Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell.

Cocaine addiction is characterized by compulsive drug seeking, including relapse after a period of withdrawal. The relapse response requires increased glutamate transmission in the nucleus accumbens (NAc). Consistent with this view, glutamate type 1 transporter (GLT1), the transporter responsible for >90% of glutamate uptake, is downregulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1-2 h/d). Human addiction, however, appears to be better modeled by extending daily drug access (6-8 h/d) and introducing long periods of withdrawal. Here, we determined the combined effects of manipulating cocaine access and withdrawal on GLT1 expression in NAc core and shell. Rats were trained to self-administer cocaine (0.25 mg per intravenous infusion) in daily limited or extended access sessions for 11 days followed by a period of short (1 day) or long (40-45 days) withdrawal. We found that although cocaine withdrawal decreases GLT1 expression in both core and shell, only in core is GLT1 downregulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is downregulated more than in shell in either the limited or extended access condition. Thus, glutamate regulation in core appears to be a critical factor in the drug-seeking behavior that follows relatively long periods of cocaine withdrawal.