In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties

In order to better define the role of 5-HT(1A) receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT(1A) agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT(1A) agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED(50)=0.04 and 1.0mg/kg, respectively), an effect reversed by the selective 5-HT(1A) antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED(50)=0.3mg/kg) and clozapine (ED(50)=1.5mg/kg) blocked the oral movements induced by the cholinomimetic agent at or below the doses required for suppression of conditioned avoidance response. The compound F-97013-GD (6-methyl-2-[4-(naphtylpiperazin-1-yl)butyl]-3-(2H)-pyridazinone), a putative antipsychotic drug that in functional in vitro and in vivo assays behaved as a mixed dopamine D(2)-antagonist and 5-HT(1A)-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED(50)=0.5mg/kg). Interestingly, pretreatment with WAY 100,635 blocked the inhibitory effect of F-97013-GD but not that of clozapine. The 5-HT depleting agent para-chlorophenylalanine (PCPA) partially attenuated tacrine-induced TJM but did not block the suppressive effect of 5-HT(1A) agonists. In addition, only high doses of F-97013-GD induced catalepsy in rodents and, like 8-OH-DPAT and clozapine, the compound reversed the haloperidol-induced catalepsy in rats. These results show that 5-HT(1A) receptors play a role in the regulation of tacrine-induced TJM and suggest that their activation by novel antipsychotics may not only reduce the extrapyramidal side effects EPS liability, but also be effective in the treatment of parkinsonian tremor.     

Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics

RATIONAL: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life. OBJECTIVE: In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze. RESULTS: The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved. CONCLUSION: These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.     

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.     

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.     

Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5 mg/kg, i.p.), sertindole (0.63, 1.3, 2.5 mg/kg, s.c.) or clozapine (0.5 and 1 mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics — olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.     

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.     

Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy

An in vivo binding assay is characterized for [(3)H]M100907 binding to rat brain, as a measure of 5-HT(2A) receptor occupancy. Dose-response analyses were performed for various 5-HT(2A) antagonist reference agents, providing receptor occupancy ED(50) values in conjunction with plasma and brain concentration levels. Ketanserin and M100907 yielded dose-dependent increases in 5-HT(2A) receptor occupancy with ED(50)s of 0.316 mg/kg and 0.100 mg/kg, respectively. The atypical antipsychotics risperidone, olanzapine, and clozapine dose-dependently inhibited in vivo [(3)H]M100907 binding with ED(50) values of 0.051, 0.144, and 1.17 mg/kg, respectively. In contrast, the typical antipsychotic haloperidol exhibited only 20.1% receptor occupancy at 10 mg/kg despite producing dose-dependent increases in plasma and brain exposure levels. The novel psychopharmacologic agent asenapine dose-dependently occupied 5-HT(2A) receptors in rat brain with an ED(50) of 0.011 mg/kg, demonstrating higher 5-HT(2A) receptor potency compared with the other atypical antipsychotics tested. This enhanced potency was supported by a lower plasma exposure EC(50) of 0.477 ng/ml, compared with risperidone (1.57 ng/ml) and olanzapine (7.81 ng/ml) and was confirmed in time course studies. The validated [(3)H]M100907 rat in vivo binding assay allows for preclinical measurement of 5-HT(2A) receptor occupancy, providing essential data for understanding the pharmacological profile of novel antipsychotic agents. Additionally, the corresponding plasma and brain drug exposure data analyses provides a valuable data set for 5-HT(2A) reference agents by enabling direct comparison with any complementary studies performed in rats, thus providing a foundation for predictive pharmacokinetic/pharmacodynamic models and, importantly, allowing for translation to human receptor occupancy studies using [(11)C]M100907 positron emission tomography.     

8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis

The selective serotonin1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06-0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 micrograms/0.5 microliter, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.     

KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia

KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (Ki=3.85 nM) for human dopamine D3 receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (Ki=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT1A receptor (Ki=6.4 nM). KKHA-761 exhibited D3 and 5-HT1A receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [35S]GTPrS binding. The in vivo pharmacological profile of KKHA-761 was compared with both typical and atypical antipsychotics including clozapine and haloperidol. Apomorphine-induced dopaminergic behavior, cage climbing, in mice was potently blocked by a single administration (i.p.) of KKHA-761 (ID50=4.06 mg/kg) or clozapine (ID50=4.0 mg/kg). Cocaine- or MK-801-induced hyperactivity in animals was markedly inhibited by KKHA-761 or clozapine. In addition, KKHA-761 significantly reversed the disruption of prepulse inhibition (PPI) produced by apomorphine in mice, indicating the antidopaminergic or antipsychotic activity of KKHA-761 in mice. However, KKHA-761 was inactive in the forced swimming behavioral despair model in mice, suggesting lack of antidepressant properties. KKHA-761 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT, in mice, whereas clozapine enhanced it. Moderate doses of both KKHA-761 and clozapine did not increase serum prolactin levels in rats. Lower doses of, however, haloperidol significantly increased prolactin secretion. KKHA-761 did not induce cataleptic response up to 20 mg/kg, but significant catalepsy was shown at lower doses of clozapine and haloperidol. Furthermore, KKHA-761 showed a low incidence of rotarod ataxia (TD50=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D3 and serotonin 5-HT1A receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.     

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.     

Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats

Rationale: Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. Objectives: The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. Methods: Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. Results: Generalization testing revealed full substitution with the atypical antipsychotics olanzapine (90.3% maximum generalization), sertindole (99.8%), and risperidone (87.1%) and partial substitution for quetiapine (seroquel, 66.4%) and the typical antipsychotics haloperidol (56.8%) and thioridazine (74.3%). Remoxipride (23.1%) and the typical antipsychotics chlorpromazine (27.9%) and fluphenazine (29.5%) did not reliably substitute for clozapine. Conclusions: In contrast to previous clozapine drug discrimination studies with higher training doses, the atypical antipsychotics olanzapine, sertindole, and risperidone reliably substituted for clozapine while typical antipsychotics did not. These results suggest that low-dose clozapine drug discrimination may be a more sensitive assay for distinguishing atypical from typical antipsychotic drugs. Received: 3 August 1999 / Final version: 9 December 1999     

Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice

We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test.Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5 mg/kg; s.c.) or clozapine (0.5 and 1 mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia.     

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine

Rationale Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects.Objectives The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone.Methods We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model.Results Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED₅₀ values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED₅₀ values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT_1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT_1A agonist.Conclusion The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT_1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.     

Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties.

A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.     

Repeated treatment with 8-OH-DPAT induces tolerance to its ability to produce the 5-HT1A behavioural syndrome, but not to its ability to attenuate haloperidol-induced catalepsy

When administered acutely, 5-hydroxytryptamine1A (5-HT1A) agonists attenuate the cataleptic side effects of antipsychotics. We investigated whether tolerance occurs to these effects after repeated administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). For comparison, we also assessed the ability of 8-OH-DPAT to produce elements of the 5-HT1A behavioural syndrome (i.e. forepaw treading, flat body posture and lower lip retraction), some of which readily demonstrate tolerance. Catalepsy was measured in rats using both the cross-legged position test and the bar test. Repeated treatment with 8-OH-DPAT (0.63-2.5 mg/kg subcutaneously), once daily for 4 days, did not significantly alter the ability of acute treatment with 8-OH-DPAT (0.01-2.5 mg/kg) to inhibit catalepsy induced by haloperidol (2.5 mg/kg) in either test. In contrast, the ability of 8-OH-DPAT to produce the 5-HT1A behavioural syndrome was significantly attenuated by the repeated treatment. The present data, showing an absence of tolerance to the anti-cataleptic effects of a 5-HT1A agonist, indicate that mixed dopamine antagonist/5-HT1A agonist compounds may continue to have a low propensity to induce extrapyramidal side effects during chronic treatment.     

