Endogenous anti-stress systems also appear to buffer the brain stress systems and influence vulnerability to the development and perpetuation of addiction. Key neurotransmitters that act in opposition to brain stress systems include neuropeptide Y, nociceptin, and endocannabinoids (tables 1, 2, circuits 10 and 11).20,28,29,49,84 In particular, with chronic drug exposure, neuro-adaptations in the endocannabinoid system, which modulates the response of the brain to stress,85 might contribute to the enhanced stress reactivity in addiction. Indeed, human brain imaging studies have reported reductions of cannabinoid CB1 receptors in cannabis abusers and alcoholics.86,87 Thus, the development of enduring aversive emotional states,88 mediated by overactivation of the stress and anti-reward systems or underactivation of the anti-stress systems, might contribute to the crucial problem in drug addiction of chronic relapse, in which individuals with addiction return to compulsive drug taking long after acute withdrawal.2
