Abstracts

Rationale: Endocannabinoids are known to act at central cannabinoid-type 1 receptors (CB1R) on nerve terminals to modulate the release of neurotransmitters such as glutamate and GABA. This association suggests that the endocannabininoid system (ECS) may be involved in the control of neuronal excitability. In this study, as a prelude to studies in patients, we investigated whether chronic administration of the commonly used anti-epileptic drugs, valproate and levetiracetam altered CB1R binding using a novel CB1R PET tracer [¹⁸F]MK-9470.Methods: Six female Wistar rats (229-280g) were treated with valproate (200 mg/kg) or levetiracetam (50 mg/kg) IP daily for 2 weeks. Dynamic imaging of 18 MBq [¹⁸F]MK-9470 (Merck Inc, USA) was performed on a FOCUS220 microPET at baseline and after chronic treatment. Pentobarbital anesthesia was used during scanning (50 mg/kg). Images were spatially normalized to Paxinos space and analyzed by predefined VOI analysis using paired t-tests. Direct binding affinity of the drugs was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human CB1R.Results: Chronic treatment significantly increased MK-9470-binding in all brain regions by 41.0±3.9 % (mean±SD) for valproate (p<0.001) and by 7.3±2.0 % for levetiracetam (p=0.03). As both drugs do not exhibit high affinity for the CB1R (displacement of [³H]-SR141716A 1.3±14.0% for valproate; 5.4±1.9% for levetiracetam), such upregulation is most likely caused by an indirect effect on the endocannabinoid system (ECS). Since literature data have shown that valproate induces decreased or unchanged cerebral blood flow (CBF) and, we have found minimal effects of CBF on the SUV macroparameter for the tracer, changes in CBF caused by these drugs, especially valproate, are not likely to confound our results.Conclusions: Since activation of the ECS has been associated with anti-seizure effects, these results suggest that the ECS is, at least indirectly, involved in the cerebral effects of valproate and levetiracetam. For PET imaging with [¹⁸F]MK-9470 in patients with epilepsy, interaction with these drugs should be taken into account when quantitatively assessing the CB1R availability.