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PubMed1976

Clinical trial of pimozide.

Pimozide and Chlorpromazine were compared in chronic schizophrenics for their therapeutic effectiveness and tolerance, for four-weeks in both cases and for twelve months for pimozide. The minimum and maximum doses were 1 mg to 4 mg single dose for pimozide and 100 to 200 mg thrice daily for chlorpromazine. No significant global differences between the range of therapeutic activity of the two regimens were observed. Slightly more improvement was observed in mood and motor activity with pimozide. Drowsiness and dizziness, and extrapyramidal effects were more prominent with clorpromazine. Other side effects were infrequent. A prolonged improvement in 8 pimozide patients was maintained with mainly weight gain. The advantages of pimozide in chronic unsocialized schizophrenics appear to rest on its single oral daily dose regime, minimal undersirable effects, its specific enhancement of social integration and absence of undersirable effect on mental and physical performance.

Adolescent↗
PubMed1993

The calcium channel antagonist, pimozide, blocks the cyclic GMP-activated current in rod photoreceptors.

The pharmacology of the cyclic GMP-activated current in rod photoreceptors is poorly understood, partly for a lack of suitable compounds with which to probe the conductance mechanism. The results described in this study characterize the capacity of the calcium channel antagonist, pimozide, to block this cyclic GMP-activated current in excised patches of rod plasma membrane. Pimozide blocks the cyclic GMP-activated current with half-maximal suppression at a concentration of about 0.8 microM and nearly complete suppression at 10 microM. The block produced by pimozide does not appear to depend on the applied voltage or on the duration of the voltage step. The extent of suppression was very similar for all voltage steps for a given concentration of pimozide. After appropriate scaling, the kinetic profiles of the cyclic GMP-activated currents were identical in the absence or presence of pimozide. These results, then, indicate that the block by pimozide is neither relieved nor enhanced by changes in the membrane potential. The other known blockers of the cyclic GMP-activated current, L-cis-diltiazem and dichlorobenzamil, are calcium channel antagonists as well, suggesting that the cyclic GMP-activated channel may have pharmacological properties that, in some ways, are similar to the voltage-dependent calcium channel.

Animals↗
PubMed2001

Synergetic effect of pimozide and thyrotropin releasing hormone on prolactin and thyrotropin release during the drying off of ewes.

The effect of pimozide and/or TRH was investigated on plasma prolactin, thyrotropin, T(4) and T(3) and udder distension in 38 ewes during drying off by feed restriction. The effect of daily injections of 2mg pimozide (s.c.), combined or not with TRH stimulation (200µg, i.v.) on three different days of the drying off period was examined. Blood samples were taken twice daily in each group for 9 days, while blood sampling on the days of TRH injection was also performed at 0, 15, 30min, and 1, 2 and 4h post-injection. Plasma was assayed for PRL, TSH, T(4) and T(3) levels. Udder distension and mastitis incidence were recorded at the end of the drying off period. TRH and pimozide both resulted in elevated plasma PRL levels and acted in a synergetic way. Udder distension and the incidence of mastitis was only influenced by pimozide. The TSH as well as the T(3) response to TRH was increased in ewes under a continuous influence of pimozide and T(3) peaks following TRH injection occurred earlier than T(4) peaks. The higher effect of pimozide upon TRH stimulated PRL and TSH release at day 8 compared to days 0 and 3 indicates a progressive involvement of dopamine on the inhibition of PRL and the sensitivity of the thyrotrophs to TRH during drying off.

Journal Article↗
PubMed1978

Effect of pimozide on the cytology of the eel pituitary. I. Prolactin-secreting cells.

