Relapse to drug-seeking: neural and molecular mechanisms

Drug Alcohol Depend. Jun-Jul 1998;51(1-2):49-60. doi: 10.1016/s0376-8716(98)00065-9.


A central determinant of addictive disorders in people is increased risk of relapse to drug use even after prolonged periods of abstinence. Recent advances in animal models of relapse indicate that drug-seeking behavior can be triggered by priming injections of the drugs themselves, by drug-associated environmental stimuli, and by footshock stress. The neural mechanisms underlying this relapse can be viewed in general terms as drug-like or proponent processes. Considerable evidence points to the mesolimbic dopamine system, and more specifically to activation of D2-like dopamine receptors in the nucleus accumbens, as a crucial neural substrate utilized by various stimuli that induce relapse. Drug-associated stimuli and stress may activate this system via neural circuits from the prefrontal cortex and amygdala as well as via the hypothalamo-pituitary-adrenal axis. There is also evidence for dopamine-independent mechanisms in relapse as well. A major effort of current research is to identify the long-lasting neuroadaptations within these various brain regions that contribute to relapse in addicted people. One potential neuroadaptation is up-regulation of the cAMP pathway in the nucleus accumbens, which occurs after chronic drug exposure, and represents a drug-opposite or opponent process. Modulation of this system has been related directly to relapse to drug-seeking behavior. Given the long-lasting nature of increased risk of relapse, it is likely that the relevant neuroadaptations are mediated via drug-induced changes in gene expression. A detailed understanding of the neural and molecular basis of relapse will facilitate efforts to develop truly effective treatments and preventive measures.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Appetitive Behavior / physiology
  • Behavior, Addictive / metabolism
  • Behavior, Addictive / physiopathology*
  • Behavior, Addictive / psychology
  • Brain* / drug effects
  • Brain* / metabolism
  • Brain* / physiopathology
  • Central Nervous System Stimulants / adverse effects
  • Cues
  • Cyclic AMP / metabolism
  • Disease Susceptibility
  • Dopamine / physiology
  • GTP-Binding Proteins / drug effects
  • GTP-Binding Proteins / metabolism
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiopathology
  • Illicit Drugs / adverse effects
  • Models, Neurological*
  • Models, Psychological
  • Narcotics / adverse effects
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / physiopathology
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiopathology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism
  • Receptors, Neurotransmitter / drug effects
  • Receptors, Neurotransmitter / metabolism
  • Recurrence
  • Self Medication / adverse effects
  • Self Medication / psychology
  • Stress, Psychological / complications
  • Stress, Psychological / physiopathology
  • Substance-Related Disorders / etiology
  • Substance-Related Disorders / physiopathology*
  • Substance-Related Disorders / psychology
  • Transcription, Genetic / drug effects
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiopathology


  • Central Nervous System Stimulants
  • Illicit Drugs
  • Narcotics
  • Receptors, Neurotransmitter
  • Cyclic AMP
  • Protein Kinases
  • GTP-Binding Proteins
  • Dopamine