CB1 cannabinoid receptor signalling in Parkinson’s disease
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:
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of special interest
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of outstanding interest
References (55)
- et al.
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain
Biochem. Biophys. Res. Commun.
(1995) - et al.
Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues
FEBS Lett.
(2002) - et al.
Anandamide: some like it hot
Trends Pharmacol. Sci.
(2001) - et al.
Fatty acid amide hydrolase localization in the human central nervous system: an immunohistochemical study
Brain Res. Mol. Brain Res.
(2002) - et al.
Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity
FEBS Lett.
(2000) - et al.
Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor ‘hybrid’ ligands
Biochem. Biophys. Res. Commun.
(2001) - et al.
Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models
Neurology
(2001) - et al.
Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha(2) adrenoceptor antagonist idazoxan
Mov. Disord.
(2001) - et al.
Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys
Exp. Neurol.
(2000) - et al.
Antiparkinsonian action of a delta opioid agonist in rodent and primate models of Parkinson’s disease
Exp. Neurol.
(2001)