α2-Adrenoceptors are targets for antipsychotic drugs

Almost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D-2 receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7) and alpha(1)- and alpha(2)-adrenoceptors in addition to their antagonist effects at D-2 receptors. This short review is focussed on the potential role of alpha(2)-adrenoceptors in the antipsychotic therapy. Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. alpha(2)-Adrenoceptors are classified into three distinct subtypes in mammals, alpha(2A), alpha(2B) and alpha(2C). Whereas the alpha(2B)-adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic alpha(2A)-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-d-aspartate receptor hypofunction model have shown that alpha(2C)-adrenoceptor blockade or the combination of D-2 receptor antagonists with idazoxan (alpha(2A/2C)-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the alpha(2A/2C)-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia. It is concluded that alpha(2)-adrenoceptors may be promising targets in the antipsychotic therapy.