Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule

Abstract

This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 µg/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1-10 µg/kg/injection) or alprazolam (1.0-100 µg/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as "alprazolam-taking" and "non-alprazolam-taking" monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs' reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT: Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.

Fig. 1.

Self-administration of fentanyl and alprazolam by rhesus monkeys (N = 6, 3 males, 3 females) trained under a progressive-ratio schedule of i.v. remifentanil (R, 0.3 μg/kg/injection) injection. Self-administration maintenance sessions alternating remifentanil and its vehicle (saline) were conducted until a consistent difference between drug and saline self-administration was obtained. Once self-administration was stable, test sessions with fentanyl or alprazolam and their vehicle (V) were added to an alternating sequence of remifentanil and saline sessions. Grouped data are expressed as the unit dose that engendered highest number of injections/session (EDMax) and one-half log-step unit dose below (−0.5 EDMax) and above (+0.5 EDMax) the EDMax dose. Data are represented as mean number of injections/session ± S.E.M., out of a total of 20 injections available in a daily session. Note that symbols obscure error bars in some instances. *P < 0.05 versus vehicle (V) (Bonferroni t tests).

Fig. 2.

Individual subject data (top panel: males; bottom panel: females) showing self-administration of fentanyl, alprazolam and 3 different ratios of fentanyl-alprazolam combinations (1:1, 1:3 and 3:1 fentanyl:alprazolam, with 1:1 being based on the ED₅₀s of drugs alone). Monkeys were trained under a progressive-ratio schedule of i.v. remifentanil (R, 0.3 μg/kg/injection) injection, and self-administration sessions alternating remifentanil and its vehicle (saline) were conducted until a consistent difference between drug and saline self-administration was obtained. Once self-administration was stable, test sessions with fentanyl, alprazolam or fentanyl-alprazolam combinations and their vehicle (V) were added to an alternating sequence of remifentanil and saline sessions. For drug combination tests, data are plotted as a function of the fentanyl dose included in each combination. Data are represented as mean number of injections/session ± S.E.M., out of a total of 20 injections available in a daily session. Note that symbols obscure error bars in some instances.

Fig. 3.

The predicted additive effects and the observed (empirically determined) effects for self-administration of fentanyl:alprazolam combinations in rhesus monkeys that self-administered alprazolam alone under a progressive-ratio procedure. Top graphs: Individual subject graphs with monkey identification (and sex in parentheses) at the top of each panel. Bottom graphs: Regression analyses for the 3:1, 1:1, and 1:3 combinations, shown in individual panels. Data are individual observed and predicted points for each monkey, not averaged. Regression lines represent the best-fit analysis for either 2 linear functions for observed versus predicted, or a single function as the default if 2 functions did not fit significantly (see Table 2 for statistics).

Fig. 4.

Grouped dose-response functions before and after drug combination tests for alprazolam-taking subjects (A) and non-alprazolam-taking subjects (B). Data are mean number of injections/session ± S.E.M., from at least 2 determinations. Note that symbols obscure error bars in some instances. R = remifentanil maintenance sessions; V = vehicle maintenance sessions.