Review
The role of endocannabinoid transmission in cocaine addiction

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Abstract

Research is beginning to outline a role for the endocannabinoid system in cocaine addiction. Human and animal studies indicate that exogenous cannabinoids modulate the acute rewarding effects of cocaine. These studies, however, cannot directly investigate the necessity of endocannabinoid transmission in cocaine addiction. Studies that do offer a direct assessment show that neither pharmacological antagonism nor deletion of the CB1 receptor alters the acute rewarding effects of cocaine. In contrast, CB1 receptors appear to be involved in the association of cocaine reward with environmental cues and reinstatement of cocaine self-administration. Together, these results point to CB1 receptor antagonists as potential anti-craving compounds in the treatment of cocaine addiction. Given the limitations of human population studies, animal research may be useful in discerning causal inferences between cannabis and cocaine use. While animal research suggests cannabis use may precipitate cocaine relapse, cross-sensitization between cannabinoids and cocaine has not been demonstrated and CB1 receptors do not mediate behavioral sensitization to cocaine. The effect of acute or chronic cocaine on endocannabinoid transmission in reward-related areas of the brain is relatively under-researched. Acute cocaine administration increases anandamide levels in the striatum, an effect that is mediated by dopamine D2-like receptors. Conversely, chronic cocaine exposure has no effect on anandamide, but decreases 2-arachidonylglycerol levels in the limbic forebrain. This review highlights research indicating that the endocannabinoid system may subserve certain aspects of cocaine addiction and suggests avenues for future investigation.

Introduction

Endocannabinoids, such as arachidonylethanolamide (anandamide) and 2-arachidonylglycerol (2-AG), are synthesized in neurons and astrocytes, and are subject to enzymatic degradation by fatty acid amide hydrolase (FAAH) and also high affinity reuptake (Beltramo and Piomelli, 2000, Beltramo et al., 1997, Bisogno et al., 1997, Bisogno et al., 2001, Desarnaud et al., 1995, Di Marzo et al., 1994, Di Marzo et al., 1998, Stella et al., 1997, Walter et al., 2002). A more detailed picture of the distribution of cannabinoid (CB1) receptors in discrete brain circuits has been mapped out, especially in reward-related areas of the brain (Freund et al., 2003, Katona et al., 2001, Robbe et al., 2003). Furthermore, endocannabinoids act as retrograde messengers, synthesized on demand and released from the postsynaptic membrane to activate presynaptically located CB1 receptors that modulate the release of neurotransmitters (Freund et al., 2003, Wilson and Nicoll, 2001).

The science of the endocannabinoid system has advanced our understanding of various disorders of the central nervous system (CNS) (Freund et al., 2003, Porter and Felder, 2001, van der Stelt and Di Marzo, 2003). Converging evidence indicates that the endocannabinoid system is an important constituent of neural substrates involved in drug addiction. For example, human studies have shown that polymorphisms in components of the endocannabinoid system, such as in genes encoding the cannabinoid CB1 receptor and FAAH, are associated with substance abuse and dependence (Comings et al., 1997, Sipe et al., 2002). Thus, the endocannabinoid system may offer a novel target in the treatment of drug addiction. This may be especially important in the treatment of cocaine abuse and dependence, where no proven effective pharmacotherapies exist (de Lima et al., 2002, van den Brink and van Ree, 2003). Furthermore, a role for endocannabinoid transmission in cocaine addiction might provide a mechanism for the “gateway hypothesis,” the view that exposure to cannabis might heighten an individual's susceptibility to becoming dependent on cocaine.

Many studies show commonalities in the neuropharmacological actions of cannabinoids and cocaine, providing prima facie evidence that endocannabinoids might play an important role in cocaine addiction. Administration of cannabinoids or cocaine increases expression of the immediate early gene, c-fos, in reward-related brain regions such as the nucleus accumbens (NAc) and the prefrontal cortex (Arnold et al., 2001b, Erdtmann-Vourliotis et al., 1999). Furthermore, exposure to cocaine or the main psychoactive constituent of cannabis,  Δ9-tetrahydrocannabinol (Δ9-THC), promotes an increase in the release of DA in the NAc (Carboni et al., 1989, Chen et al., 1990, Hernandez and Hoebel, 1988, Hurd et al., 1989, Pettit and Justice, 1989, Tanda et al., 1997). In addition, injection of either cannabinoids (Hoffman and Lupica, 2001, Manzoni and Bockaert, 2001, Szabo et al., 2002) or cocaine (Nicola et al., 1996) directly into the NAc promotes an inhibition of excitatory synaptic transmission in this brain region.

