Levodopa therapy - the gold standard in Parkinson's disease (PD) treatment - causes disabling motor complications (dyskinesias) that are largely resistant to available drugs. Studies on anti-dyskinetic therapies have paid little attention to the endocannabinoid neurotransmitter system, despite: (1) the striking abundance of cannabinoid receptors in the basal ganglia;(2) its ability to regulate basal ganglia function;(3) experimental evidence for anti-dyskinetic properties of cannabinoid drugs. So far, clinical studies addressing the therapeutic efficacy of cannabinoid receptor agonists on levodopa-induced dyskinesias (LID) have produced conflicting results. Lack of knowledge of the molecular mechanisms underlying the antidyskinetic properties of these agents and the consequent inappropriate pharmacological manipulation of the endocannabinoid system may contribute to these inconsistencies. Furthermore, little information is available on the antidyskinetic potentials of indirect cannabinoid agonists (FAAH inhibitors), which have been shown recently to ameliorate hyperkinetic disorders. Previous work from our lab carried out in rats with unilateral 6- OHDA lesions (an animal model of PD) indicates that application of direct cannabinoid agonists alleviates LID via activation of CB1 cannabinoid receptors and concomitant desensitization of TRPV1 receptors through a phosphatase-operated mechanism. On the other hand, FAAH inhibitors reduce LID through a CB1-independent mechanism requiring pharmacological blockade of TRPV1 receptors and activation of peroxisome proliferators-activated receptors (PPARs). These observations suggest that direct and indirect cannabinoid agonists alleviate LID via CB1- and non-CB1-dependent mechanisms, respectively, and that TRPV1 and PPAR receptors play a critical role in these responses. Biochemical, pharmacological and behavioral approaches will be used to test this hypothesis.
The first aim will investigate the molecular mechanisms of the antidyskinetic effects of the direct cannabinoid agonist WIN55212-2;it will focus on the cross talk between CB1 and TRPV1 receptors and the role played by the phosphates calcineurin and DARPP-32 in this interaction.
The second aim will analyze the antidyskinetic effects of the FAAH inhibitor URB597, the contribution of signaling lipids elevated by URB597 in these responses and the ability of TRPV1 and PPAR receptor antagonists to modulate these effects.
The third aim will address the efficacy of earlier treatment with direct and indirect cannabinoid agonists to prevent or delay the expression of dyskinesias, and possible differences in the development of tolerance to their behavioral effects. In conclusion, our study will identify the mechanisms of action of different cannabinoid agents, investigate their efficacy upon chronic administration and characterize novel targets for antidyskinetic therapies using a pre- clinical experimental setting.

Public Health Relevance

Several preclinical and clinical studies indicate that cannabinoid drugs reduce the motor complications (dyskinesias) induced by long-term use of medications for Parkinson's disease. This proposal investigates the mechanisms of action and pharmacological targets of different cannabinoid agents and evaluates their efficacy in reducing levodopa- induced dyskinesias in a rat model of Parkinson's disease. The study will identify new and more effective therapeutic strategies for the treatment of levodopa-associated motor complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050401-08
Application #
8230709
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2004-12-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$318,347
Indirect Cost
$103,972
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Giuffrida, Andrea; Seillier, Alexandre (2012) New insights on endocannabinoid transmission in psychomotor disorders. Prog Neuropsychopharmacol Biol Psychiatry 38:51-8
Martinez, Alex; Macheda, Teresa; Morgese, Maria Grazia et al. (2012) The cannabinoid agonist WIN55212-2 decreases L-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats. Neurosci Res 72:236-42
Cunningham, Rebecca L; Macheda, Teresa; Watts, Lora Talley et al. (2011) Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion. Horm Behav 60:617-24
Giuffrida, Andrea; McMahon, Lance R (2010) In vivo pharmacology of endocannabinoids and their metabolic inhibitors: therapeutic implications in Parkinson's disease and abuse liability. Prostaglandins Other Lipid Mediat 91:90-103
Solbrig, Marylou V; Fan, Yijun; Hermanowicz, Neal et al. (2010) A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats. Exp Neurol 226:231-41
Price, David A; Martinez, Alex A; Seillier, Alexandre et al. (2009) WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Eur J Neurosci 29:2177-86
Cunningham, Rebecca L; Giuffrida, Andrea; Roberts, James L (2009) Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase Cdelta. Endocrinology 150:5539-48
Morgese, M G; Cassano, T; Gaetani, S et al. (2009) Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2. Neurochem Int 54:56-64
Price, David A; Owens, William A; Gould, Georgianna G et al. (2007) CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem 101:389-96
Morgese, Maria Grazia; Cassano, Tommaso; Cuomo, Vincenzo et al. (2007) Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson's disease: role of CB(1) and TRPV1 receptors. Exp Neurol 208:110-9

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