THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
The dopamine hypothesis for schizophrenia was the second neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia, especially the cognitive impairment. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive and negative symptoms (emotional blunting, social withdrawal, lack of motivation), cognitive impairment, and possibly depression. It is also essential to understanding the mechanisms of action of most and probably all antipsychotic drugs.
Several lines of evidence suggest that excessive limbic dop-aminergic activity plays a role in psychosis. (1) Many antipsy-chotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic and striatal-frontal system; this includes partial dopamine agonists, such as aripiprazole and bifeprunox. (2) Drugs that increase dopaminergic activity, such as levodopa, amphetamines, and bromocriptine and apomorphine, either aggravate schizophre-nia psychosis or produce psychosis de novo in some patients.
Dopamine-receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. (4) Some but not all postmortem studies of schizophrenic subjects have reported increased dopamine levels and D2-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D2 receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release.
However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia. Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia. Postmortem and in vivo imaging studies of cor-tical, limbic, nigral, and striatal dopaminergic neurotransmis-sion in schizophrenic subjects have reported findings consistent with diminished dopaminergic activity in these regions. Decreased dopaminergic innervation in medial temporal cor-tex, dorsolateral prefrontal cortex, and hippocampus, and decreased levels of DOPAC, a metabolite of dopamine, in the anterior cingulate have been reported in postmortem studies. Imaging studies have found increased prefrontal D1-receptor levels that correlated with working memory impairments.
The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizo-phrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors. Serotonin receptors— particularly the 5-HT2A-receptor subtype—may mediate synergis-tic effects or protect against the extrapyramidal consequences of D2 antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems, eg, serotonin and glutamate. The atypical antipsychotic drugs share the property of weak D2-receptor antagonism and more potent 5-HT2A-receptor blockade.