Extrapyramidal side effects of clozapine and haloperidol

Neuroleptic-induced extrapyramidal side effects (EPS) were evaluated in 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol followed in a drug monitoring program. Side effects were measured by the Columbia University Rating Scale, the Simpson Dyskinesia Scale and the Hillside Akathisia Scale. The cumulative incidence rate for tremor was found to be 24.4% in the clozapine group and 39.3% in the haloperidol group. This did not amount to a statistically significant group difference. Bradykinesia was observed in 21.8% of the patients treated with clozapine and in 47.7% of the patients of haloperidol (P=0.011). In the clozapine group the akathisia incidence rate was 5.6%, whereas haloperidol patients showed a higher rate of 31.7% (P=0.005). Our results show higher incidence rates of tremor and bradykinesia during clozapine treatment than previous studies. We conclude that clozapine is not entirely free of EPS, but they are usually less severe and of a different quality than side effects induced by typical antipsychotics.     

Antagonism of apomorphine-induced stereotypy and emesis in dogs by thioridazine,haloperidol, and pimozide

Apomorphine was administered to dogs 1, 3 and 20 h after pretreatment with thioridazine, haloperidol or pimozide. The dogs were observed for emesis, stereotypy and side effects of the neuroleptics. All three neuroleptics effectively blocked emesis and stereotypy; haloperidol in doses as low as 0.0125 mg/kg for stereotypy and 0.050 mg/kg for emesis; pimozide, 0.025 mg/kg for stereotypy, and 0.00625 mg/kg for emesis; and thioridazine, 4.0 mg/kg for both effects.Haloperidol 0.050 mg/kg blocked emesis and stereotypy at 1 h, but the same dose of pimozide blocked only emesis at this time. Threshold doses (0.0125 mg/kg) of haloperidol blocked stereotypy but not emesis, whereas the same dose of pimozide blocked emesis but not stereotypy. A marked tremor and a gnawing syndrome were seen with haloperidol 0.050 mg/kg, but did not appear with pimozide until higher doses were administered; these side effects were not observed with thioridazine.The findings support a dopaminergic mechanism for apomorphine induced stereotypy in dogs. Differences in onset of pimozide and haloperidol suggest different permeabilities of the drugs through the blood brain barrier, as well as differences in accessibility of the chemoreceptor trigger zone and corpus striatum to circulating drugs. The different effects of threshold doses of pimozide and haloperidol may be explained by postulating the existence of two dopamine receptors.Supported by USPHS Grant MH 12383.This project was part of the fourth year medical student elective program.     

Modulation of reward and aversion processes in the rat diencephalon by neuroleptics: Differential effects of clozapine and haloperidol

The effects of clozapine and haloperidol on self-stimulation in rats were investigated in a shuttle-box that provides concurrent rate-independent indexes of the rewarding and aversive components of intracranial stimulation. The use of two concurrent measures of performance permits the differentiation of specific reward modulation effects from the variety of nonspecific performance decrements that these drugs may produce. Clozapine produced a dose-dependent reduction in reward that could be clearly dissociated from its nonspecific effects. In contrast, the apparent reduction in reward produced by haloperidol could not be dissociated from a nonspecific performance decrement. Consequently, the attenuation of self-stimulation produced by haloperidol does not indicate a direct role for dopamine in modulating reward. It is suggested that the attenuation of reward produced by neuroleptics reflects a reduction in noradrenergic transmission, whereas their nonspecific effects reflect their blockade of dopamine receptors.     

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT₂ receptor blockade.     

Apomorphine-induced disruption of prepulse inhibition that can be normalised by systemic haloperidol is insensitive to clozapine pretreatment

Rationale Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap.Objective and results We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, SC) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1–3 mg/kg, IP, or 3–30 mg/kg, PO), whereas the typical antipsychotic haloperidol (1 mg/kg,IP) completely normalised PPI performance.Conclusions Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.     

Differential sensitivity to amphetamine following long-term treatment with clozapine or haloperidol

When rats were pretreated for 8 consecutive days with 2.0 mg/kg haloperidol, injection of 2.5 or 5.0 mg/kg d-amphetamine 2 or 6 days later resulted in a larger increase in oral behaviors and a more prolonged period of focused stereotypy than in saline-pretreated controls. This increased sensitivity to amphetamine is consistent with the effects of a chronic haloperidol-induced increase in dopamine receptor sensitivity. In contrast, long-term treatment with either d-amphetamine or clozapine produced complex changes in the multiphasic behavioral response to amphetamine, which cannot be explained solely by a shift in the sensitivity of dopamine receptors.     

Subchronic effects of clozapine and haloperidol on rats’ forelimb force and duration during a press-while-licking task

 In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug’s suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine’s marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine’s effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs. Received: 27 June 1996 / Final version: 12 November 1996     

Differential effects of iloperidone,clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm

Rationale Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. Iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available.Objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol.Methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0–64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured.Results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance.Conclusion In accordance with their different pharmacological profiles, the three NLs iloperidone, clozapine, and haloperidol have different effects in this preclinical cognitive task. These results might provide important information for the development of NLs with beneficial effects on cognition.     