Pimozide, a specific blocker of dopaminergic receptors, was injected for 4 to 9 days in freshwater (FW) eels or eels acclimated to sea water (SW), for 10 to 30 days. The daily dose was 100 or 200 microgram/100 g. In FW, pimozide induces a nuclear hypertrophy in the prolactin (PRL) cells of eels; these elongated cells increase in height. The amount of erythrosinophilic granules in the cytoplasm, initially reduced, increases. Plasma electrolyte values are not modified: only the plasma sodium level slightly rises with the higher dose. In SW, PRL cells appear less active. After 10 days, this hypoactivity is not yet fully evident; pimozide stimulates PRL cells without affecting electrolyte values. After 1 month in SW, PRL cells are stimulated with pimozide and a slight regranulation may occasionally occur. The response in SW is never as marked as it is in FW; a high dose is not more effective than a low one. The higher dose significantly raises Na+, Ca2+ and Cl- plasma levels. These data suggest that prolactin synthesis and release increase with pimozide. They corroborate the hypothesis of a hypothalamic inhibitory control on PRL secretion mediated through dopaminergic fibers in the eel, but other factors may also be involved in this regulation in addition to the effect of salinity.

Animals↗
PubMed1996

Prolactin monitoring of haloperidol and pimozide treatment in children with Tourette's syndrome.

Neuroleptic therapy of children and adolescents with Tourette's syndrome (GTS) is associated with unpredictable outcome and adverse drug responses (i.e., extrapyramidal symptoms). Assessing the potential outcomes in GTS from a physiologic marker such as plasma prolactin concentration is important in limiting exposure and optimizing therapy. In a double-blind, placebo-controlled, double crossover comparison of pimozide and haloperidol therapy, prolactin, tic severity, and extrapyramidal symptoms were assessed at a 6-week end point. Twenty-six GTS patients (10.5 +/- 2.6 years), experienced clinical response rates of 69% on 3.4 +/- 1.6 mg pimozide and 65% on 3.5 +/- 2.2 mg/day haloperidol. Pimozide responders demonstrate elevated prolactin (26.1 +/- 11.8 ng/mL) versus pimozide nonresponders (10.5 +/- 3.8 ng/mL) (p = .05) and haloperidol treated patients (p = .05). Prolactin may be a marker for tic response to pimozide, and conversely, a potential marker for haloperidol-related incidence of extrapyramidal symptoms during haloperidol therapy.

Adolescent↗
PubMed1977

Effects of pimozide on noradrenergic transmission in rabbit isolated ear arteries.

In the rabbit ear artery both dopamine and noradrenaline inhibit stimulation-induced (S-I) transmitter noradrenaline efflux. Pimozide, which is reported to be a specific dopamine receptor antagonist, was used to further study the effects of dopamine on transmitter efflux. In a concentration of 0.2 micrometer pimozide blocked the inhibition of S-I efflux produced by 0.5 micrometer dopamine but not that produced by 0.5 micrometer noradrenaline. In a concentration of 10 nM, pimozide enhances transmitter release and vasoconstrictor responses to sympathetic nerve stimulation; this may be due to blockade of feedback inhibition of transmitter release by endogenous dopamine. In a concentration of 1 micrometer, pimozide reduced transmitter release and vasoconstrictor responses to sympathetic nerve stimulation. Vasoconstrictor responses to noradrenaline and histamine are antagonized by pimozide in a noncompetitive manner.

Animals↗
PubMed1995

Differences between haloperidol- and pimozide-induced withdrawal syndrome: a role for Ca2+ channels.

We investigated the behavioral and biochemical events appearing in rats after withdrawal for 24 h or 8-12 days from two classical neuroleptics, haloperidol and pimozide. The neuroleptics were given for 14 days alone or shortly after injection of the Ca2+ channel blocker nifedipine. We have found that withdrawal effects after haloperidol and pimozide were different. After haloperidol treatment we observed an increase in cortical Ca2+ channel and limbic dopamine D1 receptor density and an increase in spontaneous motor activity and apomorphine-induced hyperactivity and stereotypy. In contrast no biochemical changes were observed during pimozide withdrawal, and locomotor activity and responses to apomorphine were depressed. Co-administration of nifedipine with haloperidol prevented the observed biochemical and behavioral symptoms of withdrawal. Nifedipine administration did not change the depressant effects of pimozide. Our results suggest that the voltage-dependent Ca2+ channel is involved in the observed withdrawal syndrome of neuroleptics, and that the absence of this syndrome after pimozide may be related to its considerable Ca2+ channel-blocking properties.

