The hypothesis that neurochemical abnormalities are involved in schizophrenia has a long history (Andreasen 1995). However, empirical evidence was provided only when the mode of action of antipsychotic drugs was shown to be related to catecholamine metabolism in the brain, and more specifically to blocking the effect of these drugs on the catecholamine postsynaptic receptors (Carlsson and Lindkvist 1963). Subsequent research indicated that it was the capacity of antipsychotics to block the dopamine-2(D2) receptors that was responsible for their clinical efficacy (Peroutka and Snyder 1980). Dopamine increases the sensitivity of brain cells to stimuli. Ordinarily, this heightened sensitivity is useful in increasing a person's awareness in times of stress or danger. However, for a person with schizophrenia, the addition of dopamine's effect to an already hyperactive brain state may tip that person into a psychosis.
     Additional support for the role of dopaminergic hyperactivation in schizophrenia came from the observation that amphetamine, a drug that increases dopamine's effects, worsens and may even elicit schizophrenia-like symptoms (Meltzer and Stahl 1976). This increased dopaminergic activity in the central nervous system occurs through two mechanisms:

1. increased availability of dopamine in synaptic sites and
2. receptor hypersensitivity.

Both these mechanisms have been extensively investigated in schizophrenia, but conclusive evidence in favour of either is thus far lacking. Studies of dopamine turn-over in patients' body fluids as well as direct determination of dopamine levels in postmortem brain tissue have yielded conflicting results (Heritch 1990; Hirsch and Weinberger 1995; Bloom and Kupfer 1995).
     Neuroimaging techniques, such as PET, have recently been applied to determine dopamine receptor density in the brain. While the blocking effect of classical antipsychotics on dopamine receptors has been clearly demonstrated, findings concerning dopamine-receptor density in drug-free patients compared to controls vary considerably among researchers (Wong et al. 1986; Farde et al. 1990). Using techniques of molecular biology, an increased dopamine receptor density and sensitivity in postmortem brain tissue of drug-free patients with schizophrenia have been demonstrated (Seeman 1987, 1995; Stefanis et al. 1998). When the atypical antipsychotics (clozapine, followed by risperidone, olanzapine, and others) were introduced, researchers began to question the assumption that the D2 blocking effect of antipsychotics was the major factor accounting for their antipsychotic action. It has been demonstrated that the mode of action of the "atypical" antipsychotics involves a close affinity for several receptors besides the D2 dopamine receptors, including serotonin (5-HT) receptors. (Meltzer et al 1996). Current research findings therefore suggest that many other receptor sites, such as D1, D3, D4, 5-HT2, and NMDA, are also likely to be involved in the pathogenesis of schizophrenia (Hirsch and Weinberger 1995; Seeman 1995; Kerwin et al. 1997).

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