PKA activity is increased during withdrawal from many different addictive drugs. In rats withdrawn from cocaine, PKA activity is increased in the NAc for 30 days, returning to baseline by 90 days after withdrawal.117 In mice treated chronically with THC, withdrawal precipitated by acute administration of a CB1 antagonist transiently increases PKA activity in the cerebellum and is associated with increased somatic withdrawal signs such as shakes and tremors.90 In rat striatal neurons, morphine withdrawal precipitated by acute administration of naloxone results in enhanced PKA-mediated p-CREB induction.118 PKA activation and opiate or cannabinoid withdrawal may be causally related. Inhibition of PKA activity decreases withdrawal symptoms in rodents. In THC withdrawn mice, application of Rp-cAMPS to the surface of the cerebellar cortex decreases withdrawal signs. Similar application of Sp-cAMPS in naïve mice mimics some of the signs of THC withdrawal.90 In rats, injection of Rp-cAMPS into the locus coeruleus or periaqueductal gray matter attenuates signs of morphine withdrawal that are precipitated by naloxone.91
