The endocannabinoid system as a target for the treatment of motor dysfunction

Abstract

There is evidence that cannabinoid-based medicines that are selective for different targets in the cannabinoid signalling system (e.g. receptors, inactivation mechanism, enzymes) might be beneficial in basal ganglia disorders, namely Parkinson's disease (PD) and Huntington's disease (HD). These benefits not only include the alleviation of specific motor symptoms [e.g. choreic movements with cannabinoid receptor type 1 (CB(1))/transient receptor potential vanilloid type 1 agonists in HD; bradykinesia with CB(1) antagonists and tremor with CB(1) agonists in PD], but also the delay of disease progression due to the neuroprotective properties demonstrated for cannabinoids (e.g. CB(1) agonists reduce excitotoxicity; CB(2) agonists limit the toxicity of reactive microglia; and antioxidant cannabinoids attenuate oxidative damage). In addition, extensive biochemical, anatomical, physiological and pharmacological studies have demonstrated that: (i) the different elements of the cannabinoid system are abundant in basal ganglia structures and they are affected by these disorders; (ii) the cannabinoid system plays a prominent role in basal ganglia function by modulating the neurotransmitters that operate in the basal ganglia circuits, both in healthy and pathological conditions; and (iii) the activation and/or inhibition of the cannabinoid system is associated with important motor responses that are maintained and even enhanced in conditions of malfunctioning and/or degeneration. In this article we will review the available data regarding the relationship between the cannabinoid system and basal ganglia activity, both in healthy and pathological conditions and will also try to identify future lines of research expected to increase current knowledge about the potential therapeutic benefits of targeting this system in PD, HD and other basal ganglia disorders.

Figure 1

Location of CB₁ and TRPV1 receptors in specific neuronal subpopulations within basal ganglia circuits. Regulatory pathways are indicated in blue, whereas inhibitory and excitatory inputs are indicated in red and green respectively. Unknown neurons are shown in black. CB₁, cannabinoid receptor type 1; GABA, γ-aminobutiric acid; GLU, glutamate; TRPV1, transient receptor potential vanilloid type 1.

Figure 2

Schematic overview of the modulatory effects of endocannabinoid ligands and their receptors on the activity of the three major neurotransmitters operating in basal ganglia circuits. CB₁, cannabinoid receptor type 1; GABA, γ-aminobutiric acid; TRPV1, transient receptor potential vanilloid type 1.

Figure 3

Changes to CB₁ receptors in the basal ganglia during the progression of Parkinson's and Huntington's diseases. CB₁, cannabinoid receptor type 1.

Figure 4

On the scheme shown in Figure 1, a diagram has been superimposed to show the different targets (CB₁, CB₂ and TRPV1 receptors) that might mediate the ability of cannabinoid-based medicines to alleviate specific symptoms, or to delay/arrest the progression of the disease in basal ganglia disorders. CB₁, cannabinoid receptor type 1; DA, dopamine; GABA, γ-aminobutiric acid; GLU, glutamate; HD, Huntington's disease; PD, Parkinson's disease; TRPV1, transient receptor potential vanilloid type 1.