Blunted striatal dopamine release in cannabis dependence

Objectives Studies of dopamine (DA) release to psychostimulant challenge have consistently shown blunting in the striatum across multiple drugs of abuse, but results have been equivocal for cannabis. We examined amphetamine (AMPH) induced DA release in striatal and extra-striatal regions with PET to study cannabis dependent (CD) individuals who used cannabis heavily and no other substances, including nicotine. We used the D₃R-preferring agonist tracer [¹¹C]PHNO.

Methods 11 CD, following acute detoxification for 3 days, and 12 healthy controls (HC) underwent 2 PET scans on one day with [¹¹C]PHNO, at baseline and 3 hr following PO AMPH, 0.5 mg/kg. Scans were 2 hr and acquired on an mCT scanner. Each subject's PET data were registered to a high-resolution T1-weighted MRI image on which ROIs were drawn and transferred to the PET. Data were analyzed using SRTM with cerebellum as reference tissue. ROIs included associative striatum (AST), sensory motor striatum (SMST), limbic striatum (LST), globus pallidus (GP), thalamus (THA) and midbrain (MID). Outcome measures were BP_ND and the % change in BP_ND following AMPH (ΔBP_ND).

Results Baseline BP_ND did not differ between groups. Robust decrease of BP_ND was observed in all subjects following AMPH, but the extent of decrease was less in CD than in HC in AST (15% vs 21%, p=.008), SMST (25% vs 32% p=.005), and GP (13% vs. 23%, p=.01). Effect sizes for these differences were 1.4, 1.3 and 1.2, respectively. ΔBP_ND was decreased but not significantly different between groups in LST (26% vs 32%, p=.13 ), MID (28% vs 34%, p=.43), and THA (25% vs %27, p=.85).

Conclusions Blunted dopamine transmission in the associative and sensory motor subregions of the striatum is observed in CD with heavy use and no other substance dependencies. This pattern is different from that observed with other substances where the predominant effect is in LST. Future studies should investigate the significance of this pattern for the behavioral effects of cannabis, especially in terms of increasing the vulnerability to psychosis.

Research Support R01DA022455