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

Abstract

Δ9-Tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB1 R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB 1 R and DA D2-receptors (D2 R) suggests that D2 R 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 D2 R and D 3 R availabilities using the D2 R-prefering antagonist and the D3 R-preferring agonist radiotracers 18 Ffallypride and 3 H-()-PHNO, respectively. At 24 h after the last THC dose, D2 R and D3 R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D2 R with no change in D2 R mRNA expression, whereas in nucleus accumbens (NAcc) both D3 R 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 D2/3 R 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 D2/3 R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D2/3 R supersensitivity in NAcc and CPu. Such D 2/3 R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC. © 2012 American College of Neuropsychopharmacology. All rights reserved.