Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues.
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.
Weiss
F
F
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. bweiss@scripps.edu
Martin-Fardon
R
R
Ciccocioppo
R
R
Kerr
T M
TM
Smith
D L
DL
Ben-Shahar
O
O
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000502:physiology; D004777:Environment; D005108:Extinction, Psychological / Q000502:physiology*; D005502:Food; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012008:Recurrence; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects
D004298:Dopamine