STIMULATION OF RAT STRIATAL TYROSINE-HYDROXYLASE ACTIVITY FOLLOWING INTRANIGRAL ADMINISTRATION OF SIGMA-RECEPTOR LIGANDS

The effects of sigma ligands on turning behavior and striatal tyrosine hydroxylase activity were determined following microinjection of two chemically dissimilar sigma ligands into the rat substantia nigra. Str iatal tyrosine hydroxylase activity was monitored by measuring the amo unt of 3,4-dihydroxyphenylalanine (DOPA) formed following inhibition o f DOPA decarboxylase activity with m-hydroxybenzylhydrazine (NSD-1015) . The sigma ligands, 1,3-di-o-tolylguanidine (DTG) and (-)-deoxy-N-ben zylnormetazocine, produced a significant increase both in contralatera l turning and in tyrosine hydroxylase activity. The DTG-induced increa se in tyrosine hydroxylase activity was not antagonized by intranigral injection of the NMDA receptor antagonist, 3-(2-carboxypipera-zine-4- yl)-propyl-1-phosphonic acid (CPP). CPP alone produced significant con tralateral turning that was not accompanied by an increase in striatal tyrosine hydroxylase activity, indicating that turning per se is not sufficient to activate striatal tyrosine hydroxylase. The DTG-induced increase in tyrosine hydroxylase activity was antagonized by general a nesthetics such as halothane and chloral hydrate. These results indica te that occupancy of sigma receptors in the substantia nigra is associ ated with an activation of dopamine formation in dopaminergic terminal s in the striatum and support the concept that sigma activity in the s ubstantia nigra produces an activation of dopamine-mediated responses in the striatum.