Choksi NY, Hussain A, Myers AM, Owens CE, Harvey RD, Wyrick SD, Baldessarini RJ, Booth RG. Stimulation of brain cAMP and dopamine synthesis by adenosine A2 and σ3 agonists. Poster presented at Society for Neuroscience Annual Meeting, 1994
Guanosine binding protein (G-protein) coupled adenosine A2 receptors reportedly stimulate dopamine (DA) synthesis in rat striatum, possibly via increased adenylyl cyclase (AC) activity and intracellular adenosine-3’,5’- (cycli^-monophosphate (cAMP) concentration. We report that the adenosine A2 agonist 2-phenylaminnadennsine (2-PAD) stimulates tyrosine hydroxylase activity and DA synthesis in rat striatum in vitro (EC5O = 10 pM). 2-PAD also stimulates AC and cAMP formation in rat striatum in vitro (EC5O = 10 pM), and both effects are blocked by the adenosine A2 antagonist 3,7-dimethyl-1- prnparcylxanthine (DPMX). Using a gamma-butyrolactone (GBL) model, that isolates presynaptic neurons, 2-PAD stimulates DA synthesis in rat striatum in vivo after intracerebrnventricular (icv) injection. These results support the hypothesis that A2 agonists stimulate brain DA synthesis by activating presynaptic G-protein coupled A2 receptors to stimulate AC and cAMP. Sigma (g ) receptors also are proposed to be G-protein coupled and modulate DA synthesis in rat striatum. Novel frans-1-phenyl-3-amino-1,2,3,4- tetrahydronapthalenes (PATs) were synthesized and shown to increase brain DA synthesis by a proposed o (03) receptor. Preliminary binding data, using non-hydrolyzable cuannsine triphosphate, support the hypothesis that the [3h ]- H2PAT-03 sites are G-protein coupled. Using the GBL model, H2PAT stimulates DA synthesis in rat nucleus accumbens in vivo by 175% at 10 pg/kg icv. These results are consistent with autoradiographic mapping that indicate [3h ]-H2PAT binding is highest in nucleus accumbens. Signal transduction pathways for 03 sites are under investigation.