Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone.
BACKGROUND
Non-dependent and dependent opiate users appear to be driven by two distinct motivational factors: the primary reinforcing properties of the drug, and the negative reinforcing effects associated with relieving the negative affective component of opiate withdrawal in the dependent state.


OBJECTIVE
To investigate the motivational significance of opioid dependence on heroin self-administration (HSA) in rodents.


METHODS
Rats were trained to self-administer heroin intravenously (0.06 mg/kg per infusion; FRI), and opiate dependence was induced by subcutaneous implantation of two morphine (75 mg base) pellets. Rats in a non-dependent control group received placebo pellets. Three days after pellet implantation, HSA was resumed in daily 3-h sessions until baseline criteria were met and testing was conducted with subcutaneous injections of vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session.


RESULTS
Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet-implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a second experiment, the HSA session was shortened to 1 h and the training dose reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo pellet-implanted rats was increased only following the highest dose of the antagonist, while dependent rats were still affected by naloxone doses of 0.003-0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3), breaking point values in dependent animals were 198% above baseline.


CONCLUSIONS
The present study supports the hypothesis that dependence-induction by morphine-pellet implant in rats resulted in increased sensitivity to very small naloxone doses, as measured by changes in HSA. Taken together, these data suggest that opiate dependence, as measured by changes in sensitivity to naloxone, is a continuum which can contribute to the motivational state of drug-seeking.
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. rcarrera@scipps.edu
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D000818:Animals; D003932:Heroin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D013287:Illicit Drugs / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000503:physiopathology / Q000523:psychology; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000523:psychology; D013375:Substance Withdrawal Syndrome
D013287:Illicit Drugs; D009292:Narcotic Antagonists; D009270:Naloxone; D003932:Heroin; D009020:Morphine