The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders

Abstract

To date, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol are the best studied endocannabinoids and are thought to act as retrograde messengers in the central nervous system (CNS). By activating presynaptic cannabinoid CB₁ receptors, they can reduce glutamate release in dorsal and ventral striatum (nucleus accumbens) and alter synaptic plasticity, thereby modulating neurotransmission in the basal ganglia and in the mesolimbic reward system. In this review, we will focus on the role of the endocannabinoid system within these neuronal pathways and describe its effect on dopaminergic transmission and vice versa. The endocannabinoid system is unlikely to directly affect dopamine release, but can modify dopamine transmission trough trans-synaptic mechanisms, involving γ-aminobutyric acid (GABA)-ergic and glutamatergic synapses, as well as by converging signal transduction cascades of the cannabinoid and dopamine receptors. The dopamine and endocannabinoid systems exert a mutual control on each other. Cannabinergic signalling may lead to release of dopamine, which can act via dopamine D₁-like receptors as a negative feedback mechanism to counteract the effects of activation of the cannabinoid CB₁ receptor. On the other hand, dopaminergic signalling via dopamine D₂-like receptors may lead to up-regulation of cannabinergic signalling, which is likely to represent a negative feedback on dopaminergic signalling. The consequences of these interactions become evident in pathological conditions in which one of the two systems is likely to be malfunctioning. We will discuss neurological and psychiatric disorders such as Parkinson's and Huntington's disease, drug addiction and schizophrenia. Furthermore, the possible role of the endocannabinoid system in disorders not necessarily depending on the dopaminergic system, such as eating disorders and anxiety, will be described.

Introduction

Marijuana is one of the most widely used illegal drugs throughout the world. It can induce strong behavioral effects such as depression of locomotor activity, and may have rewarding properties (Adams and Martin, 1996). The cannabinoid CB₁ receptor is thought to be responsible for the majority of the effects in the central nervous system (CNS) elicited by Δ⁹-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in marijuana (Gaoni and Mechoulam, 1964). The cannabinoid CB₁ receptor is one of the most abundant G-protein-coupled receptors in the CNS (Matsuda et al., 1990). Activation of presynaptic cannabinoid CB₁ receptors by its endogenous ligands, the endocannabinoids: N-arachidonoylethanolamine (anandamide) Devane et al., 1992, Di Marzo et al., 1994 and 2-arachidonoylglycerol Mechoulam et al., 1995, Sugiura et al., 1995, results in inhibition of both excitatory and inhibitory neurotransmitter release (Schlicker and Kathmann, 2001). The life span of endocannabinoids in the extracellular space is limited by a rapid elimination process consisting of selective uptake into the cell and subsequent degradation by fatty acid amide hydrolase or monoacylglycerol (MAG) lipase Beltramo et al., 1997, Cravatt et al., 1996, Dinh et al., 2002. The cannabinoid receptors, endocannabinoids and the proteins for their biosynthesis and degradation constitute the endocannabinoid system (Di Marzo et al., 1998). This system is implicated in the regulation of various processes, such as learning, food uptake, pain transduction, reinforcement and motor coordination (Ameri, 1999). Its involvement in pathophysiological conditions is beginning to be unravelled and might include disorders such as Parkinson's disease, Huntington's disease, drug addiction, schizophrenia, anorexia and obesity Van der Stelt et al., 2002, Glass, 2001, Maldonado, 2002.

The endocannabinoid system has close connections with the dopaminergic system, which might explain several of its (patho)physiological aspects. The dopaminergic system is thought to play an important role in several psychiatric and neurological disorders. Dopamine is the predominant catechol neurotransmitter in the CNS and regulates a variety of functions such as locomotor activity, emotion and reward (Missale et al., 1998). Its involvement in movement control is emphasized in Parkinson's disease, where the loss of nigrostriatal dopaminergic neurons leads to severe motor deficits (Blandini et al., 2000). Mesolimbic dopaminergic neurons are also thought to have an important function in the acquisition of behavior that is reinforced by natural rewarding stimuli and substances of abuse Spanagel and Weiss, 1999, Wise, 2002. In this paper, we will review the involvement of the endocannabinoid system with several neurological and psychiatric disorders, thereby paying special attention to its interactions with dopaminergic systems.