Abstract
The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin1A receptors in the pathophysiology of schizophrenia is also discussed.
Highlights
Schizophrenia is a clinical syndrome with diverse manifestations
The present study sought to determine whether extracellular dopamine in the Nucleus accumbens (NAcc) might be a further indicator to differentiate neurochemical actions of typical and atypical antipsychotic drugs
Post hoc analysis showed that 100% catalepsy occurred only at a dose of 5.0 mg/kg of risperidone and 60% at 10.0 mg/kg of clozapine
Summary
Schizophrenia is a clinical syndrome with diverse manifestations. Dopamine (DA) D2 receptor antagonism is postulated to be a key to antipsychotic efficacy in the treatment of schizophrenia [1]. Atypical antipsychotic drugs related to clozapine, improve psychosis, cognition and negative symptoms, while producing minimal EPS, in patients with schizophrenia [7]. This appears to be mediated mainly through the combined effect of relatively more potent blockade of 5-HT1A receptors, located on cortical and hippocampal glutamatergic and GABAergic neurons, as well as cell bodies of the mesolimbic and mesocortical dopamine (DA) neurons, and weaker blockade of D2 receptors in the ventral and dorsal striatum and pyramidal neurons in cortical areas, as well as the cell bodies of DA neurons [7, 8]. The important goal of the present research on atypical neuroleptics is to develop novel compound(s) with antipsychotic potential with a low incidence of EPS
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