Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in D-Tetrahydrocannabinol–Mediated Induction of DFosB in the Mouse Forebrain s

D-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudateputamen and nucleus accumbens. However, the molecular events that underlie these interactions after THC treatment are not well understood. Our study shows that pretreatment with dopamine D1 receptor (D1R) antagonists before repeated administration of THC attenuated induction of D FBJ murine osteosarcoma viral oncogene homolog B (DFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced DFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of the dopamineand cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated DFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THCwas then acutely or repeatedly administered to wild-type (WT) and DARPP-32 knockout (KO) mice, and in vivo responses were measured. DARPP-32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to the WT mice. Agonist-stimulated guanosine 59-O-(3[S]thio)triphosphate ([S]GTPgS) binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP-32 KO andWTmice treated with vehicle or repeated THC. These results indicate that D1Rs play amajor role in THC-mediated DFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated DFosB induction and modulation of motor activity appears to be more complex.