Brain substrates for increased drug seeking during protracted withdrawal.

Studies are reviewed indicating that both increased anxiety and altered hedonic processing accompany protracted withdrawal from opiates. Increased anxiety may be most apparent in response to stress, whereas decreased motivation for natural rewards but increased interest in drugs reveals substantial alterations in hedonic values. Our recent work indicates that increased norepinephrine (NE) release in the bed nucleus of the stria terminalis (BNST) may underlie anxiety associated with protracted withdrawal. Altered plasticity in afferents to the ventral tegmental area (VTA; accumbens, amygdala and lateral hypothalamus), or in the VTA itself, may be involved in the altered hedonic processing that occurs during protracted withdrawal. We hypothesize that conditioned release of NE in the BNST in response to stressors (including drug-associated stimuli) may elevate anxiety which then augments the reward value of drugs by a negative reinforcement mechanism. We also propose that plasticity in VTA neurons and their afferents during chronic drug exposure and protracted withdrawal decreases the valence of natural rewards whereas sensitization occurs to the motivational effects of drugs that increases their motivational valence. The combination of anxiety, decreased valence of natural rewards, and sensitized incentive for drugs make a potent formula for relapse and drug seeking during protracted withdrawal.