Cannabinoids and opiates can increase PKA activity via dopaminergic stimulation of adenylyl cyclase. Acute treatment with CB1 agonists increases PKA activity in mouse striatum87,88 and NAc.88 This increased PKA activity is attenuated by antagonists of the CB187,88 or D1 receptors.88 The effect of chronic cannabinoid treatment is less clear-cut. Chronic treatment with THC in mice increases PKA activity in the cortex89 but can both increase89 and decrease PKA activity in the cerebellum.90 Similar to cannabinoids, acute stimulation of μ-opioid receptors in rat striatal neurons in vitro increases nuclear translocation of the PKA catalytic subunit and increases levels of p-CREB.68 Opiates can increase PKA signaling; this effect can be enhanced during opiate withdrawal.91 Opiates increase PKA-mediated phosphorylation in several brain regions including the NAc,92,93 striatum,92 hippocampus,94,95 and locus coeruleus,96 but do not increase this phosphorylation in the frontal cortex.97 In cultured striatal neurons, morphine activates PKA by activating μ-opioid receptors, leading to the release of Gβγ from Gi3, and subsequent activation of AC2 and AC4.68 In vivo however, morphine-induced activation of PKA in the NAc and dorsal striatum requires activation of D1 receptors coupled to Gαs/olf since it is blocked by the D1 antagonist SCH23390.92
