Roles of the Cannabinoid System in the Basal Ganglia in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.

Keywords: CB1 receptors; CB2 receptors; Parkinson’s disease; basal ganglia; cannabinoids.

FIGURE 1

Basal ganglia signaling pathways and associated receptor localization. (A) Signals from the cerebral cortex affect the output nuclei (GPi and SNpr) via direct or indirect pathways via the basal ganglia input nuclei (CPU), which in turn regulate thalamic motor function. In Parkinson’s disease (PD), the loss of dopaminergic neurons leads to enhanced activity in the indirect pathway and diminished activity in the direct pathway, with more output of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) from the GPi and SNpr, which depresses the motor thalamus, leading to the development of PD. Some receptors present in the basal ganglia play an important role in the regulation of signaling. CB1 receptors are mainly found in GABAergic and glutamatergic neurons. GPR55 is present in the nuclei of GPe, CPU, STN, and SNpr. CB2 receptors and TRPV-1 are mainly present in dopaminergic neurons originating from the SNpc. (B) Three major pathways of basal ganglia signaling.

FIGURE 2

CB1 receptor-mediated retrograde signaling mechanism. (A) Release of Glu from the cortical striatal glutamatergic neurons can stimulate the release of eCBs from postsynaptic neurons, which in turn acts on CB1 receptors in the presynaptic membrane to inhibit presynaptic Glu release. Meanwhile, dopaminergic neurons can promote cannabinoid production by decreasing postsynaptic RGS4 phosphorylation levels. (B) Stimulation of the presynaptic CB1 receptor in GPe inhibits the reuptake of GABA by GABA transporter protein 1 (GAT1), thereby increasing local GABA levels.