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.     

Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats

Rationale

Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.

Objective

We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.

Results

MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25–1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.

Conclusion

The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.     

Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats

Loxapine (0.3mg/kg s.c.), olanzapine (10 mg/ kg s.c.) and SCH 23390 (R-(+)-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine; 1mg/kg, s.c.), but not clozapine (10mg/kg, s.c.), induced catalepsy in rats. Co-administration of clozapine (1, 3 and 10mg/ kg s.c.) dose-dependently inhibited loxapine-induced catalepsy. Clozapine (10mg/kg s.c.) also prevented the induction of catalepsy by olanzapine. In addition, clozapine abolished the catalepsy induced by loxapine when it was administered after the response had fully developed. In contrast, the duration of SCH 23390-induced catalepsy was prolonged by clozapine, indicating that its anti-catalepsy effects against olanzapine and loxapine are unlikely to be caused by muscle relaxation, sedation or stimulation. Since SCH 23390-induced catalepsy is reported to be blocked by scopolamine, dizocilpine (MK-801) or 8-hydroxy-dipropylamino-tetralin, it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT_1A receptor agonism, respectively, are involved in clozapine’s action, but the mechanism by which clozapine exerts this anti-cataleptic effect remains unknown. Received: 8 August 1996 / Accepted: 10 December 1996     

The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by “atypical” antipsychotics. In contrast, some findings indicate that not all of the “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI.

In our study, we evaluated the effect of four different “atypical” antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT_2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT_1A,2A/2C receptors and muscarinic receptors.

Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment.

In summary, the four “atypical” antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.     

Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist,MDL100,907

Employing a two-lever, food-reinforced FR10 procedure, rats were trained to recognize a discriminative stimulus (DS) elicited by the 5-HT(2A) receptor antagonist and potential antipsychotic agent, MDL100,907 (0.16 mg/kg, i.p.). In generalization tests, by analogy to MDL100,907 itself (Effective Dose(50) (ED(50)), 0.002 mg/kg, s.c.), the 'atypical' antipsychotic, clozapine, which displays high affinity for 5-HT(2A) as compared to D(2) receptors, dose-dependently and fully generalized to MDL100,907 (ED(50), 0.2 mg/kg, s.c.). S16924 (0.05 mg/kg, s.c.), S18327 (0.09 mg/kg, s.c.), quetiapine (1.8 mg/kg, s.c.), risperidone (0.02 mg/kg, s.c.) and ziprasidone (0.01 mg/kg, s.c.), antipsychotics which possess-like clozapine-marked affinity for 5-HT(2A) versus D(2) receptors, also generalized to MDL100,907. In distinction, raclopride, an antipsychotic which selectively interacts with D(2) versus 5-HT(2A) receptors, did not display significant generalization. Interestingly, haloperidol, which shows only modest affinity for 5-HT(2A) versus D(2) sites, generalized to MDL100,907 (ED(50), 0.02 mg/kg, s.c.). In light of the antagonist properties of haloperidol, clozapine and all other antipsychotics tested (except raclopride) at alpha(1)-adrenoceptors (ARs), the selective alpha(1)-AR antagonists, prazosin and WB4101, were examined. Both dose-dependently and fully generalized to MDL100,907 (ED(50)s, 0.07 and 0.11 mg/kg, s.c., respectively). At doses showing pronounced generalization to MDL100,907, the only drugs which significantly suppressed response rates were haloperidol and, weakly, quetiapine. Raclopride also markedly decreased response rates. In conclusion, the antipsychotic agents, clozapine, ziprasidone, risperidone, S16924, S18327, quetiapine and haloperidol, all generalized to a DS elicited by MDL100,907. While D(2) receptors are not implicated in their actions, in addition to antagonist properties at 5-HT(2A) receptors, blockade of alpha(1)-ARs and other, as yet unidentified, mechanisms may be involved. These data underpin interest in MDL100,907 as a potential antipsychotic agent.