Adenosine A2A receptors are involved in physical dependence and place conditioning induced by THC

A(2A) adenosine and CB1 cannabinoid receptors are highly expressed in the central nervous system, where they modulate numerous physiological processes including adaptive responses to drugs of abuse. Both purinergic and cannabinoid systems interact with dopamine neurotransmission (through A(2A) and CB1 receptors, respectively). Changes in dopamine neurotransmission play an important role in addictive-related behaviours. In this study, we investigated the contribution of A(2A) adenosine receptors in several behavioural responses of Delta(9)-tetrahydrocannabinol (THC) related to its addictive properties, including tolerance, physical dependence and motivational effects. For this purpose, we first investigated acute THC responses in mice lacking A(2A) adenosine receptors. Antinociception, hypolocomotion and hypothermia induced by acute THC administration remained unaffected in mutant mice. Chronic THC treatment developed similar tolerance to these acute effects in wild-type and A(2A)-knockout mice. However, differences in the body weight pattern were found between genotypes during such chronic treatment. Interestingly, the somatic manifestations of SR141716A-precipitated THC withdrawal were significantly attenuated in mutant mice. The motivational responses of THC were also evaluated by using the place-conditioning paradigm. A significant reduction of THC-induced rewarding and aversive effects was found in mice lacking A(2A) adenosine receptors in comparison with wild-type littermates. Binding studies revealed that these behavioural changes were not associated with any modification in the distribution and/or functional activity of CB1 receptors in knockout mice. Therefore, this study shows, for the first time, a specific involvement of A(2A) receptors in the addictive-related properties of cannabinoids.