Animals↗
PubMed1980

Effects of pimozide on lever pressing behavior maintained on an intermittent reinforcement schedule.

Lever pressing for food on a variable interval (2.5 min) schedule was challenged by pretreatment with a 1.0 mg/kg dose of the dopamine receptor blocker pimozide. Large decreases in response rate were recorded even during the first few minutes of the test session before the rats had received any reinforcement. Pimozide also caused extinction-like effects, but it was clear, from comparisons between pimozide-treated rats that were rewarded and pimozide-treated rats that were not rewarded, that the rewarding effects of food were not totally blocked. It is suggested that an important aspect of the pimozide-produced response decrement is its effect on the incentive motivational properties of food-associated apparatus cues known to be important in sustaining responding under extinction and partial reinforcement conditions.

Animals↗
PubMed1981

The effects of pimozide and of reward omission on fixed-interval behavior of rats maintained by food and electrical brain stimulation.

Pimozide (0.125 to 2.0 mg/kg) was administered to rats whose behavior was maintained by a fixed-interval schedule in which the reward was either food (Experiment 1) or electrical stimulation of the brain (Experiment 2). The effects of the drug were compared with the effects of withholding reward (i.e., extinction) in both experiments. Reward omission and administration of pimozide both resulted in decreases in overall rates of responding and increases in the time taken by the subjects to complete a specified number of fixed-intervals. The typical patterning of responding during the sessions of reward omission was also characteristic of the effects of pimozide with food reward but not with brain stimulation reward. The duration of trains of brain stimulation which was under the control of the subjects in Experiment 2, was not altered by administration of pimozide. The differences between the effects of pimozide on behavior maintained by intermittent food reward or by intermittent brain stimulation reward limits a global interpretation of the effects of neuroleptics.

Animals↗
PubMed1981

Use of a fixed consecutive number schedule of reinforcement to investigate the effects of pimozide on behavior controlled by internal and external stimuli.

The effects of the neuroleptic pimozide, a specific dopamine receptor blocker, on behavior maintained under different degrees of stimulus control was examined by using a fixed consecutive number (FCN) schedule of reinforcement with pigeons. This schedule requires that at least eight consecutive responses be made on one key (work key) before a response on a second key (reinforcement key) will be reinforced. For half the birds no change in external stimuli accompanied the eight response (FCN-8) while for the other half the color of the work key changed from white to red after the eight peck (FCN-SD). Both schedules resulted in equal rates of baseline responding. Four doses of pimozide (vehicle, 0.1, 0.3, 0.5 mg/kg) were administered in a Latin Square sequence after baseline responding was stable. Similar pimozide-induced decreases in responding were observed in both conditions. However, pimozide selectively altered response patterns under the FCN-8 condition. The failure of the FCN-SD procedure to display a similar effect demonstrated that the use of salient exteroceptive stimuli can modulate behavioral deficits induced by pimozide. This conclusion has important implications for theories hypothesizing that dopamine subserves reward processes.

Animals↗
PubMed1981

The effects of pimozide on the consumption of a palatable saccharin-glucose solution in the rat.

Two experiments investigated the role of dopamine in reward mechanisms by examining the effects of the specific dopamine receptor blocker pimozide on drinking behavior in the rat. In Experiment 1, the effects of pimozide on the consumption of a palatable saccharin-glucose solution were compared to the effects of quinine adulteration of the same solution. Pimozide and quinine both reduced 30 min/day consumption, decreased lick rate early in the drinking session and reduced lick efficiency in a dose related manner. In Experiment 2, the effects of pimozide on the consumption of a saccharin-glucose solution and water were compared in thirsty and nonthirsty rats. Pimozide suppressed the consumption of both water and the saccharin-glucose solution in a dose related manner. However, saccharin-glucose solution intake was suppressed more than water intake, and this effect was independent of thirst drive. The drug also decreased lick rate early in the drinking session and lick efficiency. The results are discussed in terms of the reward and sensory-motor deficits produced by dopamine receptor blocking agents.

