The importance of dopaminergic mechanisms in the pathophysiology of schizophrenia was inferred from the association between efficacy of neuroleptic drugs and their affinity for the dopaminergic D2 receptor. Frontal cortex dysfunction in this disorder has been posited even longer. Neuroimaging and basic research studies provide robust evidence for abnormalities in both these domains in schizophrenia. A crucial question has been whether and how these pathophysiological phenomena interact. It has been proposed that exaggerated striatal dopaminergic neurotransmission in schizophrenia might result from dorsolateral prefrontal cortical dysfunction. This concept is also consistent with data demonstrating a correlation, again only in patients, between decreased N-acetyl-aspartate (a magnetic resonance spectroscopy marker of neuronal integrity) in Dorsolateral Prefrontal Cortex and exaggerated amphetamine-induced dopamine release. Deficits in working memory (WM) and in prefrontal cortical physiology are important outcome measures in schizophrenia and both have been associated with dopamine dysregulation and with a functional polymorphism (Val108/158Met) in the COMT gene that affects dopamine inactivation in prefrontal cortex. Consistently, recent studies suggest that the effects of treatment with atypical antipsychotics on prefrontal cortical functions are associated with the COMT genotype, further strengthening the significance of the relationship between dopamine in prefrontal cortex and dopamine regulation. The strategy of using partial dopamine agonists (PDAs) as antipsychotic agents is a novel approach to treating schizophrenia. PDAs behave as an agonist at autoreceptors and as an antagonist at postsynaptic receptors, blocking dopamine. Thus it has been hypothesized that a partial dopamine agonist may behave as an antagonist where and when dopamine concentration is relatively higher and as an agonist when dopamine concentration is relatively lower. Therefore, the pharmacodynamic properties of aripiprazole appear very promising and conceptually interesting for the treatment of schizophrenia. This drug is an attractive antipsychotic candidate having the potential of full action against psychosis coupled with blunted motor and negative cognitive side effects.
|Translated title of the contribution||Dopaminergic dysregulation in schizophrenia|
|Number of pages||10|
|Journal||Italian Journal of Psychopathology|
|Publication status||Published - Jun 2004|
ASJC Scopus subject areas
- Psychiatry and Mental health