Dopamine D3-preferring ligands act at synthesis modulating autoreceptors.

Several compounds exist that demonstrate a binding preference for cloned dopamine D3 receptors vs. D2 receptors, including (+/-)7-OH DPAT, (+)-UH232 and (+)-AJ76. Inasmuch as recent evidence suggests that the dopamine D3 receptor may function as a dopamine autoreceptor, we have investigated the ability of these D3-preferring ligands to act at synthesis modulating dopamine autoreceptors using the gamma-butyro-lactone model in vivo to isolate the presynaptic effects of (+/-)7-OH DPAT, (+)-UH232 and (+)-AJ76. Further, given the discrete anatomical distribution of the D3 receptor, the striatum, n. Accumbens, and olfactory tubercles were examined for comparative analyses. (+/-)7-OH DPAT displayed agonist characteristics at synthesis modulating dopamine autoreceptors with a greater potency in the olfactory tubercle vs. either the striatum or the nucleus accumbens (ED-50 values were 31.8, 38.1 and 10.2 micrograms/kg for the striatum, nucleus accumbens and olfactory tubercles, respectively). Further, (+)-UH232 and (+)-AJ76 attenuated the effects of (+/-)7-OH DPAT (60 micrograms/kg s.c.) in all three regions examined. However, the effects of (+/-)7-OH DPAT were antagonized to a lesser extent in the olfactory tubercles than in either the striatum or the nucleus accumbens. Given the relative abundance of D3 receptors in the olfactory tubercles, the data are consistent with the notion that (+/-)7-OH DPAT may exert its autoreceptor effects preferentially through dopamine D3 receptors.