Anxiogenic-like effects of spontaneous and naloxone-precipitated opiate withdrawal in the elevated plus-maze.

Withdrawal from opiates and other drugs of abuse in human addicts is associated with a state of anxiety that may be of motivational relevance for the maintenance of drug addiction. Previous attempts with rats to model the anxiogenic-like effects of opiate withdrawal using the elevated plus-maze have met with mixed success. The current study sought to determine whether spontaneous and naloxone-precipitated opiate withdrawal could be observed reliably in rats made dependent on morphine through implantation of two morphine pellets (75 mg morphine base each). Seventy-two hours after implantation of either morphine or placebo pellets, rats were tested in the elevated plus-maze. In Experiment 1, pellets were removed 8 or 12 h prior to test; results indicated an anxiogenic-like effect (reduction in time spent in the open arms) of opiate withdrawal at 8 but not 12 h postpellet removal. In Experiment 2, pellets were not removed, but withdrawal was precipitated with naloxone (0.003-0.03 mg/kg s.c.). Naloxone dose dependently precipitated a reduction in exploration of the open arms of the plus-maze. The results suggest that both spontaneous and precipitated withdrawal from continuous morphine administration via pellet implantation result in demonstrable anxiogenic-like effects in the plus-maze.

Measures of cocaine-seeking behavior using a multiple schedule of food and drug self-administration in rats.

Animal models of human drug abuse measuring (i) cocaine-seeking behavior maintained by primary or secondary reinforcers, (ii) the time to extinction of cocaine-seeking behavior, and (iii) following extinction, reinstatement of operant responding resulting in presentation of a cocaine-associated stimulus were developed in rats. Animals were trained to respond on a multiple schedule of food and intravenous cocaine reinforcement during which either food or cocaine paired with auditory or visual stimuli were available during four alternating 30-min schedule components. At the beginning of each experimental session, a 10-min component (stimulus component) was introduced during which the stimuli associated with the primary reinforcers were made available response-contingently. Subsequent non-contingent presentation of food or cocaine at the beginning of the stimulus component produced a significant increase in lever-pressing resulting in presentation of the respective reinforcer-associated stimulus. Removal of cocaine and the associated stimulus during all schedule components led to extinction of drug-seeking behavior within six days. Lever-pressing resulting in presentation of the drug-associated stimulus was subsequently by non-contingent delivery of cocaine, but not by non-contingent presentation of the stimulus alone. These results suggest that different aspects of cocaine-seeking behavior, such as operant responding resulting in presentation of a cocaine-associated external stimulus, time to extinction in the absence of primary reinforcement, and reinstatement of responding following extinction can be measured in the rat. These tests may provide useful tools for the assessment of potential treatment drugs for human cocaine abuse.