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Neuropharmacology 47 (2004) 167179 www.elsevier.com/locate/neuropharm

Summary: Neuropharmacology 47 (2004) 167179
Brain substrates for increased drug seeking during protracted
Gary Aston-Jones
, Glenda C. Harris
Department of Psychiatry, University of Pennsylvania, 705 Stellar Chance/6100, 422 Curie Blvd, Philadelphia, PA 19104-6100, USA
Received 15 April 2004; received in revised form 26 May 2004; accepted 30 June 2004
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 nor-
epinephrine (NE) release in the bed nucleus of the stria terminalis (BNST) may underlie anxiety associated with protracted with-
drawal. 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 neu-
rons 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 dur-


Source: Aston-Jones, Gary - Department of Neurosciences, Medical University of South Carolina


Collections: Biology and Medicine