ST2472: a new potential antipsychotic with very low liability to induce side-effects

ST2472 was shown to bind to multiple receptors, thus resembling the affinity spectrum of atypical antipsychotics. The present study investigates its in-vivo potential antipsychotic effects. ST2472 is effective in the conditioned avoidance response (CAR) test in rats (ED50=1.5 mg/kg p.o.), a model sensitive to antipsychotics. It antagonizes amphetamine-induced hypermotility at dosages (minimal effective dose=0.7 mg/kg p.o.) that are lower than those necessary to antagonize amphetamine-induced stereotypy (minimal effective dose=30 mg/kg p.o.), in rats. This finding, together with the fact that ST2472 does not induce catalepsy in rodents at up to 100 mg/kg p.o., indicates that ST2472 has very low liability to induce extrapyramidal side-effects. ST2472 does not increase prolactinaemia after chronic treatment. In mice, ST2472 does not appear to alter blood pressure and heart rate in a significant fashion. In conclusion, ST2472 seems to be an antipsychotic with lower liability to produce side-effects than other antipsychotics, such as haloperidol, risperidone, olanzapine and clozapine, which were evaluated as reference drugs.     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Differential behavioural effect of quinpirole in neuroleptic-pretreated rats - role of alpha(1)-adrenoceptor

This paper presents the effect of 14-day intraperitoneal (i.p.) neuroleptic treatment on the behavioural response of Wistar rats to (-)-quinpirole hydrochloride (3 mg/kg, i.p.) administered 24 h after the last neuroleptic dose. Chlorpromazine hydrochloride (10 mg/kg), haloperidol (2 mg/kg) or (+/-)-sulpiride (100 mg/kg) increased the effect of quinpirole; however, there were qualitative and quantitative differences between the neuroleptics. Chlorpromazine and haloperidol, but not sulpiride, pretreatment enhanced quinpirole-induced locomotor hyperactivity. Prazosin (0.5 mg/kg, i.p. ) given to chlorpromazine-treated rats 1 h before quinpirole attenuated the quinpirole-induced hyperlocomotion. In chlorpromazine-pretreated rats, quinpirole elicited defensive aggressive behaviour with vocalization, copulatory attempts, intense rearing and head-down sniffing. When prazosin was given before quinpirole, head-down sniffing and object-directed oral activity were mainly observed. In haloperidol-pretreated rats, quinpirole induced intense head-down sniffing, rearing, grooming and object-directed oral activity. In sulpiride-pretreated rats, quinpirole induced intense head-down sniffing, grooming and object-directed oral activity. The results of the study suggest that differences in the behavioural expression of dopamine D(2) receptor supersensitivity induced by neuroleptics may be, at least in part, caused by concurrent stimulation of alpha(1)-adrenoceptors.     

Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats: a potential model for obsessive compulsive disorder

Schedule-induced polydipsia was used to determine the effects of selective serotonin re-uptake inhibitors on adjunctive water consumption. Polydipsia was induced in food deprived rats by exposure to a fixed time feeding schedule (FT=60 s) for 150 min per day for 22 days. Selected polydipsic rats consumed 3–4 times greater volume of water compared to food deprived control rats. Chronic administration of the selective serotonin re-uptake inhibitors fluoxetine and clomipramine (CMI) at 5 mg/kg per day and fluvoxamine at 10 mg/kg twice a day significantly decreased schedule-induced polydipsia (SIP) on day 15 and throughout the remainder of the study compared to control rats. The noradrenergic re-uptake inhibitor, desipramine (DMI), only decreased SIP behavior on day 1. The neuroleptic, haloperidol (0.03 and 0.1 mg/kg), and the benzodiazepine, diazepam (2.5 mg/kg), failed to alter SIP behavior. Since obsessive-compulsive disorder (OCD) and polydipsic behavior both involve excessive expression of a normal behavior, the polydipsia model may be relevant for the prediction of compounds useful in the treatment of OCD.     

Potentiation of olanzapine substitution in rats discriminating clozapine by the D2/3 agonist quinpirole

The D2/3 agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) has been reported to enhance the ability of olanzapine to substitute for clozapine and attenuate olanzapine-induced response suppression in monkeys. These data suggest that the relatively marked D2/3 antagonist actions of olanzapine limit its substitution for clozapine. The work reported here replicated and extended these findings. Twelve rats were trained to discriminate clozapine (5 mg/kg, intraperitoneal) from vehicle in an FR30 quantal food rewarded assay. The substitution curve for olanzapine (0-2.5 mg/kg) was then computed after treatment with either vehicle or a high dose (0.1 mg/kg) of the D2/3 agonist quinpirole. The olanzapine substitution curve was shifted significantly 5.2-fold in parallel to the left by quinpirole. Olanzapine suppressed responding significantly, but this effect was not attenuated or enhanced by quinpirole, which suppressed responding itself. Thus antagonist actions at D2/3 receptors clearly limit the ability of olanzapine to substitute for clozapine. These findings suggest that the clozapine versus vehicle discrimination is probably a bioassay for agents that resemble clozapine but which do not necessarily induce D2/3 antagonism. This discrimination may therefore not specifically detect clozapine-like antipsychotics, although it may be of value in developing such antipsychotics. The low discriminability of antipsychotics in general may be because antagonist actions at D2/3 receptors limit incentive salience in discrimination assays. These data are compatible with recent theorizing that therapeutic actions of antipsychotics in schizophrenia involve D2/3 receptor-mediated attenuation of stimulus salience.     

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.     

Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D2-receptor occupancy method in the rat

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal dopamine D₂-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D₂-receptor occupancies were determined using ³H-raclopride. The doses required to achieve dopamine D₂-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day.     

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.     

Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone

RATIONALE: The pharmacological profile of risperidone is that of an atypical neuroleptic regarding its serotonin 5-HT2A and dopamine D2 receptor blocking properties. Treatment with risperidone, though, results in considerably elevated plasma prolactin (PRL) levels which are not observed with other atypical neuroleptics, such as clozapine, indicating a differentiated action on receptors that are involved in PRL release, mainly dopaminergic and serotonergic. OBJECTIVE: To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms. METHODS: Two neuroendocrine challenge tests, measuring the PRL increases induced by acute administration of serotonergic (clomipramine, 25 mg i.v.) and dopaminergic (haloperidol, 5 mg i.m.) drugs were performed in 13 male schizophrenic patients during treatment with typical neuroleptics and, later, after 6 weeks of treatment with risperidone. The tests were also performed in a group of nine healthy male volunteers. PRL was estimated in blood samples taken every 15 min for 1 h for clomipramine and every 30 min for 2 h for haloperidol. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: During treatment with neuroleptics (mean dose 1354 mg chlorpromazine equivalents, range 300-2400 mg), i.m. haloperidol caused significant elevations in plasma PRL, which were totally abolished after 6 weeks treatment with risperidone (mean dose 12.1 mg/day, range 8-16 mg/day), indicating complete D2 receptor blockade. In contrast, the PRL increases obtained after clomipramine administration during neuroleptic treatment were preserved after treatment with risperidone. Both PRL response patterns to clomipramine were similar to that of healthy controls. BPRS score was 50.2+/-9.3 points during neuroleptic treatment and was reduced after risperidone to 30.1+/-6.6 points, i.e., 40% in the mean. CONCLUSIONS: During treatment with typical neuroleptics, the PRL responses to clomipramine are normal, and they are preserved after switch to risperidone in doses that cause complete dopamine receptor blockade. Risperidone, a dopamine and 5-HT receptor blocker, does not affect 5-HT receptors that are involved in the PRL release by the 5-HT uptake blocker clomipramine, indicating a different behavior than other atypical neuroleptics such as clozapine or olanzapine, for which a reduction of the PRL release induced by serotonergic agents like fenfluramine or mCPP has been reported. A conclusive identification of the 5-HT receptor subtypes that are involved in this different action cannot be identified at present, but it should be taken into account that risperidone differs from clozapine, showing higher affinity for 5-HT2A than 5-HT2C receptors and lacking the marked affinity of clozapine to 5-HT1A receptors.     

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.     

Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D(3) receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D(3) receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D(3) receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D(3) receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.     

Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.

The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.     

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.     

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     

The receptor mechanisms underlying the disruptive effects of haloperidol and clozapine on rat maternal behavior: A double dissociation between dopamine D2 and 5-HT2A/2C receptors

Many antipsychotic drugs disrupt active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses in postpartum female rats. However, the neurochemical mechanisms underlying such a disruptive effect remain to be determined. This study examined the neurochemical mechanisms that mediate the disruptive effects of haloperidol (a typical antipsychotic) and clozapine (an atypical antipsychotic) on rat maternal behavior. Postpartum rats were administered with haloperidol (0.2 mg/kg, sc) or clozapine (10.0 mg/kg, sc) together with either vehicle (saline or water), quinpirole (a selective dopamine D₂/D₃ agonist, 0.5 or 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their maternal behaviors were tested at different time points before and after drug administration. Haloperidol and clozapine treatment disrupted pup approach, pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, dose-dependently reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, dose-dependently reversed the clozapine-induced disruptions. Quinpirole pretreatment even exacerbated the clozapine-induced disruption of pup retrieval and nest building. These findings suggest a double dissociation mechanism underlying the disruption of haloperidol and clozapine on rat maternal behavior. Specifically, haloperidol disrupts maternal behavior primarily by blocking dopamine D₂ receptors, whereas clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A/2C receptors. Our findings also suggest that 5-HT receptors are involved in the mediation of rat maternal behavior.     

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.     

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.     

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.     

Effect of acute and chronic olanzapine treatment on phencyclidine-induced behavioral sensitization in rats with neonatal dopamine loss

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT(2A)/5-HT(2C)-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT(2)-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia-a clinical syndrome linked to enhanced sensitivity to N-methyl-d-aspartate (NMDA)-receptor antagonists.     

Similarity of clozapine's and olanzapine's acute effects on rats' lapping behavior

As a way of further comparing the behavioral effects of clozapine and olanzapine, dose ranges of these drugs were studied in a task emphasizing fine motor detail of rats' tongue movements during lapping behavior. Rats lapped drops of tap water from a force-sensing disk. From this behavior four variables were derived: peakforce of tongue strikes, duration of tongue contact, number of separate tongue contacts in 2 min, and the rhythm of the lapping behavior as quantified by Fourier analysis. Both clozapine (0.5–4.0 mg/kg, IP, 45 min) and olanzapine (0.25–2.0 mg/kg, IP, 45 min) dose dependently reduced all four measures of behavior. With respect to lick rhythm, a behavioral marker which clearly distinguishes haloperidol from clozapine in this behavioral paradigm, olanzapine was about twice as potent as clozapine, with the two drugs having parallel dose-effect functions. Within-session decrements in behavior previously reported for haloperidol in the lick task were not produced by clozapine nor by olanzapine. Taken together, these data strengthen the idea that the behavioral effects of clozapine and olanzapine are strikingly similar, and thereby emphasize the potential of olanzapine as an atypical antipsychotic agent.