Midbrain dopamine neurons express inhibitory D2 dopamine autoreceptors. Therefore, D2 receptor antagonists such as the antipsychotic drug haloperidol act acutely to excite these cells. However, chronic haloperidol acts after a delay to decrease dopamine release and dopamine dependent behavior. The long-term regulation of dopamine neuron activity, which might contribute to the therapeutic action of antipsychotic drugs, has been a source of controversy because of the confounding effects of general anesthetics present during in vivo recording. We have used an experimental approach that bypasses the need for anesthetics to demonstrate that chronic haloperidol dampens the intrinsic excitability of young rat midbrain dopamine neurons. This is caused by upregulation of Kv4.3 A-type K+ channels. Furthermore, we find that this effect can be recapitulated in cell culture with chronic exposure to the D2 receptor antagonist sulpiride. In this proposal, we will determine: (i) whether Kv4.3 auxiliary subunit expression is also regulated by the antipsychotic drug, (ii) the ionic basis for irregular pacemaker activity induced by chronic haloperidol, (iii) whether an atypical antipsychotic drug acts similarly to remodel dopamine neuron excitability, (iv) the role of D2 receptors and second messengers in the long-term effect in vitro, and (v) how remodeling of dopamine neuron excitability depends on age and duration of antipsychotic drug treatment. These experiments will determine how D2 receptors and clinically used antipsychotic drugs remodel dopamine neuron intrinsic pacemaker activity. This long-term regulation may operate during normal development and in response to changes in D2 receptor activity induced by addictive and antipsychotic drugs. ? ?
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