CB1 cannabinoid receptor signalling in Parkinson’s disease

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Abstract

Signalling at CB1 cannabinoid receptors plays a key role in the control of movement in health and disease. In recent years, an increased understanding of the physiological role of transmission at CB1 receptors throughout the basal ganglia circuitry has led to the identification of novel therapeutic approaches to both the symptoms of Parkinson’s disease and the side effects of current anti-parkinsonian therapies, especially L3,4 dihydroxyphenylalamine (levodopa)-induced dyskinesia. Thus, because activation of basal ganglia CB1 receptors can modulate neurotransmission and contribute to synaptic plasticity in a manner similar to that described in other brain regions, it also appears that endocannabinoids might modulate cell–cell signalling via effects on neurotransmitter re-uptake and postsynaptic actions mediating cross talk between multiple receptor types. Recent studies in animal models and in the clinic suggest that CB1 receptor antagonists could prove useful in the treatment of parkinsonian symptoms and levodopa-induced dyskinesia, whereas CB1 receptor agonists could have value in reducing levodopa-induced dyskinesia.

Introduction

In the past two years, major advances have been made in understanding both the role of cannabinoid receptor signalling in neural function and, more specifically, the complex neuromodulatory role played by CB1 receptors within the basal ganglia. With this latter advance has come an understanding of the role played by the CB1 receptor signalling system in the generation of symptoms of Parkinson’s disease and in the development of side effects of current anti-parkinsonian therapies. This review will:

  • 1.

    Highlight recent advances in the pharmacology of signalling by endogenous cannabinoids at CB1 receptors.

  • 2.

    Describe how these advances might lead to a better understanding of Parkinson’s disease and related movement disorders.

  • 3.

    Demonstrate how such an understanding might be translated into novel therapies for these disorders.

Section snippets

Pharmacology of CB1-receptor-mediated transmission

It is now more than a decade since the first cannabinoid receptor (CB1) was cloned. A classification of cannabinoid receptors has recently been published [1] and, for the time being at least, cannabinoid receptors can be divided into two major subtypes: CB1 and CB2. The majority of cannabinoid effects within the central nervous system (CNS) are mediated through CB1 receptors. The first endogenous activators of CB1 receptors (endocannabinoids) to be described were the eicosanoids arachidonyl

Pharmacology of Parkinson’s disease

Parkinson’s disease is caused by degeneration of the dopaminergic projection from the mesencephalon to the striatum. This realisation over 40 years ago has led to the widespread use of dopamine replacement therapies in Parkinson’s disease. In particular, the dopamine precursor L3,4 dihydroxyphenylalamine (levodopa) has become the mainstay of anti-parkinsonian medication. Dopamine replacement therapy in Parkinson’s disease has undoubtedly enhanced the quality of life of patients with Parkinson’s

Neural mechanisms of Parkinson’s disease and levodopa-induced dyskinesia

In Parkinson’s disease, the initial loss of dopaminergic input to the striatum initiates a cascade of neurochemical changes both within the striatum and in other nuclei of the basal ganglia downstream of the striatum. Some of these changes represent endogenous processes that attempt to compensate for the loss of dopamine. Other changes are responsible for the generation of symptoms, those with particular relevance to the generation of symptoms include:

  • 1.

    Enhanced glutamatergic drive to

Role of CB1 receptors in functioning of the basal ganglia

CB1 receptor stimulation has a variety of effects throughout the basal ganglia circuitry. Within the striatum, CB1 receptors are expressed in high levels and are localised both presynaptically and postsynaptically 27., 28.. It has recently been described that GABAergic neurons of the striatum, both projection neurons and interneurons, are the predominant cell types expressing CB1 receptors [28]. In contrast, it appears that striatal cholinergic interneurons do not express CB1 receptors. This

Alterations in CB1 signalling in Parkinson’s disease and levodopa-induced dyskinesia

There is now a growing body of data suggesting that dramatic alterations in CB1 signalling occur in parkinsonism and following repeated dopamine replacement therapy. It is likely that some of the changes described reflect endogenous compensatory mechanisms by which plasticity in endocannabinoid signalling is invoked in an, ultimately, unsuccessful attempt to maintain the functioning of neural circuitry within physiological boundaries. Other changes probably contribute to the pathophysiology of

Therapeutic potential of manipulating CB1 receptor transmission in Parkinson’s disease and levodopa-induced dyskinesia

From this review, it should be apparent that great advances have been made in defining the role of CB1 receptor signalling in the basal ganglia, and that an understanding of how abnormalities in this signalling might contribute to symptomatology of Parkinson’s disease and levodopa-induced dyskinesia is beginning to emerge. The possibility of targeting these processes for therapeutic benefit is becoming real. However, from a theoretical perspective, there is a significant challenge in defining a

Conclusion

A greater understanding of the role of CB1 receptor signalling within the basal ganglia has developed over the past 2–3 years. CB1 receptors play important roles in regulating the transmission of glutamate, GABA and dopamine within the basal ganglia. The new understanding of CB1 receptor physiology is driving the development of novel therapeutics and within this field, clinical trials employing agents acting at the CB1 receptor are already being reported.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

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