Increased CREB phosphorylation appears to regulate cocaine reinforcement, as NAcb CREB overexpression reduced the reinforcing properties of cocaine while also increasing aversion to low cocaine doses (Carlezon et al., 1998). Conversely, NAcb CREB dominant-negative overexpression increased apparent cocaine-mediated reinforcement (Carlezon et al., 1998). However, CREB knockdown reduced the reinforcing efficacy of cocaine when measured via contingent cocaine delivery after instrumental responding (Choi et al., 2006) rather than if measured via Pavlovian conditioning following non-contingent cocaine exposure (Carlezon et al., 1998). While these data are themselves very intriguing, the diverse signaling pathways that impinge onto CREB (Shaywitz and Greenberg, 1999) are perhaps of even greater interest because phosphorylated CREB can promote the expression of transcription factors and other gene products that have also been implicated in addiction, e.g., preprodynorphin, NAC-1, and the various Homer isoforms (Hurd and Herkenham, 1993; Nestler, 2001). Thus, CREB may represent a molecular integrator of second messenger signaling systems that are common substrates of abused drugs.
