Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues

Neuropsychopharmacology. 2001 Sep;25(3):361-72. doi: 10.1016/S0893-133X(01)00238-X.


The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous cocaine (S(+)) vs. the availability of non-rewarding (S(-)) saline solution, and then placed on extinction conditions during which intravenous solutions and S(D) were withheld. The rats were then presented with the S(+) or S(-) alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S(+), a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S(+) selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D(1) antagonist SCH 39166 (10 microg/kg), the D(2/3) antagonist nafadotride (1 mg/kg), and the D(2/3) agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D(1) agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S(+) to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

Publication types

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

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Cocaine-Related Disorders / psychology*
  • Conditioning, Operant / drug effects
  • Cues*
  • Dopamine / physiology
  • Environment
  • Extinction, Psychological / physiology*
  • Food
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Recurrence
  • Self Administration
  • Synaptic Transmission / drug effects


  • Dopamine