Differential effects of haloperidol and clozapine on attention

Haloperidol (0, 0.1, 0.3, or 1.0 mg/kg), the typical butyrophenone neuroleptic, decreased investigation of novel objects by gerbils following systemic injections. When given prior to apomorphine (1 or 3 mg/kg), haloperidol blocked apomorphine-induced disruption of selective attention in a dose-dependent manner. Thus, haloperidol acts like pimozide in this paradigm. In contrast, clozapine (0, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg), the atypical dibenzodiazepine neuroleptic, increased frequency of investigation both soon after injection and 24 h later, suggesting interference with maintenance of attention. When given with apomorphine (1.0 mg/kg), clozapine did not block apomorphine effects on selective attention. The results are related to differential effects of these neuroleptics on other behaviors and to their individual pharmacological profiles.     

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.     

Different behavioral effects of haloperidol,clozapine and thioridazine in a concurrent lever pressing and feeding procedure

Rats were tested using a lever pressing/feeding procedure in which a preferred food (Bioserve pellets) was available by pressing a lever on a fixed ratio 5 schedule, but a less preferred food (lab chow) was also available concurrently in the operant chamber. The effects of repeated (14 day) injections of haloperidol, clozapine and thioridazine were compared. Haloperidol (0.05–0.15 mg/kg) significantly reduced lever pressing and increased chow intake throughout the drug treatment period. Injections of clozapine (2.0–6.0 mg/kg) suppressed lever pressing but failed to produce substantial increases in chow intake. In the haloperidol experiment there was a significant inverse correlation between lever pressing and chow intake, but in the clozapine experiment there was not. Regression analysis indicated that rats treated with the high dose of clozapine showed some tolerance to the suppression of lever pressing. Tests of sedation also were conducted before and after the instrumental behavior sessions. Haloperidol produced little or no sedative effect in the dose range tested. Clozapine produced substantial sedation during the first 10 days of administration, but this effect, like the suppression of lever pressing, showed signs of tolerance. Thioridazine (3.0–9.0 mg/kg) produced some effects that resembled haloperidol, and other effects, including sedation, that resembled clozapine. These studies indicate that haloperidol suppresses lever pressing for food at low doses that do not produce severe motivational or sedative effects that disrupt food intake. In contrast, it appears as though the suppression of lever pressing produced by clozapine stems from a sedative effect that also serves to set limits on chow intake. These results indicate that haloperidol and clozapine suppress lever pressing through different mechanisms.     

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.     

Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.     

Differential effects of acute and subchronic clozapine and haloperidol on phencyclidine-induced decreases in voluntary sucrose consumption in rats

Prior exposure to the psychotomimetic drug phencyclidine (PCP) decreases voluntary sucrose consumption in rats. This may be indicative of reduced reward function, a phenomenon associated with negative schizophrenic symptomatology. Given that atypical antipsychotics have been shown to ameliorate negative symptoms of schizophrenia more effectively than typical neuroleptics, this effect should be reversed by clozapine but not haloperidol. PCP (15 mg/kg) or saline was administered 20 h prior to testing for voluntary sucrose consumption in non-deprived rats. In the acute experiments, rats were treated with clozapine (5 mg/kg), haloperidol (0.2 mg/kg), or vehicle 45 min prior to testing. In the subchronic experiments, rats were treated with clozapine (3 mg/kg, bid), haloperidol (0.5 mg/kg, bid), or vehicle for 10 days prior to PCP administration. Acute clozapine exacerbated the PCP-induced decrease in sucrose consumption without altering water consumption. Acute haloperidol produced an overall decrease in sucrose consumption in both PCP-pretreated and control groups. Subchronic treatment with clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption. The synergistic effect of acute clozapine and PCP may reflect a PCP-induced increase in the reward-reducing properties of CLZ, normally seen only at higher doses. The observation that subchronic clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption supports the hypothesis that this effect of PCP represents a plausible animal model for negative schizophrenic symptomatology.     

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 attenuation of some effects of haloperidol in rats given scopolamine

In a series of pharmacologica tests the ability of 0.6 mg/kg of the anticholinergic scopolamine to decrease the effectiveness of the neuroleptic haloperidol varied widely. Most severely attenuated was production of catalepsy followed in order of decreasing interference by inhibition of amphetamine-induced rotation, inhibition of amphetamine- or apomorphine-induced stereotyped behavior, inhibition of conditioned avoidance responding and lastly attenuation of the haloperidol-induced increase in striatal HVA. By use of such a relatively low dose of scopolamine the behavioral effects of haloperidol were dissociated from effects on dopamine turnover in the striatum. If behavioral tests in animals can be related to the clinical effects of neuroleptic drugs, those effects of haloperidol severely reduced by scopolamine may be related to extrapyramidal effects.     

Tolerance to the behavioral and neurochemical effects of haloperidol and morphine in rats chronically treated with morphine or haloperidol

Summary The acute administration of morphine sulfate (79 moles/kg) or haloperidol (6.65 moles/kg) produced catalepsy and concomitant increase in striatal dopamine turnover in rats. The animals made dependent on morphine by 52 morphine injections (maintenance dose of 1056 moles/kg/day, given in four daily doses) and then tested during 3 days of withdrawal from morphine, showed tolerance to the cataleptic and the neurochemical effects of morphine as well as those of haloperidol. That tolerance was not seen after 14 days of withdrawal from morphine. The animals chronically treated with haloperidol for 12 days (maintenance dose of 53.2 moles/kg/day, given in two daily doses) and then tested 72 h after last haloperidol injection, did not show tolerance to the cataleptic or the neurochemical effect of haloperidol or morphine. These results suggest that dopaminergic systems underlying motor coordination and regulation of the neurotransmitter synthesis are among those susceptible to narcotic action and to the process of tolerance development during aarcotic dependence.     

