In vivo evidence for preferential role of dopamine D-3 receptor in the presynaptic regulation of dopamine release but not synthesis

Brain microdialysis was used to investigate the effects of the putative dopamine D-3 receptor agonist (+/-)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on dopamine release, metabolism and synthesis in the dorsal striatum and nucleus accumbens of awake rats. The drug administered i.p. dose dependently decreased the release, metabolism and synthesis of dopamine in both brain areas. The potency of 7-OH-DPAT to decrease dopamine release was found to be higher in the nucleus accumbens than in the dorsal striatum (ED(50) for nucleus accumbens 0.0096 mg/kg, i.p.; for dorsal striatum 0.068 mg/kg, i.p.). Dopamine metabolism, assessed by measuring 3,4-dihydroxyphenylacetic acid extracellular levels, and dopamine synthesis, determined as 3,4-dihydroxyphenylalanine output following perfusion with the L-aromatic acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (10(-5) M), were decreased at higher dose ranges of 7-OH-DPAT (ED(50) for decrease of 3,4-dihydroxyphenylalanine output in nucleus accumbens 0.124 mg/kg, i.p.; in dorsal striatum 0.101 mg/kg, i.p.). The hypomotility of rats induced by 7-OH-DPAT in doses of 0.002-0.25 mg/kg, i.p., was shown to correlate with the decreased dopamine release in the nucleus accumbens. Pretreatment of animals with 7-OH-DPAT at the putative dopamine D-3 receptor 'selective' dose of 0.05 mg/kg, i.p., was found to prevent the increase of dopamine release but not the increase in metabolism in the dorsal striatum of freely moving rats induced by (+)-AJ76, cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin HCl (7 mg/kg, i.p.) and haloperidol (0.1 mg/kg, i.p.). Local application of 7-OH-DPAT by addition into the perfusing medium also resulted in a preferential decrease of dopamine release in the nucleus accumbens as compared with the dorsal striatum (EC(50) for nucleus accumbens 1.9 nM; for dorsal striatum 11.3 nM). The present results give further support to the hypothesis that the dopamine D-3 autoreceptor is preferentialy involved in the presynaptic regulation of dopamine release, while the D-2 autoreceptor controls dopamine synthesis.