Mechanism of Action of Antipsychotic Drugs: Focus on the Nucleus Accumbens and the Prefrontal Cortex

Antipsychotic drugs have been classified as typical or atypical. To achieve an effective antipsychotic effect with typical antipsychotic drugs, e.g. haloperidol, a dopamine D2 receptor blockade of about 70% seems necessary. On the other hand, the prototype for atypical antipsychotic drugs clozapine is clinically effective already at about 45% D2 receptor occupancy. Clozapine possesses affinity for a large number of receptors and an important question is to what extent these other receptor affinities may contribute to its therapeutic action. Atypical antipsychotic drugs have been claimed to exert an advantageous effect on negative symptoms as well as cognitive deficits in schizophrenia. These symptoms/deficits are thought to be largely related to dysfunctions in the prefrontal cortex, and both preclinical and clinical studies indicate deficits in prefrontal dopamine functioning, which in turn may be linked to a glutamatergic dysfunction in the prefrontal cortex. By using in vivo voltammetry in anaesthetized rats we have examined to what extent different types of antipsychotic drugs modulate dopamine release in two subdivisions of the nucleus accumbens, the core and the shell, regions that are associated with motor control and limbic functions, respectively. Haloperidol and drugs that yield a high D2 receptor occupancy induced a higher dopamine release in the core than in the shell. In contrast, atypical antipsychotic drugs, given in doses that generate high 5-HT2but low D2 receptor occupancy, caused a higher dopamine output in the shell than in the core. Both selective 5-HT2Aand α1 adrenoceptor antagonists caused a significantly increased dopamine output exclusively in the shell region. In addition, even very low doses of haloperidol which generate very low D2 receptor occupancies still induced the highest dopamine output in the core. These results show that typical and atypical antipsychotic drugs exert differential effects on dopaminergic function in the two subdivisions of the nucleus accumbens. Whereas the typical profile largely seems to be related to the D2 receptor blockade, the atypical profile may also involve actions at other receptors, such as 5-HT2Aand α1 receptor blockade. Clozapine is a potent α2 adrenoceptor antagonist and adjunctive treatment with idazoxan, an α2 adrenoceptor antagonist, enhances the effect of typical antipsychotic drugs in treatmentresistant schizophrenia. The effects of clozapine, idazoxan, the D2/3 receptor antagonist raclopride and the combination of idazoxan and raclopride were examined on i) glutamatergic neurotransmission in the medial prefrontal cortex, using electrophysiological intracellular recording in pyramidal cells in vitro, and ii) impaired cognitive performance induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test in rats. Whereas neither idazoxan nor raclopride had any effect when given alone, the combination exerted the same facilitation of glutamatergic transmission as clozapine, an effect found to be mediated by D1 receptor activation. In similarity with clozapine, the combination of α2and D2/3 receptor blockage completely reversed the impaired cognitive function. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D2-, α2Aand α2C receptors. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable α2 adrenoceptor antagonistic properties. Schizophrenic patients are mostly heavy smokers. Nicotine has been shown to improve both cognitive dysfunction and negative symptoms in schizophrenia, and it has been suggested that the intense tobacco consumption may represent a form of self-medication with nicotine. We examined whether nicotine, when given alone or in combination with raclopride or L-745,870, a D4 antagonist, might facilitate glutamatergic neurotransmission in the medial prefrontal cortex, using intracellular recording in pyramidal cells in vitro. Neither nicotine, nor raclopride or L-745,870 showed any effect. However, combining nicotine with raclopride or L-745,870 facilitated glutamatergic transmission, supporting a cognitive-enhancing effect of nicotine in schizophrenic patients.