Endocannabinoids in basal ganglia circuits

Abstract

Endocannabinoids are endogenous lipid messengers that bind the cannabinoid (CB) receptors. These receptors mediate the multiple behavioral effects of l -Δ9 tetrahydrocannabinol, the main psychoactive component of marijuana (cannabis). The endocannabinoid system has been implicated in a large variety of functions, including regulation of appetite and energy metabolism, pain and inflammation, neuroprotection, and modulation of basal ganglia circuits.1 Not surprisingly, the endocannabinoid system has raised great interest as a potential pharmacologic target from management of disorders such as obesity, pain, nausea, and neurologic conditions such as multiple sclerosis and movement disorders. The aim of this article is to briefly review some basic concepts on the biochemistry, pharmacology, and synaptic modulatory role of the endocannabinoid system with focus on the basal ganglia circuits, and the potential implications for Parkinson disease (PD). These subjects have been covered in detail in several reviews.1–6 The family of endocannabinoids includes at least five derivatives of arachidonic acid; the two best characterized are arachydonoyl ethanolamide (named anandamide after the Sanskrit word for bliss, ananda) and 2-arachydonoil glycerol (2AG). These endocannabinoids are synthesized in postsynaptic targets on demand in response to increase in intracellular calcium (Ca2+), triggered by either depolarization or activation of metabotropic glutamate receptors1–3 (figure 1). Figure 1 Schematic representation of endocannabinoid signaling, as illustrated in this case for anandamide Influx of calcium (Ca2+) in the postsynaptic cell activates phospholipase D (PLD), which acts on N-arachydonoyl phosphatidylethanolamine (NAPE) to produce anandamide. Anandamide is released into the synaptic cleft and acts via presynaptic cannabinoid 1 (CB1) receptors. These receptors are guanine nucleotide binding (G) protein-coupled receptors coupled to Gi/o transduction pathways, and their activation leads to inhibition of adenylate cyclase (AC), opening of presynaptic potassium (K+) channels, and inhibition of presynaptic Ca2+ channels. These effects …