A series of l-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs) are proposed to modulate brain dopamine (DA) biosynthesis through interaction with a novel guanine nucleotide binding protein (G-protein) coupled sigma (a) receptor subtype, termed σ3. Brain receptor mapping studies indicate that putative σ3 sites, labeled with [3H]-(1R,3S)-(-)-trans-l-phenyl-3-(N,N-dimethylamino)-1,2,3,4- tetrahydronaphthalene ([3H]-(-)-H2-PAT), are highly localized in limbic areas of mammalian forebrain, particularly the nucleus accumbens. Using an in vivo presynaptic receptor model, icv administration of (±)- trans-H2-PAT to rats modulates DA biosynthesis in the nucleus accumbens in a biphasic manner. At 0.4 to 40 nmole/kg, (±)-trans-R2- PAT stimulates DA synthesis (ca. 200%) vs. saline-treated animals. At 90 to 900 nmole/kg, (±)-trans-H2-PAT dose-dependently decreases DA biosynthesis to control levels, indicating that (±)-trans-H2-PAT produces complex effects on DA metabolism in vivo. Studies that suggest other a receptor subtypes are G-protein coupled prompted us to evaluate if σ3 receptors also couple to G-proteins. Preliminary results show that addition of a non-hydrolyzable guanine triphosphate analog [Gpp(NH)p] decreases [3H]-(-)-H2-PAT specific binding ca. 20% from untreated tissue, suggesting that [3H]-(-)-H2-PAT labeled σ3 receptors belong to the G-protein coupled receptor family. The signal transduction pathway associated with (-)-H2-PAT labeled σ3 receptors is currently under evaluation.