The endogenous cannabinoid system and the basal ganglia: biochemical, pharmacological, and therapeutic aspects

doi:10.1016/S0163-7258(02)00253-X

Pharmacology & Therapeutics

Volume 95, Issue 2, August 2002, Pages 137-152

https://doi.org/10.1016/S0163-7258(02)00253-X Get rights and content

Abstract

New data strengthen the idea of a prominent role for endocannabinoids in the modulation of a wide variety of neurobiological functions. Among these, one of the most important is the control of movement. This finding is supported by 3 lines of evidence: (1) the demonstration of a powerful action, mostly inhibitory in nature, of synthetic and plant-derived cannabinoids and, more recently, of endocannabinoids on motor activity; (2) the presence of the cannabinoid CB₁ receptor subtype and the recent description of endocannabinoids in the basal ganglia and the cerebellum, the areas that control movement; and (3) the fact that CB₁ receptor binding was altered in the basal ganglia of humans affected by several neurological diseases and also of rodents with experimentally induced motor disorders. Based on this evidence, it has been suggested that new synthetic compounds that act at key steps of endocannabinoid activity (i.e., more-stable analogs of endocannabinoids, inhibitors of endocannabinoid reuptake or metabolism, antagonists of CB₁ receptors) might be of interest for their potential use as therapeutic agents in a variety of pathologies affecting extrapyramidal structures, such as Parkinson's and Huntington's diseases. Currently, only a few data exist in the literature studying such relationships in humans, but an increasing number of journal articles are revealing the importance of this new neuromodulatory system and arguing in favour of the funding of more extensive research in this field. The present article will review the current knowledge of this neuromodulatory system, trying to establish the future lines for research on the therapeutic potential of the endocannabinoid system in motor disorders.

Section snippets

Introduction: a general approach to the endogenous cannabinoid system

Cannabis sativa preparations (marijuana, hashish) are among the most widely consumed drugs of abuse around the world. Their active principles and derivatives, however, are now being considered as potentially useful therapeutic molecules, mainly due to the recent description of an endogenous cannabinoid system (for reviews, see Mechoulam et al., 1994, Howlett, 1995, Pertwee, 1997, Di Marzo et al., 1998), which would contain the molecular targets for the action of plant-derived cannabinoids. This

Role of the endogenous cannabinoid system in the control of motor behavior

The finding that the endocannabinoid system might be involved in the regulation of motor behavior is based on three lines of evidence. First, it has been well demonstrated that synthetic, plant-derived, and endogenous cannabinoids have powerful actions, mostly inhibitory effects, on motor activity (Crawley et al., 1993, Fride & Mechoulam, 1993, Wickens & Pertwee, 1993, Smith et al., 1994, Romero et al., 1995a, Romero et al., 1995b; for a review, see Sañudo-Peña et al., 1999). There are

Changes in the endogenous cannabinoid system in motor disorders

As observed for most of the neurotransmitter systems, endocannabinoid transmission within the basal ganglia is also influenced by normal senescence Mailleux & Vanderhaeghen, 1992b, Romero et al., 1998a, Berrendero et al., 1998b. However, the changes were weak compared with those observed in the processes of pathological aging directly or indirectly affecting the basal ganglia Glass et al., 1993, Glass et al., 2000, Richfield & Herkenham, 1994, Westlake et al., 1994. These studies have mainly

Potential therapeutic uses of endogenous cannabinoids and related compounds in motor disorders

From what has been stated in this review, it can be concluded that compounds acting on the endocannabinoid system might be of promise in improving motor deterioration in both hyper- and hypokinetic disorders (for recent reviews, see Consroe, 1998, Müller-Vahl et al., 1999a). To date, most of the research has focused on the search for new symptomatic pharmacotherapies, but evidence has also been presented that cannabinoid-related compounds might also be neuroprotective.

Concluding remarks

The studies reviewed in this article are all concordant with the view that control of movement is a key function for the endocannabinoid transmission in the CNS. We have reviewed the pharmacological and biochemical bases that sustain the involvement of the endocannabinoid transmission in the function of the basal ganglia. We have also shown that endocannabinoid transmission is altered in motor disorders, in parallel to the well-known changes in classic neurotransmitters, such as GABA, dopamine,

Acknowledgements

Studies included in this review have been supported by grants from CAM-PRI (08.5/0029/98) and CICYT (PM99-0056).

