Effects of intrastriatal infusion of D2 and D3 dopamine receptor preferring antagonists on dopamine release in rat dorsal striatum (in vivo microdialysis study)

Dopamine D2-1ike receptor antagonists haloperidol, spiperone, clozapine, cis-(+)-(1s,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ76, cis-(+)-(1s,2R)-5-methoxy-1-methyl-2-(n-di-propylamino)tetralin, (+)-UH232, and putative D3 dopamine receptor agonist (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin, 7-OH-DPAT, were infused via a transcerebral microdialysis probe into the dorsal striatum of freely moving rats. Local infusion of all the dopamine antagonists studied resulted in concentration-dependent increase of striatal dopamine release in vivo. Subsequent i.p. administration of the drugs did not produce a further rise of dopamine release as compared to the maximal increase elicited by local administration of the same substances. The difference between effects of D2 and D3 dopamine receptor preferring antagonists applied locally was observed only in the degree of dopamine release elevation [the maximal responses were about 160% for haloperidol and spiperone, 190% for clozapine and (+)-UH232 and 400% for (+)-AJ76, of basal]. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were elevated only slightly following local infusion of haloperidol, spiperone and clozapine, while systemic administration of the drugs resulted in a marked increase of metabolite extracellular levels. Both (+)-UH232 and (+)-AJ76 were found to increase significantly DOPAC and HVA levels during infusion, but the effect was less pronounced in comparison to that produced by systemic drug administration. Infusion of 7-OH-DPAT in the concentration range 5 x 10(-9) to 10(-6) M significantly decreased dopamine release but not metabolite levels down to the values observed following systemic drug administration. The present results give further evidence for the hypothesized leading role of nerve terminal dopamine autoreceptors, presumably of D3 type, in neuroleptic-induced augmentation of dopamine release in rat dorsal striatum. (C) 2001 Academic Press.