Cocaine abuse is an important problem: in the US alone it is estimated that there over 5 million cocaine users in 2000. Studies have shown that GABA-B receptor (GABABR) agonists and modulators are effective in reducing cocaine consumption in humans and/or animal models of addiction. The GABABR mediates slow metabotropic. inhibition, and expression of two subunits GABABR1 (R1) and GABABR2 (R2) is believed required for receptor function. Expression of the R1 isoforms (R1a and R1b) is under the control of alternative promoters in the R1 gene. The promoters are differentially regulated by CREB family members and by the upstream stimulatory factor (USF) that recognizes a composite CRE/Ebox site in R1b. Interestingly, chronic cocaine exposure leads to an increase in phosphorylated CREB. In this proposal, we will test the role that CREB, ATF4, and USF play in controlling endogenous expression of R1a and R1b in the nucleus accumbens (NAc) (Aim 1). Then, we will the address whether R1a and R1b regulation in the NAc is affected by chronic baclofen treatment (Aim 2) and in a rat model of cocaine self-administration (Aim 3).
