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PubMed1984

Haloperidol inhibition of monoamine oxidase in vivo and in vitro.

Haloperidol was found to inhibit monoamine oxidase (MAO) activity in sonicated platelets by 50% (IC50) at a concentration of 10(-4) M. Preincubation of the sonicated platelets with haloperidol before the assay did not shift the dose-response curve. When cultured human skin fibroblast MAO was assayed along with haloperidol, MAO activity was only slightly affected (estimated IC50 = 3 X 10(-2) M), even with 1 hr of preincubation. When fibroblasts were cultured with medium containing haloperidol, however, the haloperidol IC50 for MAO activity was 3 X 10(-7) M after 3 days, 2 X 10(-8) M after 7 days, and 3 X 10(-9) M after 14 days. We conclude that haloperidol alters MAO enzyme activity acutely in vitro and that the inhibition increases at lower concentrations with chronic treatment in vivo.

Blood Platelets↗

PubMed1981

3H and 125I radioimmunoassays of haloperidol compared with fluoroimmunoassay involving antibody coupled to magnetizable solid phase.

Radioimmunoassays for haloperidol are described, involving use of tritium- or 125I-labeled drug or tritium-labeled spiroperidol, and a rabbit antiserum to a drug/bovine serum albumin conjugate. The 125I-labeled drug was prepared by the Chloramine T iodination technique. A fluoroimmunoassay for haloperidol is also described in which the antiserum is coupled to magnetizable solid-phase medium, and fluorescein-labeled haloperidol is used. The assays have acceptable accuracy, precision, and reproducibility, and are specific for haloperidol and similar butyrophenones, with no significant interference from known metabolites and other drugs. Only the radioimmunoassays have sufficient sensitivity to cover the whole range of haloperidol concentrations in serum. The fluoroimmunoassay can be used to monitor high concentrations of haloperidol in 150-microL samples or the complete concentration range of 1-mL serum samples that are extracted and concentrated before assay.

Antibodies↗

PubMed1983

Changes in sensitivity of release modulating dopamine autoreceptors after chronic treatment with haloperidol.

The release of recently taken up [3H]dopamine ([3H]DA) elicited by electrical stimulation (3 Hz, 2 min, 16 mA) from slices of the rabbit caudate nucleus is inhibited by apomorphine (0.01-0.1 microM) in a concentration-dependent manner. This action is mediated through the activation of presynaptic inhibitory DA autoreceptors. The inhibition of [3H]DA release by apomorphine (0.1 microM) was antagonized 2 hr, but not 24 hr after the single administration of haloperidol (1 mg/kg s.c.). After 2 days of withdrawal after 28 days of chronic treatment with haloperidol (1 mg/kg s.c.) once daily, apomorphine (0.01-0.1 microM) was more effective in inhibiting [3H]DA release elicited by electrical stimulation when compared with rabbits injected chronically with either the vehicle for haloperidol or with saline. In superfused slices of the rabbit caudate nucleus, exposure to S-sulpiride (0.1 and 1 microM) increased in a concentration-dependent manner the release of [3H] DA elicited by electrical stimulation. After 28 days of chronic treatment with haloperidol, the facilitation of [3H]DA release by S-sulpiride was significantly reduced when compared with the controls. The inhibition of central noradrenergic transmission by DA receptor agonists was studied in hypothalamic slices prelabeled with [3H]norepinephrine ([3H-NE]). Apomorphine (0.01-1 microM) inhibited the electrically evoked (5 Hz, 2 min, 26 mA) release of [3H]NE from hypothalamic slices of untreated rabbits. The sensitivity to the inhibitory effect of apomorphine on [3H]NE overflow remained unaffected after 2 days of withdrawal following 28 days of chronic treatment with haloperidol. In summary, our results indicate that chronic haloperidol administration induces changes in sensitivity of the DA autoreceptors regulating dopaminergic neurotransmission but does not affect the sensitivity of DA receptors modulating NE release in the central nervous system. These results suggest that the DA autoreceptors that regulate dopaminergic neurotransmission may play a physiological role in the modulation of transmitter release and consequently are susceptible to the development of changes in sensitivity after chronic receptor blockade. The possible implication of changes in sensitivity of the DA autoreceptor during the treatment of schizophrenia with neuroleptics is discussed.

