dosing may more reliably differentiate typical and atypical neuroleptics than do changes in response rate under FR schedules.

Animals↗
PubMed1982

Inhibition of 45Ca2+ uptake and catecholamine secretion by phenothiazines and pimozide in adrenal medulla cells cultures.

The inhibition by several phenothiazine drugs and pimozide of the uptake of 45Ca2+ and secretion of catecholamines by cultured adrenal medulla cells stimulated with nicotine, veratridine, 50 mM K+, ionomycin and Ba2+ was studied. The inhibition of 45Ca2+ uptake, except for ionomycin, closely parallelled the inhibition of catecholamine secretion. The nicotine-and veratridine-stimulated effects were several fold more sensitive to inhibition by the drugs than were those stimulated by 50mM K+, ionomycin and Ba2+; the ionomycin-stimulated effects were least sensitive to inhibition. These studies indicate that the drugs have multiple effects on stimulus-secretion coupling in adrenal medulla cells. It is suggested that inhibition of the veratridine- and nicotine-stimulated events is due to membrane perturbations caused by the drugs, that inhibition of the 50mM K+- and Ba2+-stimulated events is due to alterations in the voltage sensitive membrane Ca2+ channel, and that inhibition of secretion elicited by ionomycin may be due to inhibition of Ca2+-calmodulin reactions or to more profound non specific membrane effects.

Adrenal Medulla↗
PubMed1983

Effect of FLA-63, p-chlorophenylalanine and pimozide on the metabolism and incorporation of 3H-thymidine in the brain of rat pups.

The aim of the work is to learn if norepinephrine, dopamine or serotonin have a specific role in the maintenance of normal cell proliferation in the brain of developing rats. Between 2-24 hr after the administration of FLA-63 the incorporation rate of labelled thymidine into the DNA of 10-day-old rat brain was reduced, parallel with the decrease of tissue norepinephrine level. A similar inhibition was observed under the effect of p-chlorophenylalanine, 3-72 hr after administration. The weight gain of the rat pups was also reduced by this substance. Pimozide had no influence on 3H-thymidine incorporation rate. FLA-63 and p-chlorophenylalanine significantly impaired the transport of the radioactive precursor between blood and brain tissue and its phosphorylation to thymidine nucleotides. Tissue norepinephrine and serotonin levels are considered to play regulatory role in early postnatal cell proliferation in the rat brain.

Animals↗
PubMed1983

The influence of pimozide, haloperidol, alpha-methyl-p-tyrosine and reserpine on the development of morphine dependence in rats.

It was found that pimozide, haloperidol and alpha-methyl-p-tyrosine (alpha-MT), drugs inhibiting central catecholaminergic (CA) transmission, increased the development of morphine dependence measured as wet dog shakes in rats. Reserpine inhibiting CA and serotoninergic (5-HT) transmission, decreased the development of morphine dependence in rats. The inhibitory effect of reserpine was reversed by 5-hydroxytryptophan (5-HTP), but not by L-dihydroxyphenylalanine (L-DOPA). These results suggest that wet dog shakes might develop as a result of regulatory adaptation in the 5-HT neurotransmitter system.

5-Hydroxytryptophan↗
PubMed1986

Effect of pimozide on home cage ethanol drinking in the rat: dependence on drinking session length.

A stimulus-fading procedure was used to initiate ethanol drinking in free-feeding Long Evans rats. During daily half-hour drinking sessions in the home cage, a combination of sucrose and ethanol was first presented to the rats; gradually the sucrose concentration was reduced and the ethanol concentration increased until after 7 weeks the rats were drinking 10% ethanol with no sucrose. After stabilization of intake, either pimozide (PIM, 0.25, 0.50 and 1.00 mg/kg) was injected 4 h before drinking sessions or (d)-amphetamine (DEX, 0.25 and 0.50 mg/kg) was injected 15 min before sessions. The 0.50 and 1.00 mg/kg PIM doses and the 0.50 DEX dose significantly reduced intake compared to vehicle injections. In the second part of the experiment, the rats were given 24-h access to 10% ethanol and water in a two-bottle choice procedure. In this condition, 0.50 mg/kg PIM failed to reduce intake compared to vehicle. The critical difference between the two procedures seems to be that with the 30-min sessions, PIM injections were timed to have their maximal effect during testing. With 24-h sessions, decreases in intake produced by PIM could have been compensated for by increases after the drug had worn off. The hypothesis that dopamine is necessary for ethanol reinforcement receives support from the PIM effect on the 30-min sessions. The DEX effect extends the generality of our previous finding that DEX reduces ethanol-reinforced lever pressing in free-feeding rats.

Alcohol Drinking↗
PubMed2001

Inhibition of T-cell invasion across cultured fibroblast monolayers by phenothiazine-related calmodulin inhibitors: impairment of lymphocyte motility by trifluoperazine and chlorpromazine, and alteration of the monolayer by pimozide.

