Homeostatic changes of the endocannabinoid system in Parkinson's disease

Abstract

Endocannabinoids (eCBs) are endogenous lipids that bind principally type-1 and type-2 cannabinoid (CB(1) and CB(2)) receptors. N-Arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) are the best characterized eCBs that are released from membrane phospholipid precursors through multiple biosynthetic pathways. Together with their receptors and metabolic enzymes, eCBs form the so-called "eCB system". The later has been involved in a wide variety of actions, including modulation of basal ganglia function. Consistently, both eCB levels and CB(1) receptor expression are high in several basal ganglia regions, and more specifically in the striatum and in its target projection areas. In these regions, the eCB system establishes a close functional interaction with dopaminergic neurotransmission, supporting a relevant role for eCBs in the control of voluntary movements. Accordingly, compelling experimental and clinical evidence suggests that a profound rearrangement of the eCB system in the basal ganglia follows dopamine depletion, as it occurs in Parkinson's disease (PD). In this article, we provide a brief survey of the evidence that the eCB system changes in both animal models of, and patients suffering from, PD. A striking convergence of findings is observed between both rodent and primate models and PD patients, indicating that the eCB system undergoes dynamic, adaptive changes, aimed at restoring an apparent homeostasis within the basal ganglia network.

Temporally Dependent Changes in Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens Shell are Reversed by D1-Like Dopamine Receptor Stimulation

“…A wealth of clinical evidence suggests that interaction between the dopamine and endocannabinoid systems is involved in the pathophysiology of disorders involving the limbic system (Parolaro and Rubino, 2008;Fernández-Ruiz et al, 2010;Kuepper et al, 2010;Pisani et al, 2011). Deletion of CB1 receptors reduces reinforcing properties of cocaine as does administration of CB1 receptor antagonists (Xi et al, 2006;Li et al, 2009;Ramiro-Fuentes et al, 2010).…”

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…In the excitotoxicity field, much attention has been applied to potential strategies to preserve learning and memory and other brain functions, including the neuroprotective abilities of specific signaling lipids that make up the family of endocannabinoids (for more detail see Hwang J, et al [1] Zanettini C, et al [2], Pacher and Hasko [3], and Janero DR, et al [4]). Multiple studies have linked the principal endocannabinoids in the central nervous system, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with protection against numerous diseases, including Alzheimer's, Parkinson's, and Huntington's disease, epileptic seizures, and stroke/ischemic brain damage [5][6][7][8][9][10][11][12][13][14]. In the nervous system, endocannabinoids AEA and 2-AG are synthesized and released on demand from membrane-bound phospholipids, and act at presynaptic Gi-coupled CB1 and CB2 receptors [15][16][17][18].…”

The decrease of dopamine D2/D3 receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB1 cannabinoid receptors in Parkinson's disease: A preliminary autoradiographic study with the selective dopamine D2/D3 antagonist [3H]raclopride and the novel CB1 inverse agonist [125I]SD7015

“…A severe loss of CB 1 R’s in the striatum has, consequently, been described as a landmark of HD [8,82]. On the other hand, the alteration of striatal CB 1 R population in PD is full of controversies and the most important striatal cells expressing the CB 1 R are affected in a lesser extent compared to HD and the EC systems shows a strong tendency for reorganization [18,84]. …”