Animals↗

PubMed1982

[Use of haloperidol in high doses in schizophrenia. Clinical, biochemical and pharmacokinetic study].

The effect of high doses of haloperidol on the clinical status, plasma neuroleptic and prolactin concentrations as well as on CSF HVA and GABA levels was investigated in 3 paranoid schizophrenic patients over a 6 weeks period. When the study was initiated patients had been on haloperidol (10 mg a day) for 4-10 weeks. Oral doses were increased at weekly intervals from 10 (day 0) to 100 (day 7) and 200 (days 14 to 28) mg a day and then reduced to 100 (day 35) and 10 (day 42) mg/day. A linear relationship was observed between plasmatic levels and daily doses of haloperidol. In neither patient, the increase in haloperidol dosage affected paranoid symptoms. Neurological side effects were slightly increased in 2 cases and moderately reduced in one case. Prolactin plasma levels, already high at the onset of the study rose when increasing the dose to 100 mg a day but did not increase further despite increment in the haloperidol dosage. CSF levels of HVA and GABA rose from day 0 to day 7 but were back to the initial values on day 28 in 2 patients and were decreased from day 0 to day 28 in one patient. For the 3 patients a close correlation was observed between changes in CSF HVA and GABA levels. It is concluded that high doses of haloperidol, although causing biochemical changes compatible with the occurrence of dopamine target cell supersensitivity, do not lead to any clinical improvement in the 3 studied schizophrenic patients.

Adult↗

PubMed1981

A new radioimmunoassay for haloperidol: direct measurement of serum and striatal concentrations.

A sensitive and specific radioimmunoassay for haloperidol has been developed. Antibodies were elicited in rabbits immunized with haloperidol hemisuccinate coupled to bovine serum albumin. Optimum sensitivity was obtained with a 1:4000 dilution of the antisera, permitting the detection of as little as 2.6 ng/ml of haloperidol. Major metabolites of haloperidol did not cross-react in the assay. The method does not require an extraction procedure and can be performed using as little as a 5-microliter sample. Haloperidol levels in rat serum and striatum were determined with this method, after the i.v. administration of different dosages of the drug. The distribution and elimination of haloperidol was linear over the dose range to have an elimination half-life of approximately 2.6 hr at all three dosage levels.

Animals↗

PubMed1980

Effect of haloperidol on ventilatory responses to dopamine in man.

Intravenous administration of dopamine suppresses ventilation in man through an effect on the chemoreceptor reflex. The primary goal of this study was to determine if a dopaminergic blocking agent, haloperidol, alters the ventilatory response to dopamine in man. Dopamine was infused intravenously in 10 normal men during hypoxia, before and after 2.5 mg of haloperidol intramuscularly, to block dopaminergic receptors. Before haloperidol, dopamine (5 micrograms/kg/min) decreased minute ventilation 1.7 +/- 0.5 liters/min (P less than .05) and increased arterial pCO2 3.5 +/- 0.6 mm Hg (P less than .05). After haloperidol, dopamine did not alter ventilation. The findings suggest that inhibition of the chemoreceptor reflex by dopamine in man is mediated by dopaminergic receptors. A secondary goal of this study was to test the hypothesis that, if dopamine is an inhibitory transmitter in chemoreceptors, blockade of dopaminergic receptors would increase ventilation. Haloperidol did not alter minute ventilation or arterial pCO2 during normoxia or hypoxia. The observation that haloperidol blocks the response to exogenous dopamine, but does not alter ventilation during normoxia or hypoxia, suggests that either endogenous dopamine does not play an important role in determining steady-state chemoreceptor discharge or endogenously released dopamine may have access to receptors that are relatively inaccessibly to exogenous blockers.

Adult↗

PubMed1995

[Inhibitory effect of haloperidol on evoked dopamine release from striatal slices of the rat].

Haloperidol-induced changes in evoked dopamine (DA) release from striatal slices in rats were investigated. The dose-response curves for haloperidol to changes in the evoked DA release were found to be biphasic (small doses increased the release and large doses inhibited), which were shifted to the left by longer periods of superfusion with haloperidol. This rapid tolerance or inhibition of haloperidol-induced increases in evoked DA release was reduced or attenuated by the superfusion with acetylcholine (ACh) antagonists or B-HT920 and was enhanced by ACh agonists. The microinjection of kainic acid into the rat striatum 4 days before the experiment reduced the rapid tolerance or inhibition of the haloperidol-induced increase in evoked DA release. These data indicate that intrinsic ACh neurons in the striatum may play an important role in the induction of the rapid tolerance or inhibition of haloperidol-induced increase in evoked DA release from striatal slices in rats.

