Effects of CB1 cannabinoid receptor modulating compounds on the hyperkinesia induced by high-dose levodopa in the reserpine-treated rat model of Parkinson's disease.

Abstract

The present study was designed to determine the potential of CB1 cannabinoid receptor modulating compounds in the treatment of L-3,4-dihydroxyphenylalanine (L-dopa)-induced dyskinesia in Parkinson's disease. In the reserpine-treated rat model of parkinsonism, administration of a high dose of L-dopa (150 mg/kg) but not of Cl-APB (0.5 mg/kg) or quinpirole (0.5 mg/kg) produced a hyperkinetic state characterised by an increase in horizontal and vertical activity, which likely represent correlates of antiparkinsonian and dyskinetic activity, respectively. Injection of the CB1 cannabinoid receptor antagonist SR141716 (0.1-3 mg/kg) reduced the increase in vertical activity elicited by L-dopa without affecting the increase in horizontal activity. Injection of the CB1 cannabinoid receptor agonist WIN55,212-2 (0.1-3 mg/kg) reduced the L-dopa-induced increase in vertical activity and, at the highest dose only (3 mg/kg), also reduced horizontal activity elicited by L-dopa. WIN55,212-2 (1 mg/kg) reduced motor activity induced by both the D1 receptor agonist Cl-APB (0.5 mg/kg) and the D2 receptor agonist quinpirole (0.5 mg/kg) in the reserpine-treated rat. SR141716 (1 mg/kg) had no effects on motor activity induced by Cl-APB (0.5 mg/kg) nor quinpirole (0.5 mg/kg) in the reserpine-treated rat. Injection of the inhibitor of endocannabinoid transport AM404 (0.1-1 mg/kg) did not affect the increase in horizontal or vertical activity elicited by L-dopa (150 mg/kg) in the reserpine-treated rat. The data suggest that both CB1 cannabinoid receptor antagonists and agonists can modulate the behavioural effects of L-dopa and may be useful for the treatment of the dyskinesia associated with long-term L-dopa treatment of Parkinson's disease.

• Authors: Gregorio Segovia, Francisco Mora, Alan R Crossman, Jonathan M Brotchie
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 18 Issue 2 Pg. 138-49 (Feb 2003) ISSN: 0885-3185 [Print] United States
• PMID: 12539206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Movement Disorder Society

Chemical References

• Adrenergic Uptake Inhibitors
• Antiparkinson Agents
• Cannabinoid Receptor Modulators
• Fatty Acids, Unsaturated
• Receptors, Cannabinoid
• Receptors, Drug
• Levodopa
• Reserpine

Topics

• Adrenergic Uptake Inhibitors (therapeutic use)
• Animals
• Antiparkinson Agents (administration & dosage, adverse effects)
• Behavior, Animal (drug effects)
• Cannabinoid Receptor Modulators
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fatty Acids, Unsaturated (pharmacology)
• Hyperkinesis (chemically induced)
• Levodopa (administration & dosage, adverse effects)
• Male
• Parkinson Disease (drug therapy)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cannabinoid
• Receptors, Drug (drug effects)
• Reserpine (therapeutic use)
• Time Factors