The Dopamine DA Hypothesis

Until recently, the modal hypothesis on the pathophysiology of schizophrenia was that excessive dopaminergic transmission in the forebrain is a key causative factor. This DA hyperfunction hypothesis was primarily based on the observation that all clinically effective antipsychotic drugs have potent antagonist or inverse agonist activity at DA D2 receptors, and that the therapeutic efficacy of these compounds was highly correlated with their affinity for striatal D2 receptors. In addition, the psychotomimetic properties of indirect DA agonists like amphetamine and cocaine, and observed alterations in striatal DA release in schizophrenic patients, further supported the involvement of DA in the pathophysiology of schizophrenia.

The DA hypothesis has been useful in stimulating research on the neurochemical alterations underlying schizophrenia, placing the DA D2 receptor at the center of antipsychotic drug development, in essence recapitulating existing antipsychotic agents in a circular manner. For example, DA D2 antagonists are effective in schizophrenia; therefore, schizophrenia is a dysfunction of DA D2 receptor signaling. There are several important criticisms of the DA hypothesis that suggest DA hyperfunction is not the sole cause of schizophrenia. As noted, current antipsychotics, all of which act at least in part by blocking DA D2 receptors, are uniformly ineffective in treating either the negative and cognitive symptoms of schizophrenia. In fact, at least 15% of schizophrenic patients do not respond in any significant manner to DA antagonist therapy. Interestingly, the clinical efficacy of currently available drugs develops with a time course much slower than can be accounted for by a simple model in which the antipsychotic drug binds to the DA D2 receptor. This suggests that the clinical efficacy of D2 antagonists is not an immediate consequence of acute D2 receptor blockade but is dependent on additional effects that only occur with chronic treatment, e.g., neurogenesis.10

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