Differential tolerance development to buprenorphine-, Diprenorphine-, and heroin-induced disruption of food-maintained responding in Macaque monkeys

Single daily subcutaneous injections of buprenorphine (1.0 mg/kg), diprenorphine (1.0 mg/kg), or heroin (1.0 mg/kg) were given over 25 consecutive days to examine the degree and the rate of tolerance development to drug-induced suppression of food maintained responding. One gram food pellets were available on a second order schedule (FR 4 VR 16:S) during the 1-hr sessions three times a day. All drug and saline control injections were given at 10:00 a.m., 1 hr before a food session. During the first three days of treatment all three drugs produced marked suppression of food-maintained performance. Recovery from buprenorphine-and diprenorphine-induced suppression of food-maintained responding occurred within four and eight days, respectively. By the 25th day of buprenorphine and diprenorphine treatment, operant responding for food increased significantly above control levels (p<0.01). In contrast, the significant heroin-induced disruption of food-maintained responding (p<0.01) persisted throughout the 25-day treatment period. Saline substitution for all three drugs resulted in a gradual return to control levels of food pellets earned. Linear regression analysis of the linear portion of the time-effect curve revealed significant differences in both the rate and the degree of tolerance development of these three drugs. These differences in tolerance development may reflect pharmacokinetic differences between the relatively short-acting heroin and the longer-acting diprenorphine and buprenorphine.