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l-Dopa is the most effective drug used for Parkinson's disease (PD), but after long-term treatment, the vast majority of PD patients develop abnormal involuntary movements (AIMs) termed l-Dopa-induced dyskinesia (LID). Cannabinoid receptors in the basal ganglia can modulate motor functions, but their role in the treatment of LID is controversial. Therefore, the aim of this study is to evaluate the motor behavior and mRNA expression of the cannabinoid receptor-1 (CB₁R), encoded by the Cnr1 gene, in the striatum and globus pallidus of a 6-hydroxydopamine rat model of PD. The evaluated rats had 6-hydroxydopamine-induced injury, LID, and LID treated with arachidonyl-2′-chloroethylamide (ACEA), a cannabinoid receptor agonist. Contralateral turns and AIMs were recorded to assess motor behavior. Gene expression was quantified by reverse transcription coupled with quantitative polymerase chain reaction using TaqMan probes. Behavioral evaluations demonstrated that dyskinetic rats treated with ACEA had a significant reduction in AIMs compared to the dyskinetic group. The expression of CB₁R mRNA was significantly decreased in the 6-hydroxydopamine-injured and dyskinetic rats, compared to intact rats. The striata of dyskinetic rats treated with ACEA exhibited highly significant increases in CB₁R mRNA expression. Contrary to results in the striatum, a lower CB₁R expression was observed in globus pallidus from dyskinetic ACEA-treated group. In summary, significant differences in mRNA expression of CB₁R were found between the evaluated groups of rats, suggesting the occurrence of compensatory mechanisms that may result in the ACEA-mediated reduction of dyskinesias in a rat model of PD.
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¹: Present address: Facultad de Ciencias de la Salud y de la Vida, Universidad Pompeu i Fabra, 08005-Barcelona, Spain.

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The endogenous cannabinoid system and the basal ganglia: biochemical, pharmacological, and therapeutic aspects

Abstract

Section snippets

Introduction: a general approach to the endogenous cannabinoid system

Role of the endogenous cannabinoid system in the control of motor behavior

Changes in the endogenous cannabinoid system in motor disorders

Potential therapeutic uses of endogenous cannabinoids and related compounds in motor disorders

Concluding remarks

Acknowledgements

Eur J Pharmacol

Brain Res

Neurosci Lett

Mol Cell Neurosci

Biochim Biophys Acta

Biochem Biophys Res Commun

Prog Neurobiol

Neurobiol Dis

Pharmacol Biochem Behav

Neuroscience

FEBS Lett

J Biol Chem

Biochem Pharmacol

Biochem Biophys Res Commun

Trends Neurosci

Life Sci

Trends Neurosci

Eur J Pharmacol

Eur J Pharmacol

Neuroscience

Neuroscience

Life Sci

Eur J Pharmacol

Life Sci

Pharmacol Ther

Brain Res

Pharmacol Biochem Behav

Trends Neurosci

J Neuroimmunol

Brain Res

Neuroscience

Neurosci Lett

Eur J Pharmacol

Eur J Pharmacol

Exp Neurol

Pharmacol Biochem Behav

Biochem Pharmacol

Biochem Pharmacol

Neuropharmacology

Eur J Pharmacol

Eur J Pharmacol

Brain Res

(R)-Methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability

J Med Chem

3-Nitropropionic acid's lethal triplet: cooperative pathways of neurodegeneration

Neuroreport

Cannabinoids control spasticity and tremor in a multiple sclerosis model

Nature

Aging, energy, and oxidative stress in neurodegenerative diseases

Ann Neurol

HU-211, a nonpsychotropic cannabinoid, improves neurological signs and reduces brain damage after severe forebrain ischemia in rats

Mol Chem Neuropathol

Functional role of high-affinity anandamide transport, as revealed by selective inhibition

Science

Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor

J Neurosci

Long-term electrical inhibition of deep brain targets in movement disorders

Mov Disord

Reversal of dopamine D₂ receptor responses by an anandamide transport inhibitor