Research reportEffects of 5-HT2A and 5-HT2C receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats
Research highlights
► Acute haloperidol (HAL) effects: SB242,084 but not M100,907 reduced catalepsy. ► Acute HAL effects: Neither SB242,084 nor M100,907 normalized Fos expression in the brain. ► Chronic HAL effects: SB242,084 but not M100,907 attenuated vacuous chewing movements. ► Chronic HAL effects: 5-HT2C but not 5-HT2A mRNA levels were altered in several brain regions. ► 5-HT2C antagonism could be a target property in the development of new antipsychotic drugs.
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-HT2A agonists positively modulate DA release under basal conditions, and 5-HT2A antagonism decreases evoked DA release [1]. Conversely, 5-HT2C receptors phasically and tonically inhibit DA release in the nucleus accumbens and caudate-putamen, while 5-HT2C 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-HT2A and 5-HT2C receptor subtypes in both acute and chronic motor effects induced by HAL by using potent and selective 5-HT2A and 5-HT2C antagonists, namely M100,907 (previously MDL-100,907) and SB242,084, respectively. For comparative purposes we also tested the effects of the mixed 5-HT2A/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-HT2A and 5-HT2C 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.
Section snippets
Subjects
Adult male Sprague-Dawley rats (Charles River, Quebec) were pair-housed and maintained on a 12-h light/dark cycle (lights on at 8:00 AM), with ad libitum access to food and water. All tests and treatments were conducted according to the guidelines of the Canadian Council on Animal Care and were approved by the Centre for Addiction and Mental Health Animal Care Committee. All behavioural tests were performed by a trained observer blind to treatment conditions.
Test drugs
Haloperidol and haloperidol
Catalepsy induced by acute haloperidol
A two-way ANOVA indicated significant main effects of HAL (F1,63 = 139.2, p < 0.001), 5-HT2 antagonist (F3,63 = 4.97, p < 0.004) and their interaction (F3,63 = 4.65, p < 0.005). As expected, rats receiving a single injection of haloperidol (0.5 mg/kg s.c.) showed significantly higher catalepsy scores than their vehicle-treated counterparts (p < 0.001). As shown in Fig. 1, co-administration of M100,907 or ketanserin had no affect on HAL-induced catalepsy, while SB242,084 reduced the HAL effect by more than 50%
Discussion
The aim of the present study was to assess the role of 5-HT2A and 5-HT2C receptors in both acute and chronic motoric effects induced by haloperidol. It was found that 5-HT2C, but not 5-HT2A antagonism decreased catalepsy induced by acute HAL. However, none of the 5-HT2 antagonists significantly modified the typical pattern of brain Fos expression induced by HAL, thus suggesting a dissociation between Fos induction and acute catalepsy induced by haloperidol. After chronic HAL, both the mixed 5-HT
Conclusion
This may be the first examination of effects of 5-HT 2A vs. 2C antagonism on both acute and chronic brain and behavioural effects of HAL under the same laboratory conditions. We found that 5-HT2C antagonism reduced motor effects induced by both acute and chronic HAL administration. 5-HT2A antagonism did not affect either class of motor symptoms, whereas at the doses used, the mixed antagonist ketanserin attenuated HAL-induced VCMs but had no effect on catalepsy. None of the antagonists reduced
Acknowledgements
Supported in part by funds from the Ontario Mental Health Foundation and the Canadian Institutes of Health Research. M.C.-C. was the recipient of an NSERC Graduate Fellowship. The authors thank Dr. P.J. Fletcher for making M100,907 available and Roger Raymond and Mustansir Diwan for excellent technical help.
References (52)
- et al.
Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission
Pharmacol Ther
(2007) - et al.
The effects of antipsychotic drugs on the mRNA levels of serotonin 5HT2A and 5HT2C receptors
Brain Res Mol Brain Res
(1997) - et al.
The effects of clozapine and haloperidol on serotonin-1A-2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain
Neuroscience
(1996) - et al.
Harrison PJ 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia
Neuropsychopharmacology
(1996) - et al.
Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study
Neuroscience
(1999) - et al.
SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system
Neuropharmacology
(1999) - et al.
A role for the subthalamic nucleus in 5-HT2C-induced oral dyskinesia
Neuroscience
(1996) - et al.
Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements
Pharmacol Biochem Behav
(1996) - et al.
Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding
Neuropsychopharmacology
(2002) - et al.
Effect of chronic treatment with clozapine and haloperidol on 5-HT(2A and 2C) receptor mRNA expression in the rat brain
Neurosci Res
(2007)
Expression of noradrenergic alpha1, serotoninergic 5HT2a and dopaminergic D2 receptors on neurons activated by typical and atypical antipsychotic drugs
Prog Neuropsychopharmacol Biol Psychiatry
Ritanserin counteracts both rat vacuous chewing movements and nigro-striatal tyrosine hydroxylase-immunostaining alterations induced by haloperidol
Eur J Pharmacol
Effect of 5-HT1A and 5-HT2A/2C receptor modulation on neuroleptic-induced vacuous chewing movements
Eur J Pharmacol
Increased expression of 5HT2 receptor mRNA in rat striatum following 6-OHDA lesions of the adult nigrostriatal pathway
Brain Res Mol Brain Res
Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine
Neuroscience
The treatment of tardive dyskinesia—a systematic review and meta-analysis
Schizophr Res
Study on the suitability of a rat model for tardive dyskinesia and the preventive effects of various drugs
Prog Neuropsychopharmacol Biol Psychiatry
The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: is there a relationship to dopamine D(2) receptor occupancy
Neurosci Biobehav Rev
5-HT2A and 5-HT2C receptors and their atypical regulation properties
Life Sci
Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex
Psychopharmacology (Berl)
Pathophysiology of antipsychotic drug-induced movement disorders
J Clin Psychiatry
Role of adenosine and N-methyl-d-aspartate receptors in mediating haloperidol-induced gene expression and catalepsy
J Pharmacol Exp Ther
Tardive dyskinesia and new antipsychotics
Curr Opin Psychiatry
Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens
J Neurosci
Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol
Psychopharmacology (Berl)
Extrapyramidal side effects tardive dyskinesia, and the concept of atypicality
J Clin Psychiatry
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