Elsevier

Neuroscience

Volume 181, 5 May 2011, Pages 1-17
Neuroscience

Neuroscience Forefront Review
Neurochemical basis of cannabis addiction

https://doi.org/10.1016/j.neuroscience.2011.02.035Get rights and content

Abstract

Cannabis derivatives have become the most widely used illicit substances in developed countries, and constitute a major health concern. The psychoactive compounds contained in cannabis induce their pharmacological effects by the activation of at least two different receptors, CB1 and CB2 cannabinoid receptors. Multiple studies have demonstrated the specific involvement of CB1 cannabinoid receptors in the addictive properties of cannabinoids. Several neurotransmitter systems involved in the addictive effects of other prototypical drugs of abuse, such as the dopaminergic and the opioid system are also involved in cannabis addiction. The participation of other neurochemical systems in behavioural responses of cannabinoids related to their addictive effects has also been reported. This review describes the experimental methods now available to study the pharmacological responses of cannabinoids related to their addictive effects and how these methods have contributed to advance the knowledge of the specific contribution of different neurochemical systems in cannabis addiction.

Highlights

▶Experimental methods now available to study cannabinoid addictive effects. ▶Involvement of dopamine system in cannabis addiction. ▶Involvement of the endogenous opiopid system in cannabis addiction. ▶Advancement in the neurochemical bases of cannabis addiction.

Section snippets

Cannabinoid compounds

Cannabis sativa derivatives have been known for thousands of years for their recreational use and medicinal properties. The interest for these substances has increased in the last decades due to the identification and characterization of an endogenous cannabinoid system located in the CNS and peripheral tissues that could serve as a therapeutic target. However, cannabis derivatives have become the illegal drugs with the highest consumption rate for recreational purposes, and constitute a major

Endocannabinoid system

The endocannabinoid system is composed of the cannabinoid receptors, the endogenous ligands or endocannabinoids, and the enzymes participating in the synthesis and degradation of the endocannabinoids. The best characterized cannabinoid receptors are CB1 (Matsuda et al., 1990) and CB2 (Munro et al., 1993) receptors, although other receptors, such as GPR55 (Baker et al., 2006) have also been reported to bind cannabinoid ligands. All these receptors are seven transmembrane domain-G protein-coupled

Cannabis abuse in humans

Cannabis derivatives are the most widely used illicit substance in Europe, USA and Australia (AIHW, 2005, SAMHSA, 2010, EMCDDA, 2009). Notably, recent analyses of cannabis extracts have shown an increase in potency over the last years due to enhanced THC content (Pijlman et al., 2005, McLaren et al., 2008, Mehmedic et al., 2010), which probably leads to an increase in the subjective effects of this drug. Cannabis effects will also depend on the route of administration, previous experience of

Animal models to evaluate pharmacological responses of cannabinoids related to their addictive properties

Several animal models are available to study particular responses that are related to cannabis addiction. Thus, predictive models are available in animals to evaluate the development of cannabinoid tolerance and physical dependence as well as the rewarding/reinforcing effects produced by cannabinoids. These animal models have been extremely useful to understand the neurobiological mechanisms underlying cannabis addiction and can be of great interest to evaluate the effectiveness of any possible

Involvement of CB1 cannabinoid receptors in cannabinoid addictive properties

The specific involvement of CB1 cannabinoid receptors in the pharmacological responses of cannabinoids related to their addictive properties has been clearly demonstrated in animal studies using selective CB1 antagonists and knockout mice deficient in CB1 receptors (Maldonado, 2002, Panlilio et al., 2010). Thus, CB1 receptors are selectively involved in the development of tolerance to the different pharmacological responses of cannabinoids and the somatic manifestations of cannabinoid

Involvement of dopamine in cannabinoid addictive properties

Several heterologous systems different from the endocannabinoid system also participate in the addictive properties of cannabinoids. The mesocorticolimbic system mediates the rewarding properties of all the prototypical drugs of abuse (Di Chiara et al., 2004, Fattore et al., 2008). An important component of this system is the dopaminergic projection from the ventral tegmental area (VTA) to the frontal cortex and limbic structures, such as the nucleus accumbens (NAc) and amygdala. Cannabinoids,

Involvement of the endogenous opioid system in cannabinoid addictive properties

Opioid receptors and their endogenous ligands have been demonstrated to play an important role in brain reward processes, and to modulate the behavioural and neurochemical effects of multiple drugs of abuse including cannabinoids (Trigo et al., 2010). A first evidence for this participation is the overlapping distribution of CB1 and mu-opioid receptors revealed by anatomical studies in several areas of the CNS, such as the limbic system, mesencephalon, brain stem and spinal cord (Rodríguez et

Noradrenaline and serotonin

Early studies evaluating the peripheral effects of cannabinoid exposure showed that the acute administration of THC interfered with noradrenaline release following stimulation of the rat isolated vas deferens (Graham et al., 1974), whereas the hypotensive effects of noradrenaline were not modified after chronic THC treatment (Adams et al., 1976). Subsequent studies reported that repeated cannabinoid treatment increased noradrenaline efflux in the prefrontal cortex of mice (Hillard and Bloom,

Concluding remarks

Specific animal models are now available to evaluate the different behavioural responses induced by cannabinoids that are related to their addictive properties. These experimental models have allowed an important advance in the knowledge of the neurobiological substrate underlying cannabis addiction. These models have clearly revealed that the CB1 cannabinoid receptors are responsible of all the responses related to the addictive properties of cannabinoids. However, the recent discovery of CB2

Acknowledgments

This work was supported by the Spanish “Ministerio de Ciencia e Innovación” (#SAF2007-64062), “Instituto de Salud Carlos III” (#RD06/001/001), Plan Nacional sobre Drogas, the Catalan Government (SGR2009-00131) and the ICREA Foundation (ICREA Academia-2008).

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