C Pharmacology & Toxicology 2003, 93, 66–70. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 The CB 1 Cannabinoid Receptor Agonist, HU-210, Reduces Levodopa-Induced Rotations in 6-Hydroxydopamine-Lesioned Rats Yossi Gilgun-Sherki 1 , Eldad Melamed 1 , Raphael Mechoulam 2 and Daniel Offen 1 1 Department of Neurology and Felsenstein Medical Research Center, Rabin Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, 2 Department of Medicinal Chemistry, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel (Received September 16, 2002; Accepted March 10, 2003) Abstract: Parkinson’s disease is a chronic neurodegenerative disease of the extrapyramidal system associated with dop- aminergic neuronal loss in the basal ganglia. However, several other neurotransmitters, such as serotonin, g-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-trihydroxy- phenethylamine (6-hydroxydopamine)-lesioned rats with the enantiomers of the synthetic cannabinoid 7-hydroxy-D 6 -tetrahy- drocannabinol 1,1-dimethylheptyl. Treatment with its (ª)ª (3R, 4R) enantiomer (code-name HU-210), a potent canna- binoid receptor type 1 agonist, reduced the rotations induced by levodopa/carbidopa or apomorphine by 34% and 44%, re- spectively. In contrast, treatment with the (π)ª (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. Cannabinoid components of the marijuana plant (Cannabis sativa) are known to exert behavioural and psychotropic effects, but also possess therapeutic properties. The D-9- tetrahydrocannabinol is the major psychoactive substance in marijuana. Cannabidiol and cannabinol, as D-9-tetrahy- drocannabinol, are the most abundant natural components of the marijuana plant. The main effect achieved by these compounds is through activation of the cannabinoid recep- tors, which are CB 1 (found primarily, but not exclusively in the brain) and CB 2 (found only in peripheral tissues). Other proposed mechanisms of cannabinoids include the increase of cell membrane fluidity, alternation of other neurotrans- mitters (mainly dopamine and g-amino butyric acid- GABA) and prostaglandins. CB 1 receptors are most prevalent in the hippocampus, cerebral cortex, cerebellum and especially in the basal gan- glia. The high levels of these receptors in the basal ganglia suggest a potential role for endocannabinoids in the control of voluntary movement and in basal ganglia-related move- ment disorders such as Parkinson’s disease (Di Marzo et al. 1998; Self et al. 1999). Within the basal ganglia, CB 1 recep- tors are particularly prominent on the terminals of GABA- ergic projections from the striatum to the globus pallidus and substantia nigra pars reticulata (the ‘‘indirect’’ and ‘‘di- Author for correspondence: Daniel Offen, Felsenstein Medical Re- search Center, Beilinson Campus and Tel Aviv University, and Rab- in Medical Center, Petah Tikva 49100, Israel (fax 972 3 9211478, e-mail doffen/post.tau.ac.il) rect’’ striatal output pathways respectively). The interplay between these neurotransmitters plays a crucial role in the initiation and severity of the voluntary movements regu- lated by the dopaminergic nigrostriatal system. The presence and actions of cannabinoid structure in the central nervous system led us to investigate the potential inhibitory effects of (ª)ª (3R, 4R)-7-hydroxy-D 6 -tetrahy- drocannabinol 1,1-dimethylheptyl (HU-210), a highly po- tent synthetic cannabinoid agonist (Mechoulam et al. 1988), and its enantiomer (mirror image) (π)ª (3S, 4S)-7-hydroxy- D 6 -tetrahydrocannabinol 1,1-dimethylheptyl (HU-211), an N-methyl-D-aspartate (NMDA) antagonist that lacks psy- chotropic properties (Mechoulam et al. 1988 & 1990; Fei- genbaum et al. 1989; Eshhar et al. 1995; Shohami et al. 1996), in a rat model of Parkinson’s disease. In view of the known effects of cannabidiol in neurological conditions (Consroe et al. 1998), we also investigated in the same model, the effects of this cannabinoid and of its primary metabolite, 7-hydroxy-cannabidiol (Tchilibon & Mechou- lam 2000). Since there is accumulating evidence that canna- binoids might also be neuroprotective in vitro (Eshhar et al. 1995; Hampson et al. 1998), we also examined whether HU- 210 or HU-211 might have neuroprotective effects against dopamine, 2,4,5-trihydroxyphenethylamine (6-hydroxydo- pamine), levodopa and 1-methyl-4-phenylpyridinium ion, all well known neurotoxins, in neuroblastoma SH-SY5Y cells. Our data shows that only HU-210, the CB 1 agonist, and none of the other compounds, affect rotation behavior and inhibit its induction by levodopa or apomorphine.