Acetylcholine↗

PubMedDate not supplied

The effects of chlorpromazine and haloperidol on second messenger systems related to adrenergic receptors.

The aim of this study was to investigate the binding of chlorpromazine and haloperidol to rat cerebral cortical adrenoceptors and to assess their effect on responsiveness of alpha 1- and beta-adrenoceptors measured by accumulation of second messengers, inositol phosphate and cyclic AMP, after stimulation with noradrenaline and isoproterenol. The effect of neuroleptics on protein kinase C was assessed by carrying out incubations in the absence and presence of the phorbol ester, 12-O-tetradecanoyl-phorbol 13-acetate (TPA). The effects of chronic administration of haloperidol (0.5 mg/kg/d for 14 days) on responses of second messenger systems to noradrenaline and isoproterenol in the presence and absence of TPA were also measured. The results indicate that in vitro chlorpromazine and haloperidol similarly inhibit noradrenaline-induced responses of inositol phosphate and cyclic AMP, but differently affect the potentiation of these responses by protein kinase C: the inhibitory effect of haloperidol, but not that of chlorpromazine was prevented by TPA. Similarly, only chlorpromazine inhibited the cyclic AMP responses to isoproterenol. The differences between the effects of chlorpromazine and haloperidol may be explained by their different affinity to various subtypes of adrenoceptor. In a chronic experiment haloperidol did not induce changes in responsiveness of cortical alpha 1- and beta-adrenoceptors, but inhibited TPA-induced potentiation of cyclic AMP responses.

Animals↗

PubMedDate not supplied

[Pharmaco-clinical correlations during fluoxetine administration in patients with depressive schizophrenia treated with haloperidol decanoate].

The study concerned 7 patients suffering from schizophrenic disorder according to the DSM III R criteria, treated with a stable dose of haloperidol decanoate (Haldol décanoas) added with fluoxetine (Prozac) from 20 mg to 40 mg/day because of major depression. Patients were assessed at baseline and weekly during the first cycle, and then once a month before each haloperidol decanoate injection, using the brief psychiatric rating scale (BPRS), the general clinical impression scale (CGI) and the Montgomery and Asberg depression rating scale (MADRS). Extrapyramidal and anticholinergic side-effects, blood pressure and pulse were noted. Determinations of plasma and red blood cells concentrations of haloperidol and reduced haloperidol, and of fluoxetine and norfluoxetine, were conducted at the same time than clinical evaluations. For all patients, we observed an improvement by the end of the first week, which became significant at the end of the second week, and continued in subsequent weeks (more than 30 per cent). Two weeks after the addition of fluoxetine, a very significant increase in haloperidol concentrations (more than 100 per cent) was noted; fluoxetine seems to have pharmacokinetic interactions with haloperidol, either by inhibiting its hepatic metabolism (inhibition of cytochrome P450 isoenzyme) or/and by displacing it from protein binding sites.

Adult↗

PubMed1996

Inhibition of N-methyl-D-aspartate receptors by haloperidol: developmental and pharmacological characterization in native and recombinant receptors.

The dopaminergic antagonist haloperidol also acts at the psychotomimetic sigma receptor and has been proposed to act at N-methyl-D-aspartate (NMDA) receptors. We have investigated the basis of its action at NMDA receptors using native and recombinant receptors and as a function of brain development. Haloperidol inhibits binding of 125I-(+) MK 801 to NMDA receptors formed from NR 1a/2B with high affinity but has lower affinity at receptors formed from NR 1a/2A. No differences are noted between different NR 1 splice variants transfected with NR 2B. Differences are also seen between neonatal receptors and adult receptors; neonatal receptors are inhibited by haloperidol with an IC50 value that is 50 times lower than that of adult receptors. Other agents acting at the sigma receptor inhibit binding of 125I-(+) MK 801 to NMDA receptors, and are slightly more potent at neonatal receptors. However, the rank order of potency for sigma agents at sigma receptors does not match their rank order of potency at NMDA receptors, and the prototypic sigma ligand ditolylguanidine shows no preference between NR 1a/2A and NR 1a/2B receptors. This suggests that haloperidol exerts its effects on the NMDA receptor at a distinct site from the pharmacologically defined sigma receptor. The effects of haloperidol are also modified by spermidine noncompetitively, which differs from the effects of spermidine on ifenprodil-mediated inhibition of NMDA receptors. This suggests that haloperidol interacts with NMDA receptors at a site distinct from the polyamine or ifenprodil sites.