Cannabinoids interact with CB1 receptors to produce their rewarding actions, whereas cocaine inhibits monoamine carriers, such as dopamine (DA), serotonin and noradrenaline transporters (Heikkila et al., 1979, Kuhar et al., 1991, Ledent et al., 1999, Maldonado and Rodriguez de Fonseca, 2002, Mansbach et al., 1996, Martellotta et al., 1998, Rothman and Baumann, 2003). As such, evidence of overlap between endocannabinoid and monoamine transmission may also point to a role of endocannabinoids in cocaine dependence. First, mRNA for DA D1 and D2 receptors, as well as 5-HT1B receptors, are co-localized with CB1 receptors in the striatum (Hermann et al., 2002). This co-localization implies that cross-talk may occur between CB1 and monoamine receptors at the level of signal transduction. In support of this, Glass and Felder (1997) demonstrated that stimulation of either CB1 receptors or D2 receptors leads to a decrease in cAMP accumulation. However, an increase in cAMP levels is promoted when these receptors are stimulated together. Similarly, a recent study observed that cells expressing CB1 receptors alone accumulate less cAMP when exposed to cannabinoids (Jarrahian et al., 2004). When these cells are also transfected with the D2 receptor gene, cannabinoids act to increase cAMP accumulation. Functional interactions thus exist between the endocannabinoid system and monoamine systems in reward-related areas of the brain.

Nonetheless, a more definitive analysis of the involvement of the endocannabinoid system in cocaine addiction is warranted. The current review will address human and animal experiments that assess whether endocannabinoid transmission plays a role in the habit-forming nature of cocaine. Particular emphasis will be given to animal studies where two main strategies have been implemented. Both approaches infer the functional role of CB1 receptors, either through pharmacological blockade of CB1 receptors, or by using transgenic animals engineered to lack the gene encoding the CB1 receptor (CB1 receptor knockout mice). Exogenous cannabinoid modulation of cocaine reinforcement will also be overviewed. Such research yields only tentative information on endocannabinoid transmission but may provide directives for future investigations. Finally, behavioral research will be discussed in light of molecular and neurochemical studies which underscore the involvement of endocannabinoid transmission in the neuropharmacological actions of cocaine.

Section snippets

Human studies

There exists a paucity of research into the role of the endocannabinoid system in the acute rewarding effects of cocaine. Two human studies provide evidence that cannabinoids might act to potentiate the euphoriant actions of cocaine. The first of these studies observed that human volunteers who smoked cannabis prior to intravenous (i.v.) cocaine displayed a trend for a prolonged experience of the “high” associated with these drugs (Foltin et al., 1993). Another study revealed that smoking a Δ9

The endocannabinoid system and neuroadaptive change: cocaine sensitization

Neuroadaptations in the mesolimbic DA system that accompany chronic drug use offer an explanation for why drug abusers frequently relapse after discontinuing use (Koob, 1996, Koob et al., 2004, Robbins and Everitt, 1999, Robinson and Berridge, 1993). In the field of neuropharmacology, sensitization of the mesolimbic DA system is thought to herald the expression of such neuroadaptations. Accordingly, repeated intermittent exposure to drugs such as cocaine, amphetamine, nicotine or heroin

The “gateway” theory

The “gateway” theory, a phenomenon often alleged by politicians, holds that cannabis use may predispose users to the administration of other “harder” drugs of abuse, such as cocaine. The most extensive research pertinent to the gateway theory are longitudinal studies conducted by Kandel and colleagues (Kandel et al., 1997, Kandel and Yamaguchi, 1993, Kandel and Davies, 1992). These researchers uncovered a highly predictable sequence of drug use in American adolescents which starts with alcohol

Conclusion

This review highlights that endocannabinoid transmission subserves different aspects of cocaine addiction. Evidence to date suggests that the endocannabinoid system is not involved in the acute rewarding effects of cocaine. In contrast, CB1 receptors may mediate the association of cocaine reward with environmental cues and reinstatement of cocaine self-administration. Cannabis use in humans may thus precipitate relapse and CB1 receptor antagonists may prove to be effective in preventing relapse

Acknowledgements

I am grateful to Dr. Kirsten Morley for her valuable comments on the manuscript.

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