Differential effects of clozapine and haloperidol on interval timing in the supraseconds range

The effects of clozapine (0.6, 1.2, and 2.4 mg/kg) and haloperidol (0.03, 0.06, and 0.12 mg/kg) on the timing of 10, 30, and 90-s intervals were characterized in rats. Each drug's effect on timing behavior was assessed following intraperitoneal injections using a variant of the peak-interval procedure. Although haloperidol proportionately shifted peak times rightward in a manner consistent with a decrease in clock speed, clozapine exerted the opposite effect and proportionately shifted peak times leftward in a manner consistent with an increase in clock speed. These results support the proposal that typical antipsychotic drugs such as haloperidol and atypical antipsychotic drugs such as clozapine exert differential effects on dopaminergic, serotonergic, and glutamatergic systems within the cortex and striatum, two brain regions shown to be crucial for interval timing.     

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.     

Effect of prenatal haloperidol exposure on behavioral alterations in rats

Pregnant Charles-Foster rats were exposed to haloperidol (HAL), a neuroleptic drug that binds to and blocks dopamine (DA) receptor subtypes at a dose of 2.5 mg/kg body weight (intraperitoneally) from Gestation Day (GD) 12 to 20. The animals from both treated as well as vehicle control groups were allowed to deliver on GD 21. The offspring culled at birth on the basis of sex and weight were subjected to behavioral tests at the age of 8 weeks. The HAL-treated rat offspring showed a significant increase in anxiogenic behavior on the open field, elevated plus-maze and elevated zero-maze tests when compared with the vehicle-treated (control) rat offspring of the same age group. These findings suggest that prenatal exposure to HAL during a critical period of brain development leaves a lasting imprint on the brain, resulting in abnormal anxiety states, possibly through dopaminergic neurotransmission mechanisms.     

Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats.

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45- or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.     

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

The antipsychotic drugs haloperidol and clozapine have the common action of increasing dopamine metabolism in the striatum (nucleus accumbens, caudate-putamen) of the rat. Intracerebroventricular administration of kainic acid (KA) produces neuronal loss in limbic-cortical brain regions which project directly or indirectly to the striatum. In the present study, dopamine metabolism in subregions of the striatum was examined in rats with KA lesions after acute and chronic haloperidol or clozapine administration. The main findings was that the elevating effect of acute haloperidol treatment on the dopamine metabolite, DOPAC, was blocked in the nucleus accumbens shell and diminished in medial and laterodorsal caudate-putamen of the KA-lesioned rats. In addition, the elevating effects of both acute and chronic haloperidol treatment on dopamine turnover were attenuated in the laterodorsal caudate-putamen of KA-lesioned rats. The levels of dopamine, DOPAC, and HVA after chronic clozapine treatment were greater in KA-lesioned than control rats. These results indicate that dopaminergic responses to haloperidol may be diminished by limbic-cortical neuropathology, while such pathology does not significantly alter dopaminergic responses to clozapine. Received: 30 September 1996 / Final version: 6 March 1997     

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     

Differential tolerance to the behavioral effects of chronic pimozide and clozapine on multiple random interval responding in rats

The behavioral effects of 10 days of chronic administration of the typical neuroleptic, pimozide, and the atypical neuroleptic, clozapine, were compared on a schedule of multiple random interval responding for food reinforcement and on photocell activity in rats. The low doses of both neuroleptics (0.125mg/kg pimozide, 1.25mg/kg clozapine) had little effect on any of the dependent variables measured. The high doses (1.0mg/kg pimozide, 10.0mg/kg clozapine) significantly disrupted response rates and reinforcement rates and significantly increased response duration when the drugs were first administered. Chronic administration, however, resulted in different profiles for the two drugs. While tolerance developed to the disruptive effects of clozapine, tolerance did not develop to the disruptive effects of pimozide and, on some dependent measures, an increased sensitivity developed. No tolerance developed to the disruptive effects of either drug on photocell activity. The effects of the drugs depended on the reinforcement density of the operant schedule.     

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.     

Effects of clozapine, thioridazine, risperidone and haloperidol on behavioral tests related to extrapyramidal motor function

 Evidence indicates that the antipsychotic drug clozapine has a low propensity for the induction of extrapyramidal motor symptoms, and also that clozapine has therapeutic effects in patients with idiopathic Parkinson’s disease. Because tacrine-induced tremulous jaw movements in rats have been suggested as a possible model of extrapyramidal motor dysfunctions, including parkinsonian tremor, the present work was undertaken to investigate the effects of clozapine on tremulous jaw movements. Clozapine decreased tacrine-induced tremulous jaw movements in a dose-related manner, with an ED₅₀ of approximately 3.3 mg/kg. In order to determine the relative potency of this effect compared to other behavioral effects of clozapine, suppression of lever pressing was also studied. Clozapine reduced lever pressing in a dose-related manner, with an ED₅₀ of approximately 5.4 mg/kg. This indicates that clozapine suppressed jaw movements at or below the doses required for suppression of lever pressing. In contrast, the typical antipsychotic drug haloperidol failed to suppress tacrine-induced tremulous jaw movements in doses up to 1.0 mg/kg, which is about 11-fold higher than the ED₅₀ for suppression of lever pressing with that drug. Thioridazine and risperidone also suppressed tremulous jaw movements in roughly the same dose range at which lever pressing was reduced. It is possible that the suppression of tacrine-induced tremulous jaw movements by clozapine in rats is related to the unique behavioral and motor effects of clozapine. The ratio of potencies of these effects (i.e., suppression of tremulous jaw movements versus suppression of lever pressing) could be used as a behavioral procedure for assessing clozapine-like activity in novel compounds. Received: 8 October 1996 / Final version: 3 February 1997     

Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.