The neurobiological mechanisms underlying the enhanced reactivity to negative emotions including those triggered by stressful stimuli have not been thoroughly investigated in human subjects. Preclinical studies suggest that these involve the CRF and noradrenergic systems that modulate stress reactivity (75) as well as an upregulated kappa opioid receptor signaling in the brain (76). Recent studies also suggest that the lateral habenula may be involved in drug relapse in addiction (77), including relapses triggered by negative emotionality and stress. The lateral habenula is neuroanatomically connected to circuits involved with reward and emotion (78). In nonhuman primates, neurons in the lateral habenula are inhibited by reward-predicting stimuli and activated by aversive-predicting stimuli or by unrewarded trials (79). Given that activation of the lateral habenula inhibits DA neurons in the VTA and the substantia nigra (79), this could be a mechanism that triggers drug use to compensate for the reduced DA signaling following DA-induced cell inhibition.
