Increase of morphine withdrawal in mice lacking A(2a) receptors and no changes in CB1/A(2a) double knockout mice

CB1 cannabinoid and A(2a) adenosine receptors are highly expressed in the central nervous system where they modulate numerous physiological processes including emotional behaviour and the responses of several drugs of abuse. To investigate the contribution of these receptors in emotional-like responses and opioid dependence we have generated CB1/A(2a) double deficient mice (CB1-/-/A(2a)(-/-)). The spontaneous locomotor activity was reduced in double knockout as compared to wild-type animals. Emotional-like responses of CB1-/-/A(2a)(-/-) mice were investigated using the elevated plus-maze and the lit-dark box. Mutant mice exhibited an increased level of anxiety in both behavioural models. The specific involvement of CB1 and A(2a) receptors in morphine dependence was evaluated by using A(2a) knockout mice and CB1/A(2a) double mutant mice. The severity of naloxone-precipitated morphine withdrawal syndrome was significantly increased in the absence of A(2a) adenosine receptors whereas no modifications were observed in the double knockout mice. These results suggest that both receptors participate in the control of emotional behaviour and seem to play an opposite role in the expression of opioid physical dependence.