Cocaine‐Induced Immediate‐Early Gene Expression in the Nucleus Accumbens: Roles of Separate cAMP Sensors

Immediate-early gene (IEG) induction guides elucidation of signaling pathways mediating neuronal plasticity underlying compulsive use of psychostimulants. IEG induction after psychostimulant administration has been attributed to both PKA- and RapGEF2-dependent signaling pathways initiated by D1 receptor stimulation by dopamine. However, it is not clear how each pathway contributes individually to IEG induction, dopaminoceptive neuronal activity, and neuronal plasticity. We used Cre-LoxP technology and a novel Cre-amplifier transgene to delete RapGEF2 only in D1-MSNs, and investigate its role in cocaine-induced IEG and behavioral responses. D1-MSN-specific RapGEF2 deletion blocked cocaine-induced ERK phosphorylation and Egr-1 induction, without affecting cocaine self-administration or c-Fos induction by cocaine. Deletion of Rap1 in D1-MSNs blocked cocaine-induced p-ERK and Egr-1 expression, but not the induction of c-Fos. Like RapGEF2 deletion, Rap1 deletion from D1-MSNs had no effect on final maintenance of stable cocaine self-administration, although the rate of acquisition was significantly impaired. These results suggest that D1-dependent activation of Egr1 is not ultimately required for cocaine self-administration, although it may affect the behavioral dynamics of this process. Suppressing cAMP elevation in D1-MSNs by D1-specific expression of PDE4D3-cat greatly reduced induction of both Egr-1 and c-Fos in NAc after cocaine administration, demonstrating that induction of both IEGs requires cAMP elevation in D1-MSNs. Specific inhibition of PKA activity via PKI-alpha expression in D1-MSNs also blocked both c-Fos and Egr-1 induction. Thus, acute or chronic cocaine administration activates at least two separate cAMP effectors in D1-MSNs. PKA activation leads to c-Fos induction, likely through CREB, and to Egr1 activation via Rap1, likely through a previously reported dependence on RasGRP2. RapGEF2 activation leads exclusively to Egr1 induction. The finding that PKA activates the ERK-Egr-1 signaling pathway by convergence on Rap1, and concomitantly activates c-Fos independently of Rap1, may underlie selective effects of RapGEF2 and PKA inhibition on psychostimulant-dependent behaviors in mice.