title: Bidirectional regulation of mu-opioid and CB1-cannabinoid receptor in rats self-administering heroin or WIN 55,212-2.
abstract: This study examines the effect of intravenous self-administration (SA) of either heroin or the cannabinoid receptor agonist WIN 55,212-2 on levels and functionality of mu-opioid (MOR) and CB1-cannabinoid receptors (CB1R) in reward-related brain areas, such as the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CP), hippocampus (Hippo), amygdala (Amy), hypothalamus (Hypo) and ventral tegmental area (VTA). [3H]DAMGO and [3H]CP-55,940 autoradiography and agonist-stimulated [35S]GTPgammaS binding were performed on brain sections of rats firmly self-administering heroin or WIN 55,212-2. Animals failing to acquire heroin or cannabinoid SA behaviour as well as drug-naïve animals never exposed to experimental apparatus or procedure (home-control group) were used as controls. With respect to control groups, which displayed very similar values, rats SA heroin showed increased MOR binding in the NAc (+174%), CP (+165%), Hippo (+121%), VTA (+175%), an enhanced CB1R density localized in the Amy (+147%) and VTA (+37%), and a widespread increased CB1 receptor functionality in the PFC (+95%), NAc (+313%), CP (+265%), Hippo (+38%), Amy (+221%). In turn, cannabinoid SA differently modulates CB1R binding in the Amy (+47%), Hypo (+94%), Hippo (-23%), VTA (-15%), and increases MOR levels (PFC: +124%; NAc: +68%; CP: +80%; Hippo: +73%; Amy: +99%) and efficiency (Hippo: +518%; Amy: +173%; Hypo: +188%). These findings suggest that voluntary chronic intake of opioids or cannabinoids induces reciprocal but differential regulation of MORs and CB1Rs density and activity in brain structures underlying drug-taking and drug-seeking behaviour, which could represent long-term neuroadaptations contributing to the development of drug addiction and dependence.
authors.affiliation: Institute of Neuroscience, National Research Council CNR, Section of Cagliari, Italy.
authors.forename: Liana
authors.initials: L
authors.lastname: Fattore
authors.forename: Daniela
authors.initials: D
authors.lastname: Viganò
authors.forename: Paola
authors.initials: P
authors.lastname: Fadda
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002186:Cannabinoids / Q000008:administration & dosage / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012646:Self Administration
chemical_list: D000701:Analgesics, Opioid; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D003932:Heroin; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol