SIGMA RECEPTOR REGULATION OF DOPAMINE NEURONS

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The existence of sigma binding sites in the substantia nigra and striatum is supportive of a role of sigma receptors in the regulation of nigrostriatal dopamine neurons. Further supportive of this contention are the findings that sigma ligands induce circling behavior following intranigral injections, hyperlocomotion and stereotypy following icv injections and inhibition of nigral cell firing after iv administration. The overall goal of the proposed studies is to establish the extent to which sigma receptor ligands regulate the release of dopamine from nigrostriatal dopamine neurons and determine the conditions under which this regulation might be modified. Specifically, it is proposed to 1) determine the rank order of potency and enantioselectivity of pentazocine, N-allyl-nortmetazocine and DTG-induced increases in the release of dopamine from nerve terminals and dendrites of nigrostriatal neurons; 2) determine whether the down regulation of sigma receptors induced by chronic haloperidol treatment is accompanied by a desensitization of the sigma ligand induced release of striatal and nigral dopamine; and 3) determine whether the repeated administration of methamphetamine or (+)- pentazocine results in a drug-induced sensitization of the response of striatal dopamine release to a subsequent injection of the sigma Iigand. These studies will be conducted in awake, freely moving rats in which the release of dopamine in the striatum and substantia nigra will be assessed from the quantitation of extracellular dopamine concentrations by in vivo microdialysis. The effects of an acute injection of pentazocine, N-allyl- normetazocine or DTG on the extracellular concentrations of dopamine will be determined in drug naive rats (specific aim 1), in rats treated chronically with haloperidol (specific aim 2) or in rats treated chronically with methamphetamine or pentazocine (specific aim 3). Results of the proposed studies will provide insight into the neuromodulation of nigrostriatal dopamine neurons. In view of the role of these neurons in the control of movement and posture and the high affinity of antipsychotic drugs for sigma receptors, results from these studies also have implication for understanding the motor side effects of antipsychotic drugs.