We proposed that novel brain sites, recognized by phenylaminotelralins (PATs), represented a subtype of sigma (a) receptors and termed these sites PAT-cy. Recently, however, we determined that PAT-csy receptors exhibit similar brain density and distribution not only to cq/c^ receptors, but also to histamine Hj receptors. Furthermore, the ligand binding profile at [3H]-PAT-csy receptors correlates more closely to the profile of Hs receptors (r2=0.9) than to the profile of a receptors (r2<0.1). Since the pharmacological profiles of PAT-o3 and Hi receptors in whole brain are similar, but not identical, our studies have focused on testing the hypothesis that a certain population of brain PAT receptors represent an Hj receptor subtype Functionally, several PATs moderately stimulate in vitro brain dopamine (DA.) synthesis (max. ca. 150% of control). Here we report the effects of PATs on in vivo DA synthesis in a presynaptic receptor model system. ICV administration of(i)-transH2-PAT, that has high affinity’ for PAT and H, receptors, modulates DA synthesis selectively in rat nucleus accumbens (i.e., not in striatum) in a biphasic manner. Doses from 0.08 to 8 nmole/rat. stimulate DA synthesis (ca. 200% of control), while doses from 20 to 200 nmole/rat decrease DA synthesis to control levels. (±)-CA-H2-PAT and triprolidine, antagonists that have high affinity for both PAT and H, receptors, block (±)-Zrara-H2-PAT-induced stimulation of DA synthesis. These results suggest that (±)-Zrara-H2-PAT activates nucleus accumbens DA synthesis through a presynaptic receptor mechanism. The selective H, agonist 2-thiazolylethylamine does not stimulate DA synthesis in our model, suggesting presynaptic H] receptors do not activate nucleus accumbens DA synthesis. We propose that (±)-Zrara-H2-PAT-induced stimulation of in vivo DA synthesis in rat nucleus accumbens occurs through activation of presvnaptic receptors that may represent a novel H, receptor subtype.