A cocaine analog, 2 beta-propanoyl-3 beta-(4-tolyl)-tropane (PTT), reducestyrosine hydroxylase in the mesolimbic dopamine pathway

Tyrosine hydroxylase (Th) is the rate-limiting enzyme in catecholamine bios ynthesis. Previously published results have established that chronic cocain e administration (30-45 mg/kg per day, 10-14 days) resulted in an upregulat ion of TH gene expression in dopaminergic pathways of rats. The present stu dies tested the effects of a tropane analog, PTT (2 beta -propanoyl-3 beta- (4-tolyl)-tropane), on TH expression. This drug has similar actions to coca ine, but possesses markedly different pharmacokinetics (20 times more poten t at binding the dopamine transporter, markedly increased metabolic stabili ty, and 10-20 times more potent in behavioral measures). Moreover, PTT demo nstrates an increased selectivity for the dopamine (DA) and norepinephrine (NE) transporters compared with cocaine. In direct contrast to the previous ly reported effects of cocaine, 10 days of PTT administration (3.0 mg/kg pe r day, i.p.) produced a uniform downregulation of TH protein and activity g ene expression. TH activity and immunoreactive protein where decreased by 5 4 and 69%, respectively in the nucleus accumbens. Within the ventral tegmen tal area, TH activity and protein were decreased by 33 and 19%, respectivel y. The underlying mechanisms for these fundamental differences are unclear, but likely reflect varying and selective affinities and lengths of occupan cy at biogenic amine transporters. (C) 2000 Elsevier Science ireland Ltd. A ll rights reserved.