A clozapine-like effect of cyproheptadine on progressive ratio schedule performance

The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT?) and histamine (H?) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive ratio schedules, as revealed by Killeen's (1994) mathematical model of schedule controlled behaviour. These drugs increase the values of a parameter that expresses the 'incentive value' of the reinforcer (a) and a parameter that is inversely related to the 'motor capacity' of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ?-tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5?mg?kg?1) and clozapine (3.75, 7.5?mg?kg?1) increased a and δ. Haloperidol (0.05, 0.1?mg?kg?1) reduced a and increased δ. Chlordiazepoxide (3, 10?mg?kg?1) increased a but reduced δ. THC (1, 3?mg?kg?1) had no effect. Interpretation based on Killeen's (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H? receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H? and 5-HT? receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide's effect on a is consistent with its food intake-enhancing effect.     

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.     

Effect of antipsychotics on succinate dehydrogenase and cytochrome oxidase activities in rat brain

Typical and atypical antipsychotic drugs have been shown to have different clinical, biochemical, and behavioral profiles. It is well described that impairment of metabolism, especially in the mitochondria, leads to oxidative stress and neuronal death and has been implicated in the pathogenesis of a number of diseases in the brain. Considering that some effects of chronic use of antipsychotic drugs are still not well known and that succinate dehydrogenase (SDH) and cytochrome oxidase (COX) are crucial enzymes of mitochondria, in this work, we evaluated the activities of these enzymes in rat brain after haloperidol, clozapine, olanzapine, or aripiprazole chronic administration. Adult male Wistar rats received daily injections of haloperidol (1.5 mg/kg), clozapine (25 mg/kg), olanzapine (2.5, 5, or 10 mg/kg), or aripiprazole (2, 10 or 20 mg/kg) for 28 days. We verified that COX was not altered by any drug tested. Moreover, our results demonstrated that the atypical antipsychotic olanzapine inhibited SDH in the cerebellum and aripiprazole increased the enzyme in the prefrontal cortex. We also observed that haloperidol inhibited SDH in the striatum and hippocampus, whereas clozapine inhibited the enzyme only in the striatum. These results showed that antipsychotic drugs altered SDH activity but not COX. In this context, haloperidol, olanzapine, and clozapine may impair energy metabolism in some brain areas.     

Tail suspension test does not detect antidepressant-like properties of atypical antipsychotics

The purpose of this study was to investigate the potency of atypical antipsychotics (clozapine, olanzapine, amisulpride, quetiapine, aripiprazole, risperidone) to reduce immobility time and to increase the fighting power, and the number of fights in an automated version of the tail suspension test in C57BL/6J mice. Antidepressant drugs, citalopram and imipramine were tested for comparison. Olanzapine (0.125-5 mg/kg), amisulpride (0.5-2 mg/kg), quetiapine (0.25-2 mg/kg), aripiprazole (0.25-1 mg/kg), and risperidone (0.005-0.05 mg/kg) did not produce any antidepressant-like effect. Only clozapine (0.156-2.5 mg/kg), administered at a dose of 0.312 mg/kg, significantly increased the number of fight episodes. As expected, citalopram (20-40 mg/kg) and imipramine (10-30 mg/kg) dose dependently produced antidepressant-like activity in the same procedure. The effect of antipsychotics on spontaneous locomotor activity and MK-801-induced or d-amphetamine-induced hyperactivity, were also tested in CD-1 mice to confirm the active doses of these drugs in tests commonly used to predict antipsychotic-like activity. Careful screening of potential antipsychotics for their antidepressant effects is considered to be an important part of modern drug development. Our data suggest that the tail suspension test in mice may be relatively insensitive to antidepressant-like activity of atypical antipsychotic drugs with antidepressant properties confirmed by clinical trials.     

Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine can evoke psychotic symptoms in normal individuals and schizophrenic patients. Here, we have examined the effects of PCP (5 mg/kg) and ketamine (25 mg/kg) on the efflux of serotonin (5-HT) in the medial prefrontal cortex (mPFC) and their possible blockade by the antipsychotics, clozapine, olanzapine and haloperidol, as well as ritanserin (5-HT2A/2C receptor antagonist) and prazosin (alpha1-adrenoceptor antagonist). The systemic administration, but not the local perfusion, of the two NMDA receptor antagonists markedly increased the efflux of 5-HT in the mPFC. The atypical antipsychotics clozapine (1 mg/kg) and olanzapine (1 mg/kg), and prazosin (0.3 mg/kg), but not the classical antipsychotic haloperidol (1 mg/kg), reversed the PCP- and ketamine-induced increase in 5-HT efflux. Ritanserin (5 mg/kg) was able to reverse only the effect of PCP. These findings indicate that an increased serotonergic transmission in the mPFC is a functional consequence of NMDA receptor hypofunction and this effect is blocked by atypical antipsychotic drugs.     