Phenothiazines inhibit the typical shape changes displayed by activated lymphocytes and thereby their migration through polycarbonate filters. The structure activity relationship of this effect is distinct from calmodulin inhibition. Our aim was to study this effect of phenothiazines on lymphocyte migration in an environment with living solid tissue cells. We assessed the effect of trifluoperazine and chlorpromazine (TFP and CP, two strong inhibitors of lymphocyte motility) and pimozide (PIM, a much weaker inhibitor of lymphocyte motility but a strong inhibitor of calmodulin) on invasion of human Molt-4 T-cells across precultured fibroblast monolayers. As expected invasion was inhibited by TFP and CP in the micromolar range that also inhibited motility. Surprisingly, PIM inhibited monolayer invasion at least as efficiently as TFP and CP (from 2.25 microM on). Preincubation of the monolayers or the lymphoid cells show that PIM exerted this novel invasion inhibiting effect on the monolayer. TFP and CP had a much weaker effect on the monolayer. Since these three compounds inhibit calmodulin in the same order, it is likely that this effect on the monolayer was caused by inhibition of a calmodulin-dependent pathway. KN-62, a specific inhibitor of calmodulin-dependent protein kinase II acted on the monolayer like PIM, whereas ML-7, a specific inhibitor of myosin regulatory light chain kinase, inhibited lymphoid cell motility like TFP and CP. In conclusion, invasion of T-cells across cellular monolayers is inhibited both by PIM and by phenothiazines like TFP and CP, but via distinct mechanisms: TFP and CP inhibit lymphocyte motility via a calmodulin independent pathway, whereas PIM impairs the monolayer's tolerance for invasion, most likely via a calmodulin and CamKII dependent pathway.

Animals↗
PubMed2003

Inhibitory effects of pimozide on cloned and native voltage-gated potassium channels.

The primary goal of this study was to use the cloned neuronal Kv channels to test if pimozide (PMZD), an antipsychotic drug, modulates the activity of Kv channels. In CHO cells, PMZD blocked Kv2.1, a major neuronal delayed rectifier, in a manner that depends upon time and concentration. The estimated IC50 was 4.2 microM at +50 mV. Tail current analysis shows that PMZD reduced the amplitude of the currents, with no effect on the steady-state activation curve (V(1/2) from 14.1 to 11.1 mV) or the slope (16.7 vs. 14.0 mV). From -120 to -20 mV, PMZD did not impact the deactivation kinetics of Kv2.1. PMZD also blocked Kv1.1, another neuronal delayed rectifier, with 16.1 microM of IC50. When Kv1.1 was co-expressed with Kvbeta1, approximately 50% of the Kv1.1 were converted into an inactivating A-type current and the Kv1.1/Kvbeta1 A-type currents were insensitive to PMZD. PMZD (10 microM) had minimal effect on Kv1.4, and had no effect on the M-current candidates, KCNQ2 and KCNQ3 when co-expressed in Xenopus oocytes. In hippocampal neurons, PMZD inhibited the delayed rectifiers by approximately 60%, and A-type currents were insensitive to PMZD. The results suggest that PMZD inhibits certain neuronal Kv channels in heterologous expression systems and in hippocampal neurons. PMZD was less effective on A-type currents, presumably because its ability to block requires a prolonged opening of the K channels. It is thus conceivable that the time-dependent and/or subunit-specific inhibition of Kv channels may increase the release of neurotransmitters such as serotonin and glutamate.

Animals↗
PubMed1983

Clinical experience with pimozide: emphasis on its use in postherpetic neuralgia.

Pimozide has been shown to be effective in the treatment of delusions of parasitosis and other monosymptomatic hypochondriacal conditions. In this paper it is shown that this benefit may be extended to severe cases of neurotic excoriations and to some cases of postherpetic neuralgia characterized by pain, paresthesias, and excoriations.

Aged↗
PubMed1985

Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: effects of pimozide, penfluridol, chlorpromazine, and haloperidol.

This study was designed to determine whether neuroleptic drugs have calcium channel blocking activity in isolated rings of rabbit thoracic aorta. The results confirm previous findings that pimozide and penfluridol are calcium channel blockers. However, the data do not support the conclusion that these agents are selective for the voltage-sensitive calcium channel. The results also show that both haloperidol and chlorpromazine (which represent different classes of neuroleptic drugs) are also calcium channel blockers in vascular smooth muscle.

Animals↗
PubMed1999

Antagonism by pimozide of olanzapine-induced hypothermia.

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D2 receptor antagonist pimozide (0.5 and 1 mg/kg) but not by the dopamine D1 receptor antagonist SCH 23390 (0.5 and 1 mg/kg). The dopamine D1/D2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D2 receptor populations involved in thermoregulation in the rat.

Animals↗
PubMed1983

Inhibition of growth and of thymidine incorporation into DNA in Tetrahymena by chlorpromazine, pimozide and penfluridol.

The antipsychotic drugs chlorpromazine, pimozide, and penfluridol caused a 50% inhibition of growth of Tetrahymena at concentrations of 4.5, 5.5, and 1.5 microM, respectively. The degree of growth inhibition was dependent on the concentration of cells; higher drug concentrations were needed to produce inhibition of denser cell cultures. Binding studies with penfluridol showed that 50% growth inhibition resulted when approximately 50 mumoles of drug were bound per 10(6) cells. A 20-min preincubation of cells with chlorpromazine (14.7 microM) inhibited DNA synthesis by 46%, and with penfluridol (4 microM) DNA synthesis was inhibited by 27%. The incorporation of labeled thymidine into the thymidine triphosphate pool was inhibited by chlorpromazine but not by penfluridol, indicating that the drugs produce their growth inhibitory effects by different mechanisms. TDP kinase activity was demonstrated in a particle-free fraction of the cells. Its enzymatic activity was not affected by added chlorpromazine, penfluridol, or calmodulin, suggesting that inhibition of DNA synthesis by these drugs may be a consequence of growth inhibition.

Animals↗