Chronic ??-tetrahydrocannabinol exposure induces a sensitization of dopamine D?/? receptors in the mesoaccumbens and nigrostriatal systems.

ABSTRACT: ??-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB?R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB?R and DA D?-receptors (D?R) suggests that D?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 D?R and D?R availabilities using the D?R-prefering antagonist and the D?R-preferring agonist radiotracers [¹?F]fallypride and [³H]-(+)-PHNO, respectively. At 24?h after the last THC dose, D?R and D?R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D?R with no change in D?R mRNA expression, whereas in nucleus accumbens (NAcc) both D?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 D?/?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 D?/?R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D?/?R supersensitivity in NAcc and CPu. Such D?/?R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC.

SUBMITTER: Ginovart N 

PROVIDER: S-EPMC3442351 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature