Scientific article
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English

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

Published inNeuropsychopharmacology, vol. 37, no. 11, p. 2355-2367
Publication date2012
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/pharmacology
  • Analysis of Variance
  • Animals
  • Basal Ganglia/diagnostic imaging/drug effects/metabolism
  • Benzamides/pharmacokinetics
  • Dopamine Agonists/pharmacology
  • Dopamine Antagonists/pharmacokinetics
  • Dopamine Uptake Inhibitors/pharmacology
  • Dose-Response Relationship, Drug
  • Dronabinol/pharmacology
  • Drug Interactions
  • Fluorodeoxyglucose F18/pharmacokinetics
  • Gene Expression Regulation/drug effects
  • Locomotion/drug effects
  • Male
  • Nucleus Accumbens/diagnostic imaging/drug effects/metabolism
  • Positron-Emission Tomography
  • Protein Binding/drug effects
  • Psychotropic Drugs/pharmacology
  • Quinpirole/pharmacology
  • RNA, Messenger/metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2/genetics/metabolism
  • Tritium/pharmacokinetics
  • Vitamin K 1/analogs & derivatives/pharmacokinetics
Funding
  • Swiss National Science Foundation - Effects of a subchronic treatment with Delta9-tetrahydrocannabinol (THC) on behavior and in vivo dopamine function: a positron emission tomography study in rats
Citation (ISO format)
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. doi: 10.1038/npp.2012.91
Main files (1)
Article (Published version)
accessLevelPublic
Identifiers
Journal ISSN0893-133X
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196downloads

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