Animals↗

PubMedDate not supplied

[Risperidone in the treatment of chronic schizophrenia: multicenter study comparative to haloperidol].

OBJECTIVE: This study was designed to compare the efficacy and safety of five different doses of risperidone with a fixed dose of haloperidol in patients with chronic schizophrenia. METHOD: After a 1-week single-blind, placebo washout phase, 99 chronic schizophrenic patients were randomly assigned to double-blind treatment with 1, 4, 8, 12 or 16 mg risperidone or 10 mg haloperidol daily for 8 weeks. Efficacy was assessed throughout the study by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, and Clinical Global Impression (CGI). Safety assessments included the Extrapyramidal Symptom Ratinf Scale (ESRS) UKU Side Effect Rating Scale, vital signs, body weight, ECG and laboratory screening. RESULTS: Risperidone had a bell-shaped dose-response curve, with optimal therapeutic responses occurring at a daily dose of 8 mg. The therapeutic response to haloperidol was similar to that seen with risperidone 16 mg. Risperidone was associated with significantly less extrapyramidal symptoms than haloperidol, as assessed by the ESRS. The effect was mirrored by the requirement for antiparkinson rescue medication. Furthermore, the overall incidence of adverse events was markedly lower with the optimum dose of risperidone than with haloperidol. CONCLUSIONS: Risperidone is at least as effective as haloperidol for the treatment of chronic schizophrenia. Moreover, risperidone is associated with an improved adverse event profile and significantly less extrapyramidal symptoms which will have beneficial implications on patient quality of life and compliance. These results are in agreement with the results from the international multicenter trial.

Adult↗

PubMed1976

[Acute and chronic effects of carpipramine, clozapine, haloperidol and sulpiride on the metabolism of biogenic amines in the rat brain (author's transl)].

In acute and chronic experiments investigations were made concerning the effect of clozapine, haloperidol, sulpiride and carpipramine on MHPG, HVA and 5-HIAA in rat brain and on motor activity of the animals. The activity of the rats treated with clozapine and haloperidol was reduced on the first day. After 10 days of treatment this effected of clozapine was significantly diminished. The MHPG level increased slightly on the first day of treatment with all four drugs. This elevation was maintained after chronic treatment with carpipramine and sulpiride, whereas clozapine and haloperidol decreased the MHPG content. 5-HIAA values did not show significant changes in acute experiments, whereas in chronic ones there was an increase. Haloperidol and clozapine induced a strong increase of HVA which decreased after 11 days in those animals treated with haloperidol. In comparison to haloperidol, after clozapine application the percentage of HVA-increase was higher in the limbic system than in the nigrostriatum.

Animals↗

PubMed1997

Multireceptor interactions of haloperidol on rat cerebral frontal cortex "in vitro".

As several side effects of neuroleptics would be related to their interactions with several neurotransmitter receptors (R) haloperidol action on muscarinic cholinergic (mACh) R on frontal cerebral cortex preparations was analyzed. Here we show that haloperidol was able to inhibit in a concentration dependent manner the binding of specific mAChR radiolabeled antagonist on cerebral cortex membranes. This effect would be related to its interaction on mAChR of the M1 subtype as haloperidol blocked the stimulation of phosphoinositides (PIs) turnover induced by low concentrations of carbachol similarly as the M1 antagonist pirenzepine. However at high carbachol concentrations haloperidol triggered a potentiating stimulation of PIs hydrolysis that was only blocked by the alpha 1 adrenergic antagonist prazosin indicating an alpha 1 agonistic action of haloperidol on these Rs. These multireceptor actions of haloperidol found "in vitro" would strengthen its association with "in vivo" neuroleptic-induced side effects.

