While all known antipsychotics have the common property of blockade of dopamine (DA) D2 receptors, it is still not evident how this translates into antipsychotic action. There is now considerable amount of evidence that the limbic regions of the cortex are directly affected in schizophrenia. It is thought that the limbic regions of the striatum recipient of limbic cortical efferents should play a particularly important role in the gating of this disturbed """"""""limbic""""""""- related neuronal processing. Since this, in turn, is modulated by the mesolimbic DA system several hypotheses have been developed to explain how antipsychotics might function in this system through DA D2 receptors. A renewed interest in the possibility that the actions of antipsychotics are directly mediated through D2 receptors has been fueled by the cloning of new members of this DA receptor family. The three identified members of the D2 receptor, the D2, D3 and D4 receptor, family show different patterns of expression in the rat and human brain. The D2 receptor is highly expressed in the terminal region of the nigrostriatal DA system and the D3 receptor in the terminal regions of the mesolimbic DA system, whereas the D4 receptor resides largely outside the basal ganglia. The differential anatomy of the D2 and D3 receptor has reintroduced the hypothesis that it is the mesolimbic DA system that is the site of antipsychotic action and the nigrostriatal DA system the site most directly implicated in the extrapyramidal actions of the antipsychotics. This time because different members of the D2 receptor family might mediate the actions of distinct DA pathways. Evidence has not been developed to directly implicate a """"""""disturbed"""""""" mesolimbic DA system in schizophrenia. We propose to test if the concentration of DA D3 receptors in the limbic striatum and its outputs is altered in schizophrenic tissue collected at post-mortem as compared to matched controls. Furthermore, if the concentration of D3 receptors is modified by concurrent antipsychotic treatment, unlike that for the D2 receptor, suggesting a direct mechanism of antipsychotic action. We hypothesize that elevations in D2 receptors reflect a response to antipsychotic treatment not observed for the D3 receptor. We propose to examine the relationship between D2 and D3 receptors and their mRNAs in the nigrostriatal and mesolimbic DA systems in schizophrenics on or off medication. The presynaptic components of the mesolimbic DA systems in schizophrenics on or off medication. The presynaptic components of the mesolimbic DA system differs from that of the nigrostriatal DA system in many biochemical features. We propose to explore if there are systematic differences in levels of tyrosine hydroxylase and the dopamine transporter, as well as their mRNAs, in the nigrostriatal and mesolimbic DA systems in these same cases to see if both pre- and postsynaptic components of the DA systems are modified in schizophrenia and antipsychotic treatment. Finally, effects of chronic antipsychotic treatment on D2 and D3 receptors and their mRNAs will be examined in an animal model to support conclusions of post-mortem human studies.
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