The role of serotonin receptor effects in the development of antipsychotic medications
The improvement of the secondary negative symptoms, along with the symptoms of depression often associated with schizophrenia, has been an important feature of the SGAMs. Such findings may reflect the actions of the SGAMs on serotonin (5-hydroxytryptamine, 5HT) sub-type 5HT2A and 5HT1A receptors in addition to their actions on dopamine receptors. For example, all these drugs have a high affinity for 5HT 2A and 5HT2C receptors and, to a lesser extent, 5HT 1A, 5HT 6 and SHT 7 receptors . For these reasons, several compounds have been developed with a high affinity for 5HT2 receptors. Of these, pipamerone, a highly selective 5HT2/dopamine (D)2 antagonist, has been shown to have an antiautistic, disinhibiting and resocializing effect and a low frequency of EPSs . By contrast, MDL 100,907 (Hoest/Marion Roussel, New Jersey, USA), a compound largely lacking D2 antagonism but which is a potent 5HT 2A antagonist, while showing promising antipsychotic properties in preclinical studies, was not found to be as effective as haloperidol in the treatment of schizophrenia. Similarly, the D4/5HT2A antagonist fananserin lacked clinical efficacy despite a promising experimental profile . It is not without interest that several selective D4 antagonists have failed to show clinical efficacy in the treatment of schizophrenia, despite the evidence that some typical (e.g. haloperidol) and atypical (e.g. clozapine) agents increase the density of these receptors following chronic treatment . Thus, it would appear that the 5HT2A antagonism, together with D2 antagonism, may contribute to the atypical profile of the new antipsychotic drugs, but the 5HT2A antagonism alone does not appear to confer antipsychotic effects.
Adrenergic receptors and antipsychotic action
While most schizophrenia research has focused on the importance of dopamine, there is evidence that hyperactivity of the noradrenergic system also occurs in these patients. There is clinical evidence that the alpha-2 adrenoceptor antagonists can improve memory in patients with schizophrenia, and that SGAMs are more effective than typical neuroleptics in normalizing the cognitive deficits in these patients, presumably because of their actions on alpha-2 receptors . There is also evidence that both alpha-1 adrenoceptors and 5HT2A receptor stimulation of the prefrontal cortex can cause cortical dysfunction . As many of the SGAMs are antagonists of both alpha-1 and 5HT2A receptors, such actions could help to explain the improved cognitive function seen with these drugs. So far, such clinical and experimenta1 findings have not been extended to the development of novel antipsychotic drugs with a view to enhancing the improved cognitive action of SGAMs.
Glutamatergic Receptors And Antipsychotic Action
Recent experimental and clinical evidence suggests that the glutamatergic system plays a vital role in the pathophysiology of schizophrenia and may also contribute to the efficacy of SGAMs . In post-mortem brains from patients with schizohrenia, changes in RNA expression of the kainate and ?-amino-3-hydroxy-5-methyl-4-isoxa-zolepropionic acid (AMPA) metabotrophic receptors and in the subtypes of the ionotrophic NMDA receptors have been reported. Clozapine has been shown to decrease the densities of some of the NMDA-receptor subtypes, a change which correlates with an increase in