Animals↗

PubMed1998

D2 dopamine antisense RNA expression vector, unlike haloperidol, produces long-term inhibition of D2 dopamine-mediated behaviors without causing Up-regulation of D2 dopamine receptors.

Long-term inhibition of D2 dopamine receptors using classic D2 dopamine receptor antagonists such as haloperidol often causes a compensatory up-regulation of the D2 dopamine receptors. We investigated whether the long-term inhibition of D2 dopamine receptors using an eukaryotic expression vector housing a cDNA sequence encoding an antisense RNA directed to the D2 dopamine receptor transcript (D2 antisense vector) would also produce up-regulation of the D2 receptors. Single, bilateral injections of the D2 antisense vector into the corpora striata of mice inhibited the stereotypy induced by acute challenge injections with the D2/D3 dopamine receptor agonist quinpirole but did not inhibit the grooming induced by acute challenge injections with the D1 agonist SKF 38393. Similar treatment with the D2 antisense vector produced a long-term (>1 month) cataleptic response without producing tolerance to challenge injections with haloperidol. By contrast, catalepsy induced by a single injection of haloperidol lasted only approximately 2 days, and tolerance developed to its effects after long-term treatment. Repeated treatment of mice with haloperidol resulted in an inhibition of apomorphine-induced climbing behavior throughout the time of treatment with haloperidol, but the climbing behavior markedly increased to levels significantly higher than that of the control mice immediately after withdrawal from haloperidol treatment. This increased climbing was accompanied by increased levels of D2 dopamine receptors in the striatum. By contrast, single, bilateral intrastriatal injections of the D2 antisense vector significantly inhibited apomorphine-induced climbing for approximately 30 days but failed to increase the climbing behavior or the levels of D2 dopamine receptors in striatum over those of the control values. These results suggest that a single injection of a D2 antisense RNA expression vector into mouse striatum produces specific, long-term inhibition of D2 dopamine receptor behaviors without causing a compensatory increase in the levels or function of D2 dopamine receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1998

Haloperidol-induced potentiation of latent inhibition: interaction with parameters of conditioning.

If a stimulus (e.g. tone or light) is repeatedly pre-exposed without consequences, it subsequently shows retarded conditioning when paired with a reinforcer (e.g. footshock) compared with a non-pre-exposed stimulus. This is latent inhibition (LI). Haloperidol-treated animals show potentiated LI, and it has been suggested that this is due to retarded switching to respond according to the stimulus-reinforcer contingency. Recently, it has been argued that the slowed control of behaviour by the stimulus-reinforcement contingency is due to a haloperidol-induced decrease in the impact, or salience, of the reinforcer, and thus should be antagonized by increasing the impact of reinforcement. Two experiments tested this prediction. In both, LI was assessed using an off-baseline conditioned emotional response procedure in rats licking for water. In Experiment 1, rats were given 10 light pre-exposures and conditioned with two footshocks of either a low (0.5 mA) or a high (1 mA) intensity. In Experiment 2, rats were given 30 pre-exposures and conditioned with either two or five footshocks of 1 mA. In Experiment 1, no-drug controls did not show LI at both shock intensities. Haloperidol (0.1 mg/kg) was ineffective in potentiating LI at low-intensity shock, but produced LI when shock level was increased. In Experiment 2, no-drug controls showed LI with two but not five conditioning trials. Haloperidol was ineffective in potentiating LI with two conditioning trials, but produced LI with five conditioning trials. Although the effect of haloperidol on LI could thus be modified by manipulating shock intensity or the number of conditioning trials, the direction of such modification indicates that the potentiating effect of haloperidol on LI is not in general antagonized by increasing the impact of reinforcement.

Animals↗

PubMed1981

Effects of apomorphine and haloperidol on plasma cortisol levels in conscious dogs.

