The discovery of clozapine, and drugs like it, led to the dopamine hypothesis of schizophrenia,1 which had a high impact on the search for neurotransmitter functions. However, the pathophysiology of schizophrenic symptoms and the related mechanism of action of antipsychotics could not be fully explained. It became increasingly evident that schizophrenia is both a

complex disease, in which numerous factors contribute Inhibitors,research,lifescience,medical to the symptomatology, and a heterogeneous disease, most probably resulting from many different pathological causes. To underline this, no convincing evidence of abnormal biological findings valid for all or most of the patients with schizophrenia could be found. However, most clinical Inhibitors,research,lifescience,medical studies could demonstrate that antipsychotics were an effective treatment, in schizophrenia and that they considerably ameliorated the outcome of the disease. The disadvantage of these drugs are their major side effects, such as parkinsonian symptoms, dyskinesia, and akathisia, due to the extrapyramidal motor system, and sometimes depressive effects. Current knowledge suggests that the antipsychotic effect. of the typical antipsychotics is mediated by the ability to reduce mesolimbic selleck chemicals DAPT secretase dopaminergic activity, whereas the side effects

related to the extrapyramidal motor system are caused by a decreased Inhibitors,research,lifescience,medical dopaminergic activity in the nigrostriatal system.2 The introduction of clozapine with its unique pharmacological profile pointed Inhibitors,research,lifescience,medical to various theories. The unique effect, of clozapine contributed to the relative preponderance of clozapine in the mesolimbic system. Other biochemical features have been related to its pharmacological profile. Clozapine has different, affinities for the different dopamine receptor subtypes.

There are two major types of dopamine receptor: D1 and D2 receptors. Inhibitors,research,lifescience,medical The D1 receptor family includes D1 and D5, which are positively coupled to G-proteins, whereas the three D1-like receptors, D1, D1, and D1, inhibit the G-protein adenylate cyclase GSK-3 system. Clozapine has relatively stronger effects on the D1 and D2 receptors than other classic pathway signaling neuroleptics, which predominantly block the D2 receptors; o-benzamides like sulpiride and amisulpride have a relatively strong effect on the D3 receptors. In the case of clozapine, the ratio of D4 to D2 receptors is also crucial. In the last few years, this limited thinking focused on dopamine receptors has been abandoned in favor of a broader approach including other neurotransmitter systems in neuronal circuits. Clozapine and the new atypical antipsychotics also influence other neurotransmitter systems, notably the serotonin (5-hydroxy tryptamine) 5-HT2A receptor, the α1 and α2 adrenergic receptors, and sometimes the histaminic and muscarinic receptors.