Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys

Abstract

Opioid withdrawal can produce a constellation of physiological and behavioral signs, including an increase in opioid self-administration. Different mechanisms mediate different withdrawal signs, and the present study used pharmacologic tools to assess mechanisms underlying withdrawal-associated increases in opioid reinforcement. Five rhesus monkeys were rendered heroin dependent via daily 21-h heroin self-administration sessions. One hour after each heroin self-administration session, monkeys chose between heroin (0-0.1 mg/kg per injection) and food (1 g pellets) during 2-h choice sessions. Under these conditions, heroin maintained a dose-dependent increase in heroin choice, such that monkeys responded primarily for food when low heroin doses were available (0-0.01 mg/kg per injection) and primarily for heroin when higher heroin doses were available (0.032-0.1 mg/kg per injection). Periods of spontaneous withdrawal were intermittently introduced by omitting one 21-h heroin self-administration session, and test drugs were administered during these withdrawal periods. Untreated withdrawal robustly increased heroin choice during choice sessions. Withdrawal-associated increases in heroin choice were completely suppressed by the mu opioid agonist morphine (0.032-0.32 mg/kg/h, i.v.), but not by the alpha-2 noradrenergic agonist clonidine (0.01-0.1 mg/kg/h, i.v.), the dopamine/norepinephrine releaser amphetamine (0.032-0.1 mg/kg/h, i.v.), or the kappa-opioid antagonist 5'-guanidinonaltrindole (1.0 mg/kg, i.m.). The corticotropin-releasing factor 1 antagonist antalarmin (1.0-10 mg/kg per day, i.m.) produced a morphine-like suppression of withdrawal-associated increases in heroin choice in one of three monkeys. These results suggest that mechanisms of withdrawal-associated increases in the relative reinforcing efficacy of opioid agonists may be different from mechanisms of many other somatic, mood-related, and motivational signs of opioid withdrawal.

Figure 1. Effects of heroin withdrawal on % heroin choice, number choices completed and withdrawal scores

Panels a and b show % heroin choice for the entire session and for each component of the choice session, respectively (maximum = 100 % heroin choice for total session and for each component). Panels c and d show total # choices for the entire session and for each component of the session, respectively (maximum = 50 for the entire session and 10 for each component of the session). Panel e shows the withdrawal score (maximum score =8). Closed bars and symbols show data for baseline sessions, which were defined as sessions immediately preceding test sessions. Open bars and symbols show data obtained after 22hr of heroin withdrawal, which was produced by omitting one supplemental session of heroin self-administration. Abscissae (top panels): withdrawal state of the subjects. Abscissae (bottom panels): unit dose heroin in mg/kg/inj available during each sequential component of the choice session. All figures show mean data for 5 monkeys, and error bars indicate SEM. Data in panels a, c, and e were evaluated with t-tests to compare baseline and withdrawal data. There was a significant effect of withdrawal on Total % Heroin Choices [t(4)=7.00, p=0.002], Total # Choices [t(4)=3.20; p=0.033], and Withdrawal Score [t(4)=8.55; p=0.001]. Asterisks in panels a, c and e indicate significant differences from baseline. *p<0.05, **p<0.01.

Figure 2. Effects of morphine treatment (0.032-0.32 mg/kg/hr) during heroin withdrawal

Panels a and b show % heroin choice for the entire session and for each component of the choice session, respectively (maximum = 100 % heroin choice for total session and for each component). Panels c and d show total # choices for the entire session and for each component of the session, respectively (maximum = 50 for the entire session and 10 for each component of the session). Panel e shows the withdrawal score (maximum score =8). Abscissae (top panels): Dose morphine in mg/kg/hr. Closed bars above “BL” and open bars above “WD” show data from baseline and heroin withdrawal sessions, respectively. Abscissae (bottom panels): Unit dose heroin in mg/kg/inj available during each component of the choice session. All figures show mean data from 4 monkeys, and error bars indicate SEM. ANOVA was used to compare data for each drug dose with “WD” in panels a, c and e, and there was a significant effect of morphine dose on Total % Heroin Choice [F(3,9)=15.87, p<0.001] and Withdrawal Score [F(3,9)=10.07, p=0.003], and the effect on Total # Choices approached significance [F(3,9)=3.07, p=0.07]. Asterisks in panels a and e indicate morphine doses producing effects significantly different from “WD” as determined by a Dunnett post hoc test. *p<0.05, **p<0.01.

Figure 3. Effects of clonidine treatment (0.01-0.1 mg/kg/hr) during heroin withdrawal

Abscissae (top panels). Dose clonidine in mg/kg/hr. All panels show mean data in three monkeys, except that effects of 0.032 mg/kg/hr clonidine were examined in only 2 monkeys. ANOVA was used to compare data for each drug dose with “WD” in panels a, c and e, and there was not a significant effect of clonidine dose on any measure (p>0.05). All other details as in Figure 2.

Figure 4. Effects of amphetamine treatment (0.032-0.1 mg/kg/hr) during heroin withdrawal

Abscissae (top panels). Dose amphetamine in mg/kg/hr. All panels show mean data in 3 monkeys. ANOVA was used to compare data for each drug dose with “WD” in panels a, c and e, and there was not a significant effect of amphetamine dose on any measure (p>0.05). † Indicates that only one monkey responded during treatment with the highest amphetamine dose, and % heroin choice could be determined only in this one monkey. All other details as in Figure 2.

Figure 5. Effects of antalarmin treatment (1.0-10 mg/kg/day) during heroin withdrawal

Abscissae (top panels). Dose antalarmin in mg/kg/day. ANOVA was used to compare data for each drug dose with “WD” in panels a, c and e, and there was not a significant effect of antalarmin dose on any measure (p>0.05). All panels show mean data in 3 monkeys. All other details as in Figure 2.

Figure 6. Effects of antalarmin treatment (1.0-10 mg/kg/day) during heroin withdrawal in monkey RQ2393

All details as in Figure 5.

Figure 7. Effects of GNTI treatment (1.0 mg/kg) during heroin withdrawal

Abscissae (top panels). Dose GNTI in mg/kg. All panels show mean data in 3 monkeys. A T-test was used to compare data for GNTI with “WD” in panels a, c and e, and there was not a significant effect of GNTI on any measure (p>0.05). All other details as in Figure 2.