The CB1 cannabinoid receptor agonist, HU-210, reduces levodopa-induced rotations in 6-hydroxydopamine-lesioned rats.
Parkinson's disease is a chronic neurodegenerative disease of the extrapyramidal system associated with dopaminergic neuronal loss in the basal ganglia. However, several other neurotransmitters, such as serotonin, gamma-amino-butyric acid and glutamate, are also related to the symptoms of Parkinson's disease patients and their response to levodopa treatment. The co-expression of cannabinoid and dopamine receptors in the basal ganglia suggests a potential role for endocannabinoids in the control of voluntary movement in Parkinson's disease. In the present study we treated unilaterally 2,4,5-trihydroxyphenethylamine (6-hydroxydopamine)-lesioned rats with the enantiomers of the synthetic cannabinoid 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl. Treatment with its (-)- (3R, 4R) enantiomer (code-name HU-210), a potent cannabinoid receptor type 1 agonist, reduced the rotations induced by levodopa/carbidopa or apomorphine by 34% and 44%, respectively. In contrast, treatment with the (+)- (3S, 4S) enantiomer (code-name HU-211), an N-methyl-D-aspartate antagonist, as well as the psychotropically inactive cannabis constituent: cannabidiol and its primary metabolite, 7-hydroxy-cannabinol, did not show any reduction of rotational behavior. Our results indicate that activation of the CB1 stimulates the dopaminergic system ipsilaterally to the lesion, and may have implications in the treatment of Parkinson's disease.
Gilgun-Sherki
Yossi
Y
Department of Neurology, Rabin Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel.
Melamed
Eldad
E
Mechoulam
Raphael
R
Offen
Daniel
D
D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology; D002230:Carbidopa / Q000009:adverse effects / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000187:drug effects*; D012399:Rotation; D013378:Substantia Nigra / Q000187:drug effects / Q000293:injuries
D002186:Cannabinoids; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D007980:Levodopa; D013759:Dronabinol; D016627:Oxidopamine; D002230:Carbidopa; D001058:Apomorphine; C062018:HU 211