Cannabinoid receptor availability modulates the magnitude of dopamine release in vivo in the human reward system: A preliminary multitracer positron emission tomography study.

The established role of dopamine (DA) in the mediation of reward and positive reinforcement, reward processing is strongly influenced by the type 1 cannabinoid receptors (CB Rs). Although considerable preclinical evidence has demonstrated several functional CB R-DA interactions, the relation between human CB R availability, DA release capacity and drug-reinforcing effects has been never investigated so far. Here, we perform a multitracer [ F]MK-9470 and [ F]fallypride positron emission tomography (PET) study in 10 healthy male subjects using a placebo-controlled and single-blinded amphetamine (AMPH) (30 mg) administration paradigm to (1) investigate possible functional interactions between CB R expression levels and DA release capacity in a normo-DAergic state, relating in vivo AMPH-induced DA release to CB R availability, and (2) to test the hypothesis that the influence of striatal DAergic signalling on the positive reinforcing effects of AMPH may be regulated by prefrontal CB R levels. Compared with placebo, AMPH significantly reduced [ F]fallypride binding potential (hence increase DA release; ΔBP ranging from -6.1% to -9.6%) in both striatal (p < 0.005, corrected for multiple comparisons) and limbic extrastriatal regions (p ≤ 0.04, uncorrected). Subjects who reported a greater dopaminergic response in the putamen also showed higher CB R availability in the medial and dorsolateral prefrontal cortex (r = 0.72; p = 0.02), which are regions involved in salience attribution, motivation and decision making. On the other hand, the magnitude of DA release was greater in those subjects with lower CB R availability in the anterior cingulate cortex (ACC) (r = -0.66; p = 0.03). Also, the correlation between the DA release in the nucleus accumbens with the subjective AMPH effect liking was mediated through the CB R availability in the ACC (c' = -0.76; p = 0.01). Our small preliminary study reports for the first time that the human prefrontal CB R availability is a determinant of DA release within both the ventral and dorsal reward corticostriatal circuit, contributing to a number of studies supporting the existence of an interaction between CB R and DA receptors at the molecular and behavioural level. These preliminary findings warrant further investigation in pathological conditions characterized by hypo/hyper excitability to DA release such as addiction and schizophrenia.