Effects of environmental enrichment on self-administration of the short-acting opioid remifentanil in male rats

Abstract

Background: Opioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting μ-opioid remifentanil.

Methods: Rats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21 days of age and were trained to lever press for 1 or 3 μg/kg/infusion remifentanil in young adulthood. Acquisition of self-administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated.

Results: In all phases, Enr rats lever pressed significantly less than Std and Iso rats, with Enr rats pressing between 9 and 40% the amount of Iso rats. Enr rats did not acquire remifentanil self-administration when trained with 1 μg/kg/infusion, did not increase responding over increasing FR when trained at either dose, and their dose-response curves were flattened compared to Std and Iso rats. When expressed as economic demand curves, Enr rats displayed a decrease in both essential value (higher α) and reinforcer intensity (Q ₀) compared to Std and Iso rats at the 1 μg/kg/infusion training dose.

Conclusion: Environmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse.

Keywords: Environmental enrichment; Opioid; Remifentanil; Self-administration; Social isolation.

Figure 1:. Effect of Environmental Enrichment on Acquisition of Remifentanil Self-Administration.

Active lever presses (A) and inactive lever presses (C) during the self-administration phase of acquisition by rats trained with 1 μg/kg/infusion remifentanil. Active lever presses (B) and inactive lever presses (D) by rats trained with 3 μg/kg remifentanil. Enr: gray triangles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Std: black squares (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Iso: white circles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg). Note the difference in scales between the upper and lower panels.

Figure 2:. Effect of Environmental Enrichment on Remifentanil Self-Administration after Increasing Fixed Ratio Requirement.

Active lever presses (A) and inactive lever presses (C) after increasing FR by rats trained with 1 μg/kg/infusion remifentanil. Active lever presses (B) and inactive lever presses (D) by rats trained with 3 μg/kg/infusion remifentanil. Enr: gray triangles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Std: black squares (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Iso: white circles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg). Note the difference in scales between the upper and lower panels.

Figure 3:. Effect of Environmental Enrichment on the Remifentanil Dose Response Curve.

Active lever presses (A) and inactive lever presses (C) at saline, 0.1, 0.3, 1, 3, or 10 μg/kg/infusion remifentanil by rats trained with 1 μg/kg remifentanil. Active lever presses (B) and inactive lever presses (D) by rats trained with 3 μg/kg remifentanil. Enr: gray triangles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Std: black squares (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Iso: white circles (n = 7 for 1 μg/kg; n = 5 for 3 μg/kg). Note the difference in scales between the upper and lower panels.

Figure 4:. Effect of Environmental Enrichment on Demand Curves for Remifentanil.

Remifentanil demand curves for Enr (gray triangles; n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), Std (black squares; n = 7 for 1 μg/kg; n = 5 for 3 μg/kg), and Iso (white circles; n = 7 for 1 μg/kg; n = 5 for 3 μg/kg) rats that were trained with 1 μg/kg remifentanil (A) or 3 μg/kg remifentanil (B).

Figure 5:. Effect of Environmental Enrichment on Stimulant Dose Response Curves.

(Top) Methylphenidate dose response curve for Enr (EC, black circles) and Iso (IC, white squares) rats that were trained with 0.3 mg/kg/infusion. MPD: methylphenidate. Used with permission from (Alvers et al. 2012). (Bottom) Cocaine dose response curve for Enr (EC, black circles) and Iso (IC, white circles) rats that were trained with 0.5 mg/kg/infusion. Used with permission from (Green et al. 2010).