ABSTRACT
RATIONALE: Four-hour pretreatment with a single dose of morphine or related opioids sensitizes rats responding for intracranial self-stimulation (ICSS) to the rate-decreasing effect of naltrexone, indicative of antagonist-precipitated withdrawal from acute opioid dependence. OBJECTIVES: To determine whether sensitization to naltrexone could be observed in morphine-pretreated rats responding under a progressive ratio (PR) schedule of ICSS and to determine whether acute pretreatment with benzodiazepines produces similar sensitization to flumazenil. METHODS: Rats with an electrode in the medial forebrain bundle were trained to respond under an ICSS PR schedule, in which the number of responses required for a 250-ms stimulus started at one, then increased gradually. If no responding occurred for 30 s, the response requirement reverted to a single response and the break point was operationally defined. RESULTS: Pretreatment (4-h) with 3.0 mg/kg or 5.6 mg/kg morphine reduced the ED25 values of naltrexone for decreasing response rate from 18+/-6.7 mg/kg to 0.021+/-0.006 mg/kg and 0.006+/-0.001 mg/kg, respectively. Changes in break point usually paralleled changes in response rate. In contrast, 4- to 24-h pretreatment with the benzodiazepines chlordiazepoxide (30 mg/kg and 100 mg/kg) or diazepam (3.0 mg/kg and 10 mg/kg), behaviorally-active doses, did not significantly alter sensitivity to the effects of flumazenil (1.0-30 mg/kg). CONCLUSIONS: These results show that PR ICSS provides a stable behavioral baseline for testing drugs in rats and extend to this procedure the generality of the phenomenon of acute opioid dependence. There was no comparable evidence of acute benzodiazepine dependence, suggesting that there are differences in the ways that opioid and benzodiazepine agonists initiate the adaptive changes that underlie the state of physical dependence.
