Withdrawal from Repeated Cocaine Alters Dopamine Transporter Protein Turnover in the Rat Striatum

Abstract

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. 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.

Presynaptic regulation of dopaminergic neurotransmission

“…2002). With chronic cocaine treatment, most evidence points to a decrease in DAT expression following a sufficient withdrawal period (Kuhar and Pilotte 1996), although both decreased and increased mRNA/protein levels have been reported (for a recent review of the literature see Kimmel et al . 2003).…”

Cocaine administration increases the fraction of CART cells in the rat nucleus accumbens that co-immunostain for c-Fos

“…Turnover measurements reflect release and/or synthesis rates that have been found to change and reflect activity even when levels do not. Similarly, protein levels may not change while changes in turnover rates are significant (for example, Kimmel et al, 2003). However, methods for measuring turnover rates of most peptides have not been developed.…”

Measuring levels of proteins by various technologies: Can we learn more by measuring turnover?

“…It is assumed that the rate of return of binding reflects new synthesis, rather than the chemical separation and loss of RTI-76 blockade. Studies by Kimmel, et al, [10, 11] have shown (Table 1), that acute cocaine administration can cause a significant increase in the half-life of DATs, while the change in Bmax (or level) of the transporters is not significantly different. Similarly, withdrawal from repeated cocaine results in a significant decrease in half-life, while again there is no change in the Bmax or levels of DATS in treated animals versus control animals.…”