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

Neuropsychopharmacology. 2012 Oct;37(11):2355-67. doi: 10.1038/npp.2012.91. Epub 2012 Jun 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Analysis of Variance
  • Animals
  • Basal Ganglia / diagnostic imaging
  • Basal Ganglia / drug effects
  • Basal Ganglia / 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
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Positron-Emission Tomography
  • Protein Binding / drug effects
  • Psychotropic Drugs / pharmacology*
  • Quinpirole / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Tritium / pharmacokinetics
  • Vitamin K 1 / analogs & derivatives
  • Vitamin K 1 / pharmacokinetics

Substances

  • 2-phytyl-1,4-naphthoquinone
  • Benzamides
  • Dopamine Agonists
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Psychotropic Drugs
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Fluorodeoxyglucose F18
  • Tritium
  • Quinpirole
  • Dronabinol
  • Vitamin K 1
  • Amphetamine
  • fallypride