The effects of clozapine on shuttle-box avoidance responding in rats: comparisons with haloperidol and chlordiazepoxide

Previous studies have shown that clozapine produces effects different from those of other antipsychotic drugs on positively reinforced responding but may give rise to similar disruptions of avoidance behavior. To investigate the actions of clozapine on avoidance responding in more detail the effects of this drug were compared with those of haloperidol and chlordiazepoxide in rats trained to avoid shock in a shuttle-box. Acute administration of all three drugs reduced avoidance responses and increased escape failures although clozapine produced this latter effect only at a high dose. With repeated administration of each drug over 4 days tolerance developed rapidly to the effect of clozapine, the effect of haloperidol increased and there was no systematic change in the action of chlordiazepoxide. Disrupted avoidance responding after acute administration of clozapine does not reflect the clinical antipsychotic action of this drug.     

Relative effectiveness of pimozide,haloperidol and trifluoperazine on self-stimulation rate-intensity functions

Rats were trained to lever press for 60 Hz sine wave stimulation of the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. Rate intensity functions were determined by stepping down the current intensity by 0.05 log₁₀ units every five min. Haloperidol shifted the function approximately one step to the right at 0.08 mg/kg, with lower doses producing no effect. Pimozide shifted the curve in a dose-dependent manner over the range of 0.06 to 0.24 mg/kg; 0.12 mg/kg produced an approximate one-step shift. Trifluoperazine also produced dose related shifts to the right over the range of 0.08 to 0.32 mg/kg; this agent, unlike the others, appeared to shift the curve down as well as to the right. Less than a one-step shift was produced by 0.08 mg/kg; more than a one-step shift was produced by 0.16 mg/kg. On a molar basis, the order of potency for displacing the curves to the right was haloperidol, pimozide and trifluoperazine. While this order of potency is not predicted from simple in vitro binding affinities for the D₂ receptor, this may be due to differences in the penetration of these agents to central D₂ receptors in vivo.     

Effects of clozapine,olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

Rationale. Antipsychotic drugs, particularly the newer atypical compounds, have been associated with rapid weight gain in a clinical setting. However, there are few reported animal models producing reliable hyperphagia correlating with the human weight gain liability of these drugs. Objective. To compare the effects of the classic neuroleptic haloperidol with the atypical antipsychotics clozapine and olanzapine on the microstructure of ingestive behaviour in rats. Methods. Male hooded Lister rats drank a palatable high-calorie fat emulsion (10% Intralipid) during 30-min test sessions and microstructural analyses were made following administration of each drug over a range of doses. Results. Clozapine (0.3 mg/kg) and olanzapine (0.1, 0.3, 1 mg/kg) significantly increased intake, whilst haloperidol (0.05, 0.1, 0.2 mg/kg) significantly decreased drinking. No significant changes in the latency to the first lick were observed following any of the drugs tested. Median interlick intervals showed small, dose-related increases after clozapine (3.0 mg/kg), olanzapine (0.3, 1.0 mg/kg) and haloperidol (0.1, 0.2 mg/kg). Olanzapine (1.0 mg/kg) significantly elevated the number of clusters of licking (bouts of licking separated by pauses greater than 500 ms), whilst clozapine and haloperidol did not. Mean cluster size (licks per cluster) was not affected by clozapine or olanzapine, but haloperidol (0.025, 0.05, 0.1, 0.2 mg/kg) produced marked, significant decreases in cluster size. Conclusions. Clozapine and olanzapine increased fat intake whereas haloperidol did not, and this resembles the greater weight gain liability of atypical antipsychotics in humans. A delay or reduction of the post-ingestive satiety signal combined with preserved palatability appears to be the mechanism responsible for fat hyperphagia in rats treated with clozapine and olanzapine. Conversely, haloperidol leaves satiety unaffected but reduces the palatability of the fat emulsion resulting in reduced intake. Electronic Publication     

Effects of clozapine, chlorpromazine and haloperidol on schedule-controlled behavior

The effects of clozapine, chlorpromazine, and haloperidol were determined in mice and pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 sec schedule of food presentation. In both species, low doses were without effect and moderate to high doses of all three antipsychotics decreased responding. In contrast to other behavioral tests used to predict antipsychotic activity, clozapine was equipotent or more potent than chlorpromazine in decreasing responding under the multiple fixed-ratio 30, fixed-interval 600 sec schedule. The order of potency observed in the mouse was: haloperidol greater than chlorpromazine greater than or equal to clozapine. The order of potency in the pigeon was: haloperidol greater than clozapine greater than chlorpromazine. In mice and pigeons, the rate of responding under the fixed-ratio component was decreased at lower than, or the same doses of clozapine as that required to decrease fixed-interval responding. However, in both species, chlorpromazine and haloperidol decreased fixed-interval responding at lower doses or the same dose as that required to decrease fixed-ratio responding.     

Unlike haloperidol,clozapine slows and dampens rats' forelimb force oscillations and decreases force output in a press-while-licking behavioral task

In order to detect putative differences in the behavioral effects of clozapine and haloperidol, rats were trained to use a single forelimb to exert continuous pressure on a force-sensing operandum. Behavior was maintained by presenting a water-filled dipper for consumption only as long as the force remained above a specified level (the water fountain task). Effects of clozapine (2.0, 4.0, 8.0 mg/kg) and haloperidol (0.02, 0.04, 0.08, 0.12 mg/kg) on the forelimb force oscillations manifested during the operandum pressing episodes were analyzed with power spectral analysis and other quantitative methods. All rats exhibited force oscillations with a fundamental frequency near 7 Hz. Clozapine shifted the frequency to lower values (i.e., oscillation slowing), while haloperidol shifted oscillations to slightly higher frequencies. Moreover, clozapine reduced power in the region of the spectrum above 5 Hz. In contrast, haloperidol tended to increase power in these regions. Time domain analyses of the force-time waveforms indicated that haloperidol increased force emission during the hold phase of the forelimb response, and clozapine decreased this measure. The results are congruent with the high extrapyramidal side effects of haloperidol and the lack of such effects of clozapine in the clinic. In addition, clozapine may have antitremor effects in rats as it does in humans.     

Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: Studies with chronic clozapine and haloperidol

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and cholien acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced ³H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tuberele) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on ³H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.     

The effects of kainic acid lesions on locomotor responses to haloperidol and clozapine

 Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg SC) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg SC) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine. Received: 1 April 1997/Final version: 6 August 1997     

Comparison of the effects of clozapine, haloperidol, chlorpromazine and d-amphetamine on performance on a time-constrained progressive ratio schedule and on locomotor behaviour in the rat

Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on "reinforcer efficacy". It has been proposed that the effects of neuroleptic drugs on operant behaviour are mediated by a reduction of "reinforcer efficacy". We examined the effects of two "conventional" neuroleptics (haloperidol and chlorpromazine) and an "atypical" neuroleptic (clozapine) on progressive ratio schedule performance; d-amphetamine was used as a comparison compound. In experiment 1, rats responded for a sucrose reinforcer on a time-constrained progressive ratio schedule (75-min sessions). After 66 preliminary training sessions, the rats received single doses (IP) of haloperidol (0.05, 0.1 mg kg(-1)). chlorpromazine (2, 4 mg kg(-1)), clozapine (0.5, 1, 2, 4, 8 mg kg(-1)), and d-amphetamine (0.2, 0.4, 0.8 mg kg(-1)), and the corresponding vehicle solutions. The highest ratio completed was reduced by haloperidol and chlorpromazine, and increased by clozapine. All three neuroleptics reduced the peak response rate, at least at the highest doses administered. Response rates on the lower and intermediate ratios could be described by a three-parameter equation proposed to account for fixed ratio schedule performance. Haloperidol reduced, and clozapine dose-dependently increased the "motivational" parameter (a); d-amphetamine reduced it at low doses and increased it at high doses. The three neuroleptics increased the "response time" parameter (delta). Un-reinforced locomotor behaviour, measured in experiment 2, was not significantly altered by haloperidol, chlorpromazine or clozapine, but was increased by d-amphetamine. These results are consistent with a reduction of reinforcer efficacy produced by haloperidol and an increase produced by clozapine; clozapine's effect is unlikely to reflect a general increase in locomotion. All three neuroleptics induced some degree of motor debilitation. The quantitative analysis of progressive ratio schedule performance may provide a useful adjunct to existing methods for separating effects of drugs on motivational and motor processes.     

Effects of the antipsychotics haloperidol,clozapine, and aripiprazole on the dendritic spine

Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist (e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole (1?µM or 10?µM) and clozapine (1?µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3 beta Ser9. On the other hand, haloperidol (1?µM or 10?µM) or an inappropriate concentration of clozapine (10?µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Effects of chronic amphetamine or reserpine on self-stimulation responding: Animal model of depression?

The acute effects of 5 neuroleptic drugs were tested in rats implanted with stimulating electrodes in the medial forebrain bundle and trained in a brain selfstimulation threshold procedure. Haloperidol (0.01–0.10 mg/kg) and loxapine (0.03–0.56 mg/kg) produced increases in reinforcement thresholds accompanied by reductions in response rates. Chlorpromazine (0.10–3.0 mg/kg) did not significantly alter reinforcement thresholds, but did produce dose-dependent reductions in response rates. Pimozide (0.1–1.75 mg/kg) was similar to chlorpromazine and significantly increased the reinforcement threshold only at the highest dose, although a graded decrease in response rates occurred over a wide dose-range. Clozapine (0.1–1.75 mg/kg) increased reinforcement thresholds without producing any significant changes in response rates, but when 3.0 mg/kg was administered, a marked disruption of behavior occurred. The results suggested that a distinction can be made between the effects of neuroleptics on motor behavior and on central reinforcement thresholds, and this may help in the interpretation of the relation between the chemical and clinical potency of antipsychotic drugs.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.