Chronic Δ⁹-tetrahydrocannabinol exposure induces a sensitization of dopamine D₂/₃ receptors in the mesoaccumbens and nigrostriatal systems.
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.
University Department of Psychiatry, University of Geneva, Geneva, Switzerland. nathalie.ginovart@unige.ch
Nathalie
N
Ginovart
Benjamin B
BB
Tournier
Marcelle
M
Moulin-Sallanon
Thierry
T
Steimer
Vicente
V
Ibanez
Philippe
P
Millet
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001549:Benzamides / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004347:Drug Interactions; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009714:Nucleus Accumbens / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000493:pharmacokinetics
C510195:2-phytyl-1,4-naphthoquinone; D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019788:Fluorodeoxyglucose F18; D014316:Tritium; D019257:Quinpirole; D013759:Dronabinol; D010837:Vitamin K 1; D000661:Amphetamine; C574003:fallypride