title: Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor-mediated signalling in midbrain and striatum.
abstract: This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence.
authors.affiliation: Biomarkers of vulnerability Unit, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Tournier
authors.affiliation: Biomarkers of vulnerability Unit, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland; University Department of Psychiatry, University of Geneva, Geneva, Switzerland.
authors.forename: Stergios
authors.initials: S
authors.lastname: Tsartsalis
authors.affiliation: University Department of Psychiatry, University of Geneva, Geneva, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dimiziani
authors.affiliation: Biomarkers of vulnerability Unit, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Millet
authors.affiliation: Biomarkers of vulnerability Unit, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland; University Department of Psychiatry, University of Geneva, Geneva, Switzerland. Electronic address: nathalie.ginovart@unige.ch.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
mesh_terms: D000818:Animals; D001345:Autoradiography; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000187:drug effects / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013997:Time Factors
chemical_list: C000607792:DRD2 protein, rat; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C581680:Syap1 protein, human; D019257:Quinpirole; D013759:Dronabinol
keywords: Behavioral sensitization; D(2/3) receptors; Dopamine; Quinpirole; THC