Chronic exposure to Δ⁹-tetrahydrocannabinol induces increased dopamine transporter availability

Abstract

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Objectives: A tight association exists between the brain cannabinoid system and dopaminergic circuits involved in addiction, schizophrenia and movement disorders. Ex vivo measurements have shown that delta-9-tetrahydrocannabinol (Δ⁹-THC), a cannabinoid-1 receptor agonist and the major active constituent of marijuana, may alleviate reduced striatal dopamine transporter (DAT) density in schizophrenia (Dean,Biol Psych 2003). Cannabinoids have been reported to be neuroprotective in acute and chronic neurodegeneration, e.g. against 6-hydroxydopamine toxicity in the model for PD (Lastres-Becker,Neurobiol Dis 2005). The aim of this study was to quantify the effect of Δ⁹-THC on in vivo striatal and midbrain DAT binding by microPET.

Methods: Six healthy Wistar rats (female, 200-250g, age 15-18w) were investigated in baseline condition, after acute (single injection of 0.5mg/kg IV) and chronic (2 weeks, 3mg/kg IP daily) administration of Δ⁹-THC (Lipomed, Switzerland, purity > 97 %). Behavioral testing using the cylinder test was done at day 0,2,7 and 14. Anesthesia was done using 60 mg/kg pentobarbital IP. After tail vein IV bolus injection of 17 MBq of ¹⁸F-FECNT, static acquisitions (40 min, start 3h p.i.) were conducted on a FOCUS microPET system. FPB reconstructed data were anatomically standardized and analyzed using a predefined VOI approach. Regional DAT binding ((activity-cerebellum)/cerebellum) was analyzed using paired t-tests.

Results: Cylinder tests showed increasing akinesia with chronic Δ⁹-THC exposure. FECNT binding in the striatum and substantia nigra was not affected by a single injection of Δ⁹-THC (all p>0.1). However, chronic Δ⁹-THC administration resulted in augmented DAT binding in the striatum, compared to baseline (+13 %, p=0.04). In the midbrain, FECNT binding was not affected.

Conclusions: Chronic Δ⁹-THC exposure induces DAT expression and/or affinity increases. These first-time in vivo findings contradict a possible role of Δ⁹-THC as DAT inhibitor to explain increases in extracellular dopamine levels (Sakurai, Pharm Biochem Behav 1989), but support alternative mechanisms e.g. by changes in cell firing (Pistis, Brain Res 2002; French, Neuroreport 1997). This quantitative pharmacological effect needs to be considered when investigating the neuroprotective effect of cannabinoid agonists in animal models of PD using DAT as biomarker, in the evaluation of cannabinoid-dopamine interactions in drug abuse and schizophrenia, or in evaluating patients for neurodegenerative movement disorders with previous chronic exposure to cannabis.

Research Support (if any): Supported by: EU FP6 DIMI project, K.U.Leuven Fund OT 05/59, IWT Flanders-Animone and FWO G.0548.06.