Abstract
Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB 1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.
Highlights
Parkinson’s Disease (PD) treatment has been based on dopamine (DA) replacement therapy for 35 years
To test the hypothesis that endocannabinoids act as endogenous antidyskinetic agents with modulatory effects on abnormal basal ganglia circuits, we examined endocannabinoid production in specific areas of the basal ganglia of rats infected with Borna disease virus (BD rats) and how cannabinoid agonists and antagonists affect their motor behaviors
BD rats develop spontaneous dyskinesias, retrocollis, dystonia, locomotor hyperactivity, stereotypies, together with regional differences in anandamide levels in the basal ganglia circuit compared to NL rats [ F(9,99) = 3.682 P = 0.001]
Summary
Parkinson’s Disease (PD) treatment has been based on dopamine (DA) replacement therapy for 35 years. Side effects resulting from long-term use of DA agonists, namely dyskinesias and on–off responses, are prompting investigations of alternative neurotransmitter manipulations to modulate basal ganglia function and normalize motor activity. Dyskinesias often result from lesion or disturbance. Endocannabinoids, the endogenous ligands of cannabinoid (CB) receptors, are synthesized upon demand by neurons in response to depolarization (Freund et al, 2003), and, once released, diffuse backwards across synapses to suppress pre-synaptic GABA or glutamate release
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