Effects of 5-HT_2A and 5-HT_2C receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats

Abstract

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT₂) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT_2A antagonist M100,907, the 5-HT_2C antagonist SB242,084 and the mixed 5-HT_2A/C antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT₂ receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT_2C but not 5-HT_2A mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2_2C receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT_2C antagonism could be targeted as a key property in the development of new antipsychotic medications.

Introduction

Treatment with classical antipsychotic drugs (APDs) such as haloperidol (HAL) is associated with both acute and chronic motor side effects. Acutely, these drugs may induce extrapyramidal symptoms (EPS), including akathisia, rigidity, tremor and bradykinesia, while prolonged treatment may result in tardive dyskinesia (TD) or tardive dystonia. Acute EPS and tardive syndromes differ in time of onset, clinical manifestation, persistence, and response to pharmacological agents [14], [16]. While both acute and chronic motor side effects are less likely to occur with so called atypical APDs, the latter are not completely devoid of acute EPS effects [8] and, more importantly, are associated with other health-threatening side effects such as excessive weight gain and potentially fatal metabolic complications [35]. Renewed interest in mechanisms involved in motor side effects of classical APDs is also due in part to the need to develop effective treatments for patients that have developed persistent TD before the advent of atypical APDs [40] and to inform the development of new medications devoid of such effects.

A prevailing hypothesis for the decreased incidence of EPS associated with atypical antipsychotics centers on serotonin-2 (5-HT₂) receptor antagonism [18], [19], [24], [25], [26], [41]. In vivo brain imaging has revealed low occupancy of 5-HT₂ receptors by HAL at therapeutic doses, while the atypical APDs, olanzapine, sertindole, risperidone and clozapine occupy 80–100% of these receptors at therapeutic doses [44]. Given the inhibitory role of 5-HT on dopamine (DA) release from axon terminals, it has been suggested that antagonism of 5-HT₂ receptors would increase DA release and this might potentially reverse the effects of D₂ receptor blockade selectively in the nigrostriatal pathway [6].

5-HT_2A agonists positively modulate DA release under basal conditions, and 5-HT_2A antagonism decreases evoked DA release [1]. Conversely, 5-HT_2C receptors phasically and tonically inhibit DA release in the nucleus accumbens and caudate-putamen, while 5-HT_2C antagonism disinhibits DA release throughout the mesostriatal system [9], [10]. There is evidence to suggest a differential involvement of 2A vs. 2C subtypes in the development of EPS [12], [24], [25], [33]. A particularly relevant possibility relates to evidence that 2A and 2C antagonism may in several cases lead to opposite functional effects [15].

Previous work addressing the role of 5-HT receptors in HAL motoric side effects often failed to distinguish acute from long-term effects and used test compounds with limited specificity. In the present study, we re-examined the respective contributions of 5-HT_2A and 5-HT_2C receptor subtypes in both acute and chronic motor effects induced by HAL by using potent and selective 5-HT_2A and 5-HT_2C antagonists, namely M100,907 (previously MDL-100,907) and SB242,084, respectively. For comparative purposes we also tested the effects of the mixed 5-HT_2A/2C antagonist ketanserin. In acute studies catalepsy was used as a prototypical behavioural index of HAL-induced EPS, and patterns of brain Fos expression were chosen as a typical brain response. We were particularly interested in the possibility that addition of 5-HT₂ antagonists could convert the characteristic Fos pattern induced by HAL into a pattern similar to the one obtained with atypical APDs such as clozapine [36], [37]. In chronic HAL studies we tested the effects of 5-HT₂ antagonists on vacuous chewing movements (VCMs), a well-documented behavioural effect of prolonged classical APD use [14], [43], [47]. We also examined chronic HAL effects on 5-HT_2A and 5-HT_2C gene expression in brain, in an effort to further ascertain the contribution of each of these receptor subtypes to the pathophysiology of chronic HAL-induced motor side effects.