Animals↗
PubMed1986

Feeding behavior in rats is differentially affected by pimozide treatment depending on prior experience.

It has been observed in previous research that rats treated with the dopamine receptor antagonist, pimozide, failed to eat palatable food pellets. Two possible interpretations for this effect were evaluated, namely, a reduction in the primary level of food motivation or drug-induced hypokinesia resulting in a subsequent failure to find the food. The effects of several doses of pimozide (1.0, 2.0 and 4.0 mg/kg IP) on feeding in rats with or without experience eating food pellets in an experimental chamber were tested. Pimozide had little effect on feeding in rats with prior experience whereas the drug produced a dose-dependent impairment in rats without similar experience. In addition, although the initial impairment was severe, the nonexperienced rats became more efficient at locating the food despite pimozide treatment. These results appear to rule out a primary motivational interpretation for the effect of pimozide on feeding; rather, the impairment is likely due to the drug's hypokinesia-producing properties.

Animals↗
PubMed1986

Effects of pimozide on positive and negative incentive contrast with rewarding brain stimulation.

Positive and negative contrast effects with brain-stimulation reward were inferred from significant differences in rate/intensity curves obtained by ascending, random and descending orders of current presentation. The neuroleptic drug pimozide caused a dose-related attenuation of both positive and negative contrast. A dose of 0.1 mg/kg blocked positive contrast obtained by comparing ascending and random rate/intensity curves. Negative contrast and threshold current intensities for brain-stimulation reward at sites in the ventral tegmental area were unaffected by the low dose (0.1 mg/kg) of pimozide. Higher doses of pimozide (0.25, 0.4 mg/kg) blocked both positive and negative contrast effects, and caused a significant elevation in threshold current intensities under the random order condition. Two doses (0.25, 0.4 mg/kg) of pimozide were associated with performance deficits as the response rates at the maximum current intensities were attenuated significantly with each order of current presentation. These demonstrations of both positive and negative contrast are consistent with the theoretical position linking brain-stimulation reward to incentive motivation. Furthermore the effects of the dopamine receptor antagonist pimozide are consistent with a role for dopamine in brain-stimulation reward and also raise the possibility of dopaminergic involvement in incentive contrast phenomena.

Analysis of Variance↗
PubMed1988

Assessment of pimozide's motor and hedonic effects on operant behavior in rats.

The present study examined the effects of the neuroleptic pimozide on several measures of motor capacity and reinforcement efficacy in rats trained to respond according to a multiple random interval (RI) food reinforcement schedule (mean interreinforcement intervals of 10, 20, 40, 80, and 160 sec). Pimozide (0.125, 0.25, 0.5, and 1.0 mg/kg) produced a dose-dependent suppression of response rates for all five RI schedules and a dose-dependent increase in response duration. An independent measure of motor activity in photocell activity chambers also was decreased by pimozide in a dose-dependent manner. Photocell activity was significantly correlated with response duration and with the Matching Equation parameter k. Thus, all three measures of motor performance revealed similar decreases in motor capacity at the high dose of pimozide. Reinforcement efficacy also was reduced by the 1.0 mg/kg dose of pimozide as indicated by an increase in the Matching Equation parameter Re. The parameters k and Re were not significantly correlated, suggesting that these two Matching Equation parameters do provide independent measures of motor capacity and reinforcement efficacy, respectively. The present results demonstrate the importance of obtaining measures other than simple response rates in order to assess drug effects on operant behavior.

