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Title

Chronic Δ⁹-tetrahydrocannabinol exposure induces a sensitization of dopamine D₂/₃ receptors in the mesoaccumbens and nigrostriatal systems

Authors
Moulin-Sallanon, Marcelle
Published in Neuropsychopharmacology. 2012, vol. 37, no. 11, p. 2355-2367
Abstract Δ⁹-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB₁R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB₁R and DA D₂-receptors (D₂R) suggests that D₂R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1 mg/kg/day; 21 days) on D₂R and D₃R availabilities using the D₂R-prefering antagonist and the D₃R-preferring agonist radiotracers [¹⁸F]fallypride and [³H]-(+)-PHNO, respectively. At 24 h after the last THC dose, D₂R and D₃R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D₂R with no change in D₂R mRNA expression, whereas in nucleus accumbens (NAcc) both D₃R binding and mRNA levels were upregulated. These receptor changes, which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation, correlated with an increased functionality of D₂/₃R in vivo, based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly, the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D₂/₃R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D₂/₃R supersensitivity in NAcc and CPu. Such D₂/₃R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC.
Keywords Amphetamine/pharmacologyAnalysis of VarianceAnimalsBasal Ganglia/diagnostic imaging/drug effects/metabolismBenzamides/pharmacokineticsDopamine Agonists/pharmacologyDopamine Antagonists/pharmacokineticsDopamine Uptake Inhibitors/pharmacologyDose-Response Relationship, DrugDronabinol/pharmacologyDrug InteractionsFluorodeoxyglucose F18/pharmacokineticsGene Expression Regulation/drug effectsLocomotion/drug effectsMaleNucleus Accumbens/diagnostic imaging/drug effects/metabolismPositron-Emission TomographyProtein Binding/drug effectsPsychotropic Drugs/pharmacologyQuinpirole/pharmacologyRNA, Messenger/metabolismRatsRats, Sprague-DawleyReceptors, Dopamine D2/genetics/metabolismTritium/pharmacokineticsVitamin K 1/analogs & derivatives/pharmacokinetics
Identifiers
PMID: 22692568
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Article (Published version) (782 Kb) - public document Free access
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Research group Neuroimagerie moléculaire en psychiatrie (983)
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GINOVART, Nathalie et al. Chronic Δ⁹-tetrahydrocannabinol exposure induces a sensitization of dopamine D₂/₃ receptors in the mesoaccumbens and nigrostriatal systems. In: Neuropsychopharmacology, 2012, vol. 37, n° 11, p. 2355-2367. https://archive-ouverte.unige.ch/unige:92656

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Deposited on : 2017-03-16

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