On the mechanisms of action of atypical antipsychotic drugs : an experimental study

A majority of schizophrenic patients respond to classical neuroleptic drugs which are believed to act largely via blockade of dopamine (DA) D2 receptors in limbic structures. However, a significant proportion do not respond to conventional D2 receptor blocking drugs or show a rather incomplete therapeutic effect, particularly on negative and cognitive symptoms. Moreover, the concomitant blockade of D2 receptors in the basal ganglia has been associated with appearance of extrapyramidal side effects (EPS). In comparison with classical neuroleptics atypical antipsychotic drugs such as for example clozapine and risperidone have been found to possess improved efficacy against negative symptomatology and caese a reduced incidence of EPS in clinically effective doses. Despite considerable research efforts, the neurobiological basis for this advantageous pharmacological profile remains to be fully understood. The present work was undertaken in an attempt to gain further insights into the mechanisms of action of atypical antipsychotic drugs.

Methodologically, microdialysis of extracellular DA and serotonin (5-HT) was carried out in freely moving rats. Moreover, neuronal activity of 5-HT neurons in the dorsal raphe nucleus (DRN) was registered by means of single cell recording in vivo. Behavioral techniques were also used, including conditioned avoidance response (CAR) and catalepsy ratings, preclinical tests with documented predictive value as regards antipsychotic effect and EPS liability, respectively. Systemic administration of clozapine or risperidone as well as amperozide markedly enhanced DA efflux. in the medial prefrontal cortex (mPFC), an effect that was not mimicked by the D2/3 or 5-HT2A/C receptor antagonists raclopride or ritanserin, respectively. In similarity with the [alpha]2A/D adrenoceptor antagonist idazoxan both risperidone and amperozide increased cortical 5-HT efflux and, by means of local, intracortical drug administration, risperidone was shown to antagonize the effect on 5-HT output induced by [alpha]2A/D adrenoceptor stimulation. Furthermore, systemic administration of risperidone increased 5-HT efflux. in the DRN and caused a corresponding attenuation of serotonergic cell firing in this nucleus. Administration of idazoxan alone was found to preferentially enhance DA output in the mPFC and, significantly, to specifically and largely potentiate the only minimal increase in cortical DA efflux induced by raclopride. In parallel behavioral experiments idazoxan caused a dramatic augmentation of the suppression of CAR induced by raclopride, without any increase in catalepsy scores.

These results indicate that the facilitation of cortical DA efflux per se may represent a critical component in the mode of action of atypical antipsychotic drugs when compared with that of classical D2 receptor antagonists, an effect that can be effectively achieved by combined [alpha]2A/D and D2/3 receptor blockade alone. The enhanced cortical DA output may be important both for the superior general efficacy of e.g. clozapine and for the advantageous effect on negative as well as cognitive symptoms in schizophrenia. The facilitatory action of risperidone and amperozide on cortical 5-HT efflux, an effect that also appears largely related to blockade of cortical [alpha]2A/D adrenoceptors, may be of further significance in this context, particularly as regards affective symptoms. Consequently, blockade of [alpha]2A/D adrenoceptors may represent both a rational and effective component of the pharmacological profile of an atypical antipsychotic drug.