Analysis of Variance↗
PubMed1988

Main effects of current and pimozide on prepared and learned self-stimulation behaviors are on performance not reward.

This work examined four independent variables which influence behavior of self-stimulating rats: site of electrode placement (cingulate cortex versus lateral hypothalamus), type of operant response (lever press versus nose poke), current intensity (50, 100, 150 microA) and pimozide dosage (0.125, 0.250, 0.500 mg/kg). The dependent measures were: total responding, alternation between two identical manipulanda and mean duration per response. Naive rats made more nose pokes than lever presses, suggesting nose pokes are more "prepared." The cingulate cortex was insensitive to current and pimozide manipulations in contrast with hypothalamic sensitivity, tentatively suggesting a cingulate role in release of prepared behaviors, hypothalamic in plasticity of learned ones. Lever pressing, more prevalent with lateral hypothalamic stimulation, was more affected by current and pimozide manipulations than nose poking. More prepared nose pokes might thus be less susceptible to brain stimulation reward manipulations. Intensifying current produced more but shorter responses, increasing pimozide dosage produced fewer and nonsignificantly longer ones, suggesting a primary effect on motor performance not reward. Decrements in performance over nondrug days were tentatively attributed to long-lasting effects of pimozide.

Animals↗
PubMed2000

Acute and subchronic effects of pimozide on isolation-induced aggression in male mice.

The aim of this study was to examine the effects of pimozide (0.25-1.25 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic "standard opponents" 90 min after pimozide injections, and the encounters were videotaped and evaluated using an ethologically based analysis. 3. After acute treatment pimozide did not affect significantly aggression and immobility. However, mice treated subchronically with pimozide (0.75 and 1.25 mg/kg) showed a significant reduction in offensive behaviors (threat and attack) and an increase of immobility (1.25 mg/kg). The antiaggressive and motor actions of pimozide were more marked after subchronic treatment than after acute treatment. It might reflect an accumulation of the drug over time, an effect also described with other neuroleptics such as amisulpride.

Aggression↗
PubMed1992

Influence of pimozide on a TRH induced TSH secretion in the rat during food deprivation.

Adult Wistar rats food deprived for 3 days had lower basal levels of TSH compared to normal fed animals. An increase of these lower levels to normal values was obtained following a prolonged (injections during 3 consecutive days) or acute treatment (single injection) with pimozide (1 mg/injection). Blood samples obtained after the last or an only injection of pimozide contained profound increased prolactin levels. Prolactin increase was more than 100-fold in fed and more than 30-fold in starved rats following prolonged pimozide treatment and more than 25-fold and 10-fold following a single injection of pimozide. An injection of 250 ng of TRH increased plasma concentrations of TSH in all groups, but this increase was more pronounced in fasted rats injected with pimozide during 3 consecutive days. It is concluded that fasting results in a dopaminergic inhibition of the sensitivity of the thyrotrophs to a TRH challenge.

Animals↗
PubMed1982

Pimozide versus Haloperidol in acute schizophrenia. A double blind controlled study.

Thirty acutely hospitalized schizophrenic patients were treated under double blind condition with either haloperidol (40-60 mg/day) or pimozide (40-60 mg/day) for 30 days. Ten patients in the pimozide and eleven in the haloperidol group showed a very good or good clinical response. There were no definite differences of treatment results as assessed by the Global Clinical Impression. Both groups showed a statistically significant decrease of the global scores of the Brief Psychiatric Rating Scale (p less than 0.01). There was a significant decrease of affective bluntedness and anergia in the pimozide but not in the haloperidol group. Extrapyramidal side effects were more pronounced in patients on pimozide who therefore needed more anticholinergic drugs. There was no consistent correlation between drug serum levels and global scores or single factors of the BPRS in either treatment group. It is concluded that pimozide in dose ranges from 40-60 mg has powerful antipsychotic properties indistinguishable from those of haloperidol but exerts stronger extrapyramidal side effects.

Acute Disease↗