Acute administration of psychostimulants increases PKA activity and PKA-mediated phosphorylation of downstream targets. In rodents, acute injections of cocaine increase PKA-mediated phosphorylation of DARPP-32, NR1, and GluR1 in the medial prefrontal cortex and NAc,81 as well as phosphorylation of DARPP-32 in the striatum.72 Acute administration of cocaine in mice can increase PKA-mediated activation of protein phosphatase 2A (PP-2A), which then dephosphorylates DARPP-32 at the Cdk5-mediated phosphorylation site (Thr-75), promoting PKA-mediated signaling.72 The effect of chronic cocaine on PKA signaling depends on the species examined. In rats, chronic exposure to cocaine increases the level of Cdk5 in the striatum, attenuating the effects of PKA82 (discussed in the next section). However, chronic treatment of monkeys with cocaine for one year upregulates PKA catalytic subunit mRNA and protein in the NAc,83 suggesting that there may be an overall upregulation of PKA activity in primate NAc by prolonged exposure to cocaine.
