Effects of pharmacological and environmental manipulations on choice between fentanyl and shock avoidance/escape in male and female rats under mutually exclusive and non-exclusive choice conditions

Abstract

Substance use disorders are defined by persistent drug consumption despite adverse consequences. Accordingly, we developed two fentanyl-vs-shock avoidance/escape choice procedures in which male and female rats responded under a fixed-ratio (FR)1:FR1 concurrent schedule of shock avoidance/escape and IV fentanyl under either mutually exclusive or non-exclusive choice conditions. Initial experiments using a discrete-trial procedure determined behavioral allocation between mutually exclusive shock avoidance/escape and different fentanyl doses (0.32-18 μg/kg/infusion; Experiment 1). Shock intensity (0.1-0.7 mA) and shock avoidance/escape response requirement (FR1-16) were also manipulated (Experiment 2). Next, we used a free-operant procedure in which shock avoidance/escape and fentanyl were continuously available under non-exclusive conditions, and response-shock (R-S) interval (30-1000 s) was manipulated (Experiment 3). Finally, we tested the hypothesis that extended-access fentanyl self-administration would produce fentanyl dependence, establish fentanyl withdrawal as an endogenous negative reinforcer, and increase fentanyl choice in both procedures (Experiments 4 and 5). The shock avoidance/escape contingency decreased fentanyl self-administration, and rats consistently chose shock avoidance/escape over fentanyl in both choice conditions. Decreasing shock intensity or increasing shock avoidance/escape response requirement failed to increase fentanyl choice, suggesting that fentanyl and shock avoidance/escape are independent economic commodities. Increasing the R-S interval increased fentanyl choice but failed to increase shock delivery. Extended fentanyl access engendered high fentanyl intake and opioid withdrawal signs but failed to increase fentanyl choice under either choice condition. These results suggest that neither positive fentanyl reinforcement nor negative reinforcement by fentanyl withdrawal is sufficient to reduce shock avoidance/escape-maintained responding and increase foot shock as an adverse consequence.

Fig. 1. Behavioral allocation between fentanyl and the negative reinforcer of shock avoidance/escape under mutually exclusive and non-exclusive concurrent choice conditions as a function of unit fentanyl dose and reinforcer availability.

A Trials completed for fentanyl+shock (FR1) or shock avoidance/escape (FR1, 0.7 mA) in a nine discrete-trial, mutually exclusive fentanyl-vs-shock avoidance/escape procedure as a function of fentanyl dose. * denotes significant (p < 0.05) difference between fentanyl+shock and shock avoidance/escape at a given fentanyl dose. B Trials omitted in the mutually exclusive fentanyl-vs-shock avoidance/escape procedure as a function of fentanyl dose. Filled symbol denotes significant difference compared to 3.2 µg/kg/inf fentanyl. C Fentanyl trials completed (FR1) as a function of fentanyl dose in the mutually exclusive choice procedure when shock avoidance/escape (0.5 mA) and associated discriminative stimuli were present (filled bars) or absent (open bars) * denotes significant difference. D Reinforced responses for fentanyl (FR1) or shock avoidance/escape (FR1, mean shock intensity 0.5 mA [0.4–0.6 mA]) in a non-exclusive fentanyl-vs-shock avoidance/escape choice procedure as a function of fentanyl dose, grouped by R-S interval. E Shocks received as a function of fentanyl dose in a non-exclusive fentanyl-vs-shock avoidance/escape procedure under two R-S conditions. ^# denotes significant difference from 0.32 µg/kg/inf fentanyl collapsed across R-S conditions. F Fentanyl infusions earned (0.32 µg/kg/inf, FR1) when the shock stimulus (mean 0.5 mA) is present (filled bar) or absent (open bar) * denotes significant difference. A, B, D, E Points and bars represent group mean ± SEM. C, F Points represent individual subjects, bars represent group mean. A n = 6–10 (2–4 M/4-6 F); B, C n = 8 (4 M/4 F); D–F n = 7 (4 M/3 F).

Fig. 2. Effects of manipulating shock intensity and response requirement on fentanyl-vs-shock avoidance/escape choice in a mutually exclusive, discrete-trial choice procedure.

A Trials completed for fentanyl+shock (FR1), shock avoidance/escape (FR1), or omissions as a function of shock intensity. * denotes a significant (p < 0.05) difference between fentanyl+shock and shock avoidance/escape within a given shock intensity. Filled symbols denote a significant difference in omissions at 0.1 mA compared to all other shock intensities. B Trials completed for fentanyl+shock, shock avoidance/escape (0.5 mA), or omissions as a function of shock avoidance/escape response requirement. Filled symbols denote significant difference within a reinforcer or omission compared to FR1. All points represent mean ± SEM; A n = 14 (7 M/7 F); B n = 8 (4 M/4 F).

Fig. 3. Effects of manipulating response-shock (R-S) interval on fentanyl-vs-shock avoidance/escape choice in a non-exclusive, free-operant choice procedure.

Abscissae: R-S interval. A Number of 0.32 μg/kg/infusion fentanyl responses. B Number of shock avoidance/escape responses. C Percent fentanyl choice. D Shocks received. *denotes significant (p < 0.05) multiple comparisons. Points represent individual subjects (n = 7, 4 M/3 F) and bars represent group mean.

Fig. 4. Effects of extended fentanyl access on somatic opioid withdrawal score, fentanyl-vs-shock avoidance/escape choice, and start latency in a mutually exclusive, discrete-trial choice procedure.

Abscissae: experimental day. A Schematic of experimental design. B Number of fentanyl infusions earned (FR1 / TO10 s, 3.2 µg/kg/inf) and corresponding fentanyl intake during the extended-access self-administration session. C Opioid somatic withdrawal scores as a function of extended access day. D Trials completed for shock avoidance/escape, fentanyl+shock, or omissions during the mutually-exclusive fentanyl-vs-shock avoidance/escape choice procedure. E Latency in s to complete the initial fentanyl-only trial as a function of extended access day. Filled points denote significant (p < 0.05) difference compared to baseline. ^# indicates a significant difference between shock avoidance/escape and fentanyl regardless of extended access day. All points represent mean ± SEM, n = 14 (8 M/6 F). BL baseline, EA extended access.

Fig. 5. Effects of extended fentanyl access on somatic opioid withdrawal score and fentanyl-vs-shock avoidance/escape choice in a non-exclusive, free-operant choice procedure.

Abscissae: A, B experimental day; C–F response-shock interval. A Schematic of experimental design. B Number of fentanyl infusions earned (FR1 / TO10 s, 3.2 µg/kg/inf) and corresponding fentanyl intake during the extended-access self-administration session. Filled symbols denote significant difference from Day 1. C Opioid somatic withdrawal scores. Filled symbols denote significant difference from BL. D Percent fentanyl choice. E Shocks received. F Number of fentanyl infusions earned during the choice session. G Number of shock avoidance/escape responses during the choice. Points represent individual subjects (n = 7, 4 M/3 F); bars represent group mean. Brackets represent significant multiple comparisons between R-S conditions. BL baseline, EA extended access.