REGULATION OF IMMEDIATE EARLY GENE-EXPRESSION AND AP-1 BINDING IN THE RAT NUCLEUS-ACCUMBENS BY CHRONIC COCAINE

Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into long-term changes in cellular functioning. We therefore examined changes in the mRNA levels for the IEGs c-fos, c-jun, fosB, junB, and zif268 in the NAc of rats treated acutely and chronically with cocaine. A single cocaine injection increased the mRNA levels of all of the IEGs examined. Following chronic cocaine treatment, however, IEG expression had returned to control levels and was not significantly increased following a further acute challenge with cocaine, suggesting desensitization in the ability of cocaine to induce these IEGs. Similarly, levels of Fos-like immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels in chronic cocaine-treated rats. Fos, Jun, and a number of related proteins activate or repress transcription of genes by binding to DNA response elements called AP-1 sites. As would be expected from the RNA data and immunohistochemistry, acute cocaine administration increased AP-1 binding activity in the NAc, an effect that reverted completely to control levels within 8-12 hr. In contrast, AP-1 binding activity in the NAc of animals treated chronically with cocaine remained elevated at acute levels 18 hr after the last chronic injection, a time at which c-fos and c-jun mRNA levels and Fos-like immunoreactivity had returned to control values. An additional acute cocaine challenge did not further increase AP-1 binding. The data suggest that chronic cocaine treatment leads to a persistent increase in AP-1 binding activity, which may be involved in some of the physiological and behavioral aspects of cocaine addiction.