Participación del sistema cannabinoide endógeno en los fenómenos de adicción. Interacción con otros sistemas de neurotransmisión

Abstract

Cannabinoid addiction includes complex neurobiological and behavioural processes. Recently, several animal models allowing the exploration of the neurobiological basis of cannabinoid addiction have been developed. Acute cannabinoid reinforcing effects play a major role in the initiation of cannabinoid addiction, whereas the negative consequences of drug abstinence have a crucial motivational significance for relapse and maintenance of the addictive process. To further explore the neurobiological basis of cannabinoid addiction, we have conducted several pharmacological and molecular studies. The neuroanatomical substrate of cannabinoid physical dependence has been investigated in mice chronically receiving the cannabinoid agonist WIN 55,212-2. Interestingly, the cerebellum and in a lesser extent the hippocampus and the amygdala are shown to participate in the behavioural expression of cannabinoid withdrawal. All these brain areas have a high density of CB1 cannabinoid receptors. Moreover, we have evaluated the involvement of various neurotransmitter systems, such as the purinergic and opioid systems, in the behavioural responses of cannabinoids related to their addictive properties, including rewarding effects and the development of physical dependence. For this purpose, we have used genetically modified mice. Mice lacking A2A adenosine receptors reveal lower motivational responses to cannabinoids and a decreased cannabinoid withdrawal syndrome, suggesting a specific involvement of these receptors in the addictive-related properties of cannabinoids. On the other hand, the opioid system has also been implicated in the addictive properties of cannabinoids. Here, by using double mutants for mu- and delta-opioid receptors, we show that a cooperative action of both receptors is required for the entire expression of cannabinoid dependence. Finally, taking into account that the cannabinoid system has been reported to participate in the addictive properties of other drugs of abuse, such as ethanol, cocaine and MDMA, we have investigated the possible role of the cannabinoid system in the addictive properties of nicotine. We have evaluated nicotine behavioural responses in mice lacking CB1 cannabinoid receptors. In this regard, our main findings are that some acute effects and motivational responses of nicotine can be modulated by the endogenous cannabinoid system which could be of interest in order to find new therapies to facilitate tobacco smoking cessation.