Psychostimulants can also interact with AMPAR plasticity in more complex ways. The capacity of ΔFosB to modulate AMPA subunit expression is limited by a negative feedback loop involving inhibition of PKA by Cdk5 and phospho-Thr75 DARPP-32 via ΔFosB. The DARPP-32 phospho-Tyr75 form is the predominant form of DARPP-32 following repeated cocaine exposure (Scheggi et al., 2007). AMPAR activation leads to dephosphorylation of phospho-Thr75 of DARPP-32 thereby disinhibiting PKA (Nishi et al., 2002). Thus, the capacity of ΔFosB to limit PKA signaling can be counteracted by increased AMPAR recruitment (Juo et al., 2007; Kelz et al., 1999; Olson et al., 2005) In accord with possible AMPAR-mediated PKA disinhibition, Cdk5 inhibitors augment behavioral sensitization (Bibb et al., 2001). Thus, ΔFosB upregulation appears in part homeostatic (Winstanley et al., 2009), perhaps through a Cdk5-mediated inhibition of PKA, since the ΔFosB downstream target Cdk5 can interface with AMPAR and DARPP-32 to modulate psychostimulant reinforcement, motivation, and sensitization.
