Involvement of the endocannabinoid system in drug addiction,
Rafael Maldonado, Olga Valverde and Fernando Berrendero
Trends in Neurosciences, 2006, 29, (4), 225-232.
Doi : 10.1016/j.tins.2006.01.008
Recent studies have shown that the endocannabinoid system is involved in the common neurobiological
mechanism underlying drug addiction. This system participates in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, through the release of endocannabinoids in the ventral tegmental area. Endocannabinoids are also involved in the motivation to seek drugs by a dopamine-independent mechanism, demonstrated for psychostimulants and opioids. The endocannabinoid system also participates in the common mechanisms underlying relapse to drugseeking behaviour by mediating the motivational effects of drug-related environmental stimuli and drug reexposure. In agreement, clinical trials have suggested that the CB1 cannabinoid antagonist rimonabant can cause smoking cessation. Thus, CB1 cannabinoid antagonists could represent a new generation of compounds to treat drug addiction.
Drug addiction is a chronic relapsing brain disorder, characterized by neurobiological changes leading to
compulsive drug seeking and drug taking despite serious negative consequences, and by loss of control over drug use . Addiction includes complex behavioural and neurobiological processes. All the drugs of abuse produce reinforcing effects that are responsible for the initiation of the addictive disorder. However, other behavioural processes are also crucial for the maintenance of addiction, including the negative consequences of drug abstinence and the different stimuli leading to relapse (e.g. drug-associated cues, stressors and drug re-exposure) .
Several groups of compounds that produce different pharmacological effects can lead to addictive behaviour, including opioids, psychostimulants, cannabinoids, alcohol and nicotine. The initial mechanism of action of these drugs implicates different neurochemical targets . However, all these compounds produce neural dysregulations involving similar neurochemical and neuroanatomical
pathways . Indeed, multiple studies support the existence of common neurobiological mechanisms for the addictive properties of most drugs of abuse. This information is based on findings showing the crucial role of the mesocorticolimbic dopaminergic pathways, the endogenous opioid system, and the brain and pituitary stress system in the addictive processes. Drugs of abuse interact with these common brain circuits producing adaptive changes leading to a profound dysregulation of brain motivational and reward pathways . The mesocorticolimbic system represents a common neuronal substrate for the reinforcing properties of drugs of abuse, where both dopamine and opioid transmission are crucial . The major components of this drug reward circuit are the ventral tegmental area (VTA), which contains the dopaminergic cell bodies, and the terminal areas in the basal forebrain [the nucleus accumbens
(NAc), olfactory tubercle, amygdala, and frontal and limbic cortices] . These neurochemical circuits are also involved in the negative motivational consequences of drug withdrawal . Mesolimbic dopaminergic neurons receive highly processed information from the cerebral cortex and other areas involved in cognitive functions, and dopamine release in the forebrain has been proposed to serve as a learning signal. Dopamine neurons in the NAc interact with glutamatergic projection neurons from the
cerebral cortex, hippocampus and amygdala, providing information about external context and about internal emotional and physiological states. Hence, drug-induced plasticity in these NAc projections contributes to addiction by consolidating reward-driven behaviour [3,7]. Recruitment of brain stress pathways has also been reported as a common change during drug abstinence that seems be crucial in the reinstatement of drug seeking behaviour . However, the common mechanisms involved in the development of the addictive processes have not been yet completely identified. This review focuses on the recent findings supporting participation of the endocannabinoid system in the common circuitry underlying drug addiction and proposes a mechanistic explanation for this physiopathological role.
Endocannabinoid system and brain reward circuitry
Knowledge of the endocannabinoid system has been largely improved since the cloning in 1990 of the CB1 cannabinoid receptor, which is activated by D9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa. This system consists of cannabinoid receptors, endogenous ligands and several proteins responsible for their synthesis and degradation. To date, two subtypes of cannabinoid receptors, CB1 and CB2, have been characterized and cloned. CB1 receptors are the most abundant G-protein-coupled receptor in the CNS and are also found in peripheral tissues. CB2 receptors are mainly located in the cells of the immune system , but they have also been recently identified in brainstem, cortex and cerebellum neurons . Several endogenous cannabinoids have been isolated from brain tissue, anandamide and 2-arachidonoylglycerol being the best characterized . Endocannabinoids are thought to act as retrograde messengers in the CNS  and behave as neuromodulators in many physiological processes. Accordingly, endocannabinoids released from postsynaptic neurons upon depolarization activate presynaptic CB1 cannabinoid receptors, resulting in inhibition of the release of both excitatory and inhibitory neurotransmitters. This endocannabinoid
retrograde control has also been recently demonstrated after synaptic activation of group I metabotropic glutamate receptors  and D2 dopamine receptors .
Several studies support the view that the endocannabinoid system represents a new candidate for the control of drug rewarding properties. Indeed, CB1 cannabinoid receptors are abundant in the brain reward circuitry and participate in the addictive properties induced by different drugs of abuse. The dopaminergic neurons of the mesocorticolimbic pathway are controlled by excitatory and inhibitory inputs that are modulated by CB1 cannabinoid receptors. Thus, endocannabinoids can be released following depolarization in the NAc  and from dopaminergic neurons in the VTA [13,15], and they
modulate glutamatergic and GABAergic afferents by acting as retrograde messengers on CB1 receptors. The presence of CB1 receptors in other structures related to motivation and reward, such as the basolateral amygdala and the hippocampus, also contributes to this function of the endocannabinoid system . In addition, endocannabinoids participate in synaptic plasticity in the mesolimbic
(…)endocannabinoids and addiction