Synergistic effects of cocaine with lateral hypothalamic brain stimulation reward: lack of tolerance or sensitization.

The curve-shift (rate-frequency) paradigm was used to quantify the interaction of cocaine administration with the rewarding effects of lateral hypothalamic electrical stimulation. First, eight animals were tested at 48-h intervals with increasing doses of cocaine (0.5, 1, 2, 4, 8, 16 or 32 mg/kg i.p.); tests with saline were given on intervening days. Cocaine produced dose-orderly leftward shifts of the functions relating response rate to stimulation frequency, which reduced, for each animal, the amount of stimulation required to sustain responding; the two highest doses of the drug shifted the mean rate-frequency curve by 0.47 log units, more than doubling the rewarding potency of the brain stimulation. Baseline thresholds did not change between tests. Next, evidence for sensitization or tolerance was sought from five additional groups of animals, one group given 4 mg/kg and two groups given 16 mg/kg of cocaine at 48-h intervals, and another two groups maintained for 7 days with thrice-daily injections of 10 mg/kg of cocaine or saline. Consistent with results seen in other brain stimulation reward paradigms, there was no evidence of tolerance or sensitization to cocaine's reward-potentiating effects as quantified in the rate-frequency paradigm.