Withdrawal from repeated cocaine alters dopamine transporter protein turnover in the rat striatum

Several studies have shown that repeated cocaine administration, followed by withdrawal, alters dopamine transporter (DAT) levels in the rat. These changes must arise from changes in either transporter protein production or degradation, or both. Previously, our laboratory developed an approach to measure the synthesis rate, degradation rate constant, and half-life of DAT in the rat striatum and nucleus accumbens after administration of the irreversible dopamine transporter ligand, RTI-76 [3beta-(3-p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride]. Transporter binding was measured with [(3)H]GBR12935 [1-(2-[diphenylmethoxy]ethyl)-4-[3-phenylpropyl]piperazine]. These initial studies showed that: 1) the half-life of the transporter was between 2 and 3 days in these two brain regions; 2) pretreatment with dopamine D1 and D2 receptor agonists and antagonists over several days differentially altered DAT half-lives in the striatum and nucleus accumbens; and 3) pretreatment with cocaine for several days increased the half-life of DAT by decreasing the degradation rate constant in both brain regions. In the present study, we determined that repeated pretreatment (10 days) with 20 mg/kg cocaine (i.p.) and a subsequent withdrawal period (10 days) alters the dopamine transporter turnover in the rat striatum, but not in the nucleus accumbens. Cocaine pretreatment and withdrawal reduced the half-life of the transporter protein from 2.1 days to 0.94 day in the striatum, but did not alter the half-life of 2.2 days in the nucleus accumbens. The results indicate the complex and long-lasting effects of cocaine administration on cellular processes. The mechanism(s) of these effects remains to be elucidated.