title: Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.
abstract: Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB₁R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB₁R desensitization varies by brain region, with CB₁Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB₁R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB₁Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB₁R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB₁R-mediated G-protein activation was assessed using CP55,940-stimulated [(35)S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB₁R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB₁R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB₁R signaling and adaptation in the striatum and limbic system.
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
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, VA, USA.
authors.forename: Bethany G
authors.initials: BG
authors.lastname: David
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
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, VA, USA. Electronic address: ljsimsel@vcu.edu.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D019204:GTP-Binding Proteins / Q000378:metabolism; D016758:Genes, jun; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D043884:Receptor, Cannabinoid, CB1; D018808:Transcription Factor AP-1; D013759:Dronabinol; D019204:GTP-Binding Proteins
keywords: Amygdala; Basal ganglia; Dopamine receptor; G-protein; Striatum; Δ(9)-Tetrahydrocannabinol
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