The effect of chronic treatment with clozapine and haloperidol on stimulus control by DOM

The present study investigated the effects of chronic treatment with the atypical antipsychotic, clozapine, or the typical antipsychotic, haloperidol, on the stimulus properties of 2,5-dimethoxy-4-methylamphetamine ([-]-DOM) in rats trained to discriminate [-]-DOM (0.3 mg/kg; 75 min pre-treatment time) from vehicle. As compared with control values, treatment with clozapine (25 mg/kg.d) for 7 d caused a statistically significant 57% reduction in [-]-DOM-appropriate responding. Unlike clozapine, treatment with haloperidol (1 mg/kg.d) for 7 d did not affect the stimulus properties of [-]-DOM. These findings demonstrate that a functionally significant decrease in 5-HT2A receptor-mediated activity is a unique component of the in-vivo response to chronic treatment with clozapine but not haloperidol and, therefore, might account for some of the clinical differences associated with atypical antipsychotics.     

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     

Atypical antipsychotics,clozapine and sulpiride do not antagonise amphetamine-induced stereotyped locomotion

An automated tracking system which converted an animal's path between quadrants of a circular open field into a series of trips was used to analyse stereotyped locomotion in amphetamine treated rats. Amphetamine (3.5 mg/kg) increased the horizontal distance moved and the number and proportion of thigmotaxic trips around the perimeter of the apparatus (length 4 trips). To investigate the hypothesis that classic antipsychotics, but not atypical antipsychotics, would antagonise the repetitive boundary patrolling associated with amphetamine-induced hyperactivity, animals were pretreated with haloperidol (0.01, 0.025, 0.05, 0.075 mg/kg), clozapine (5, 10, 20 mg/kg) or (±)sulpiride (10, 20, 50 mg/kg) 30 min before 3.5 mg/kg amphetamine. The results showed that the classic antipsychotic haloperidol antagonised both hyperactivity and the increased proportion of length 4 trips. In marked contrast, the atypical antipsychotics clozapine and sulpiride antagonised hyperactivity but did not reduce the proportion of length 4 trips. The inability of atypical antipsychotics to reduce the repetitive boundary patrolling associated with amphetamine-induced hyperactivity is consistent with the action of these drugs on other forms of amphetamine-induced stereotyped behaviour, and indicates that locomotor routes under amphetamine are stereotyped. The measurement of trip lengths provides a sensitive tool for examining drug action on the spatial distribution of open field locomotion.     

Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex

Classical antipsychotic drugs such as haloperidol produce akinesia and catalepsy, whereas clozapine and related atypical antipsychotics fail to elicit these behaviors even at relatively high doses. Despite these behavioral differences, a cataleptic dose of haloperidol (2.0 mg/kg) produces changes in neuronal activity in the neostriatum and nucleus accumbens comparable to those produced by a non-cataleptic dose of clozapine (20.0 mg/kg). To further elucidate the brain mechanisms underlying the differential behavioral response to these drugs, an electrophysiological analysis was extended to neurons in the rat amygdaloid complex. Whereas an intraperitoneal injection of 2.0 mg/kg haloperidol generally failed to alter the firing rate of amygdaloid neurons, 20.0 mg/kg clozapine typically produced a prolonged increase in activity. Similarly, clozapine, but not haloperidol, reversed the depression of firing rate produced by 1.0 mg/kg d-amphetamine. The results suggest that neurons in the amygdaloid complex are more responsive to antipsychotic drugs devoid of extrapyramidal side effects than to antipsychotics which elicit parkinsonian-like motor dysfunctions.     

Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain

Aripiprazole,7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2 receptor partial agonist with functional 5-HT2A receptor antagonist, and 5-HT1A receptor partial agonist properties as well. Other atypical antipsychotic drugs, e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce significant increases in dopamine and acetylcholine release in the medial prefrontal cortex in rats, effects believed to be related to the ability to improve cognitive function. The increase in the medial prefrontal cortex dopamine release by the atypical antipsychotic drugs has been shown to be partially inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly but significantly increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. These increases were significantly inhibited by WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly decreased dopamine release in the nucleus accumbens but not the medical prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased dopamine release in the both regions. Aripiprazole had no effect on acetylcholine release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1 mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited that in the nucleus accumbens. The present study demonstrated that aripiprazole, at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial prefrontal cortex and hippocampus. It also suggests that the function of both the medial prefrontal cortex and hippocampus may contribute to the ability of aripiprazole to improve negative symptom and cognition.     

Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test

Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and alpha2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1-30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia.     

Effect of antipsychotics on creatine kinase activity in rat brain

Typical and atypical antipsychotic drugs have different clinical and behavioural profiles. It is well described that inhibition of creatine kinase activity has been implicated in the pathogenesis of a number of diseases, especially in the brain. In this work, we evaluate the effect of haloperidol, clozapine, olanzapine or aripiprazole chronic administration on creatine kinase activity in brain of rats. Adult male Wistar rats received daily injections of haloperidol (1.5 mg/kg), clozapine (25 mg/kg), olanzapine (2.5, 5 or 10 mg/kg) or aripiprazole (2, 10 or 20 mg/kg). Our results demonstrate that haloperidol did not affect the enzyme activity in brain of rats. Clozapine inhibited the enzyme activity only in cerebellum and prefrontal cortex of rats. Aripiprazole did not affect creatine kinase in hippocampus, cerebellum and prefrontal cortex. The administration of 2.0 mg/kg aripiprazole did not alter creatine kinase activity, but 10.0 and 20.0 mg/kg aripiprazole activated the enzyme in striatum and cerebral cortex. Finally, the higher dose of olanzapine (10.0 mg/kg) activated the enzyme in striatum of rats. In hippocampus and cerebral cortex, we could not verify any effect of olanzapine on creatine kinase activity. The inhibitory effect of clozapine and olanzapine on creatine kinase activity in cerebellum and prefrontal cortex suggest that these drugs may impair energy metabolism in these brain areas.     

Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.     

No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol: a double-blind placebo-controlled trial

Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis.     

Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and rats.

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg p.o.) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.     

Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats. Haloperidol and clozapine produced a short-term increase in food intake. Haloperidol (0.05-0.2 mg/kg) enhanced meal size (maximal at 0.1 mg/kg) and reduced feeding rate (monotonic decrease with increasing dose). Neither clozapine (1-10 mg/kg) nor olanzapine (0.3-3 mg/kg) enhanced meal size, although both drugs produced similar reductions in feeding rate to haloperidol. These data suggest that enhancement of meal size may be correlated with a high level of extrapyramidal side effects in an antipsychotic drug. The absence of an increase in meal size by two atypical compounds suggests that the increase in body weight associated with clinical treatment with these drugs cannot be modelled by acute stimulation of meal size in the rat.     

Discriminative stimulus properties in rats of the novel antipsychotic quetiapine

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear.     

Differential effects of ondansetron, haloperidol and clozapine on electrical self-stimulation of the ventral tegmental area

The effects of 5-HT(3), receptor blockade with ondansetron (0.025-0.2mg/kg) on intracranial self-stimulation of the ventral tegmental area were compared with effects of the typical antipsychotic drug haloperidol (0.01-0.3mg/kg) and the atypical antipsychotic drug clozapine (1.25-10mg/kg). Rats were trained to self-stimulate using unipolar ventral tegmental electrodes (200μm diameter) to deliver 1s trains of 0.2ms cathodal pulses of constant current stimulation as a reinforcer. The animals were tested daily in frequency threshold tests. The frequency that maintained half maximal response rates (M50) and the maximal number of responses at a single frequency (RMAX) and the number of responses per session (TRESP) were used to measure drug effects. Ondansetron had no effects on the behavioural measures in this study. Haloperidol induced a significant increase in M50 at 0.3mg/kg without altering RMAX; TRESP was reduced by 0.1 and 0.3mg/kg of this drug. Clozapine increased M50 at 5.0mg/kg; following 10.0mg/kg of clozapine responding was completely abolished and no M50 measure could be calculated. Clozapine reduced RMAX at 1.25, 5.0 and 10.0mg/kg; TRESP was decreased by 5.0 and 10.0mg/kg of clozapine. The present results indicate that ondansetron had no measurable effects under conditions in which haloperidol and clozapine increase reinforcement thresholds and decrease response rates maintained by ventral tegmental self-stimulation.     

Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies.

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.