title: Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol-Mediated Induction of ΔFosB in the Mouse Forebrain.
abstract: Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen 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 Δ FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced ΔFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of the dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated ΔFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was 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 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP-32 KO and WT mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated ΔFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated ΔFosB induction and modulation of motor activity appears to be more complex.
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Lazenka
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Tomarchio
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.).
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (M.F.L., A.J.T., A.H.L., D.E.S., L.J.S.-S.); and Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York (P.G., M.F.) ljsimsel@vcu.edu.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*
chemical_list: D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C483819:Fosb protein, mouse; C497929:Ppp1r1b protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D013759:Dronabinol; D004298:Dopamine