Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months.
OBJECTIVE
We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months.


METHODS
Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, i.p.; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions.


RESULTS
Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods.


CONCLUSIONS
Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.
Lu
Lin
L
Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Grimm
Jeffrey W
JW
Dempsey
Jack
J
Shaham
Yavin
Y
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000503:physiopathology*; D003042:Cocaine / Q000008:administration & dosage* / Q000009:adverse effects; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D007260:Infusion Pumps; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D012008:Recurrence; D012646:Self Administration / Q000379:methods; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013997:Time Factors
D003042:Cocaine