The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders
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.
Section snippets
The endocannabinoid system
To date, the family of endocannabinoids is expanding. There are at least five different arachidonoyl derivatives, which can activate the cannabinoid receptor (Fig. 1). Anandamide and 2-arachidonoylglycerol are the two best studied members. 2-Arachidonoylglyceryl ether (noladin ether) (Hanus et al., 2001), O-arachidonoylethanolamine (virodhamine) (Porter et al., 2002) and N-arachidonoyldopamine (Huang et al., 2002) have only been recently identified as endogenous ligands for the cannabinoid
Interactions between dopaminergic transmission and the endocannabinoid system in the nigrostriatal pathway
The basal ganglia consist of four nuclei: dorsal striatum (caudate and putamen), globus pallidus, substantia nigra and subthalamic nucleus, which play a major role in normal voluntary movement (Fig. 2). They do not have direct input or output connections with the spinal cord, but they receive their primary input from the cerebral cortex and send their output via the thalamus back to the cortex. The primary input center is the dorsal striatum, which controls planning and execution of motor
Interactions between dopaminergic transmission and the endocannabinoid system in the mesocorticolimbic pathway
Dopaminergic neurons in the mesocorticolimbic pathway are mainly located in the A10 cell group of the ventral tegmental area and project topographically to limbic forebrain structures such as the prefrontal cortex and to the nucleus accumbens (Fig. 3). The nucleus accumbens, which is a part of the ventral striatum, also receives glutamatergic input from the prelimbic cortex. GABAergic interneurons within the ventral tegmental area and a long-loop feedback projection from GABAergic medium spiny
Anxiety disorders
Anxiety disorders are characterized by an increased fearfulness towards threatening situations or for events that do not present a real danger. They can be subdivided into several types, including panic disorder, post-traumatic stress disorder, social phobia, obsessive–compulsive disorder or generalized anxiety disorder. Although anxiety is not identical to fear, it is closely linked to fear learning (Kent et al., 2002). The amygdala is the key brain structure in coordinating the fear response.
Concluding remarks
We have described here data published in the literature pointing to involvement of the endocannabinoid system in neurological and psychiatric disorders, with particular emphasis on the possible role played in this context by the capability of cannabinoid CB1 receptors to interfere, either directly, or more probably, indirectly, with the activity dopaminergic neurons. Furthermore, we have mentioned evidence suggesting that endocannabinoids intervene in neuropsychiatric dysfunctions also
References (197)
- et al.
The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice
Neuropharmacology
(2001) The effects of cannabinoids on the brain
Prog. Neurobiol.
(1999)- et al.
Effects of cannabinoid receptor stimulation and blockade on catalepsy produced by dopamine receptor antagonists
Eur. J. Pharmacol.
(1996) - et al.
Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters
Pharmacol. Biochem. Behav.
(2001) - et al.
Addiction, dopamine, and the molecular mechanisms of memory
Neuron
(2000) - et al.
Functional changes of the basal ganglia circuitry in Parkinson's disease
Prog. Neurobiol.
(2000) CB(1) cannabinoid receptor signalling in Parkinson's disease
Curr. Opin. Pharmacol.
(2003)- et al.
The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia
Trends Neurosci.
(1996) - et al.
Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use
Neuroscience
(2001) - et al.
Attenuation of spontaneous opiate withdrawal in mice by the anandamide transport inhibitor AM404
Eur. J. Pharmacol.
(2002)
Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington's disease mice
Neuroscience
Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action
Trends Neurosci.
Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues
Eur. J. Pharmacol.
Anandamide receptors
Prostaglandins Leukot. Essent. Fat. Acids
Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system
Pharmacol. Biochem. Behav.
Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice
Brain Res.
Endocannabinoids and basal ganglia functionality
Prostaglandins Leukot Essent Fatty Acids
delta9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors
Neurosci. Lett.
Cannabinoid transmission and reward-related events
Neurobiol. Dis.
It could be habit forming: drugs of abuse and striatal synaptic plasticity
Trends Neurosci.
Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors
Eur. J. Pharmacol.
The role of cannabinoids in neurodegenerative diseases
Prog. Neuro-psychopharmacol. Biol. Psychiatry
The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease
Neuroscience
Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB(1) receptor binding and mRNA levels
Drug Alcohol Depend.
Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine
Brain Res.
Chronic (−)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats
Eur. J. Pharmacol.
Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice
Eur. J. Pharmacol.
Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?
Brain Res.
Neuronal localization of cannabinoid receptors in the basal ganglia of the rat
Brain Res.
Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain
Neuroscience
Cellular signal transduction by anandamide and 2-arachidonoylglycerol
Chem. Phys. Lipids
Molecular targets in the treatment of anxiety
Biol. Psychiatry
Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells
Neuron
Chronic treatment with Delta(9)-tetrahydrocannabinol enhances the locomotor response to amphetamine and heroin. Implications for vulnerability to drug addiction
Neuropharmacology
Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB(1) receptors in the basal ganglia of a transgenic model of Huntington's disease
Brain Res.
Cannabis: pharmacology and toxicology in animals and humans
Addiction
Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors
Psychopharmacology (Berl.)
Functional role of high-affinity anandamide transport, as revealed by selective inhibition
Science
Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor
J. Neurosci.
Involvement of the opioid system in the anxiolytic-like effects induced by Delta(9)-tetrahydrocannabinol
Psychopharmacology (Berl.)
Cannabinoid receptor-regulated cyclic AMP accumulation in the rat striatum
J. Neurochem.
Evidence for a new G protein-coupled cannabinoid receptor in mouse brain
Mol. Pharmacol.
Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP
J. Neurosci.
Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum
J. Neurochem.
Behavioral effects of cannabinoid agents in animals
Crit. Rev. Neurobiol.
Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide
EMBO J.
Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis
Psychopharmacology
SR141716, a central cannabinoid (CB1) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats
Behav. Pharmacol.
Precipitated and spontaneous withdrawal in rats tolerant to anandamide
Psychopharmacology (Berl.)
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Nature
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2021, NeuroscienceCitation Excerpt :For the close interactions between the two receptors, the present WIN 55,212-2-induced bidirectional modulation of the firing activity of pallidal neurons may due to the possible involvement of dopamine D2 receptors in the GP. Meanwhile, previous studies revealed that activation of presynaptic CB1R may inhibit GABA reuptake in the GP (Maneuf et al., 1996; Brotchie, 2003; van der Stelt and Di Marzo, 2003; Benarroch, 2007; More and Choi, 2015). For example, WIN 55,212-2 induces a concentration-dependent decrease of GABA uptake in the GP (Maneuf et al., 1996).