α 2 -Adrenoceptors are targets for antipsychotic drugs

Rationale 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-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 6 , 5-HT 7 ) and α 1 - and α 2 -adrenoceptors in addition to their antagonist effects at D 2 receptors. Objective This short review is focussed on the potential role of α 2 -adrenoceptors in the antipsychotic therapy. Results Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. α 2 -Adrenoceptors are classified into three distinct subtypes in mammals, α 2A , α 2B and α 2C . Whereas the α 2B -adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic α 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 α 2C -adrenoceptor blockade or the combination of D 2 receptor antagonists with idazoxan (α 2A/2C -adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the α 2A/2C -adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia. Conclusions It is concluded that α 2 -adrenoceptors may be promising targets in the antipsychotic therapy.