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(1)Rs). Although considerable preclinical evidence has demonstrated several functional CB1R-DA interactions, the relation between human CB1R availability, DA release capacity and drug-reinforcing effects has been never investigated so far. Here, we perform a multitracer [F-18]MK-9470 and [F-18]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 CB1R expression levels and DA release capacity in a normo-DAergic state, relating in vivo AMPH-induced DA release to CB1R 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 CB1R levels. Compared with placebo, AMPH significantly reduced [F-18]fallypride binding potential (hence increase DA release; Delta BPND 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 CB1R 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 CB1R 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 CB1R availability in the ACC (c ' = -0.76; p = 0.01). Our small preliminary study reports for the first time that the human prefrontal CB1R 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 CB1R 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.