Cortisol levels were measured in peripheral plasma of conscious dogs after i.v. administration of apomorphine, a dopaminergic agonist, haloperidol, a dopaminergic antagonist, or apomorphine in combination with haloperidol. Apomorphine in a dose of 0.001 and 0.005 mg/kg did not cause any release of cortisol whereas 0.01 and 0.05 mg/kg caused a dose dependent and peakshaped increase of plasma cortisol levels from 20 to 30 and from 20 to 60 ng/ml respectively. Basal levels were reached again within 1 h. Haloperidol (0.1 mg/kg), when given alone, induced a continuous rise of plasma cortisol levels. After 60 min the levels were approximately 80 ng/ml and still tended to rise. If apomorphine (0.01 mg/kg) was given 30 min after the injection of haloperidol (0.5 mg/kg) no further effect of the apomorphine injections was observed. We therefore speculate that apomorphine activates central dopaminergic receptors which cause a release of ACTH from the pituitary into the circulation, which in turn stimulates the release of cortisol from the adrenals. The fact that not only apomorphine but also haloperidol stimulated cortisol release suggests a complex role or dopamine transmission involving different dopaminergic pathways as well as different dopamine receptors. It is also possible that injection of haloperidol induces a stress reaction in the dogs, which causes a release of cortisol from the adrenals.

Animals↗

PubMed1989

Neuroleptics and conditional discrimination tasks: cholinergic mediation of the accuracy- and response rate-altering effects of chlorpromazine and clozapine but not haloperidol.

The effects of the neuroleptic compounds clozapine, chlorpromazine and haloperidol were examined alone and in combination with the muscarinic cholinergic agonist oxotremorine in pigeons responding under a fixed-consecutive-number schedule. Under this procedure, nine or more consecutive responses on one response key followed by a single response on a second response key produced 3sec access to grain. In one component of this schedule (FCN 9-SD), an external discriminative stimulus was presented following the completion of the response requirement on the first response key, whereas no stimulus change was programmed in the other component (FCN 9). When administered alone, clozapine (0.1-5.6mg/kg) and chlorpromazine (3.0-170mg/kg) decreased accuracy (i.e. increased the mean number of response runs per reinforcer) under the FCN 9 at doses that had no effect under the FCN 9-SD. In contrast, haloperidol (0.03-1.7mg/kg) and oxotremorine (0.001-0.1mg/kg) had no effect on accuracy under either variant of the FCN schedule. Under both variants of the FCN schedule, clozapine, chlorpromazine, haloperidol and oxotremorine produced dose-related decreases in rates of responding. When administered in combination, oxotremorine (0.01 and 0.03mg/kg) antagonized the accuracy- and response rate-decreasing effects of both clozapine and chlorpromazine. Although neither haloperidol or oxotremorine decreased accuracy when administered alone, these drugs produced large decreases in accuracy when administered in combination. In most instances, the magnitude of these decreases in accuracy was larger than those obtained following the administration of clozapine or chlorpromazine. The effects of the co-administration of oxotremorine and haloperidol on rate of responding were generally additive. These findings indicate that both the accuracy- and response rate-decreasing effects of clozapine and chlorpromazine are, in part, mediated by their antagonist actions at muscarinic cholinergic receptors. In addition, the finding that the co-administration of haloperidol and oxotremorine decreased accuracy provides support at the behavioral level for an interaction of the dopaminergic and cholinergic systems.

Journal Article↗

PubMed1976

In vivo actions of clozapine and haloperidol on the turnover rate of acetylcholine in rat striatum.

We have measured acetylcholine (ACh) content and turnover rate (TRACh) in striatum and cortex of rats receiving haloperidol and clozapine i.p. Both clozapine (30 mumol/kg) and haloperidol (10 mumol/kg) reverse the decrease in striatal TRACh elicited by apomorphine (11 mumol/kg) while each antipsychotic affects the steady state and the TRACh in striatum differently. Haloperidol fails to change striatal ACh content but increases the TRACh; chozapine (15 and 30 mumol/kg) neither decreases the content of ACh nor changes the TRACh in striatum. Moreover, 60 or 90 mumol/kg of clozapine causes a 40% decrease in ACh content without affecting the TRACh. Clozapine, but not haloperidol, antagonizes the increase in ACh content and the decrease in TRACh elicited by arecoline (64 mumol/kg) and oxotremorine (9 mumol/kg) in striatum. Clozapine resembles trihexylphenidyl (14 mumol/kg) and benztropine (12 mumol/kg) because it decreases the ACh content of striatum without changing the TRACh. Moreover, clozapine and benztropine reverse the increase in striatal TRACh elicited by haloperidol. The increase in striatal TRACh elicited by haloperidol could be of value to explain the extrapyramidal action of this drug. The anticholinergic action of clozapine could explain the absence of extrapyramidal side effects observed with this drug.

Animals↗