Punishment and reinforcement by opioid receptor agonists in a choice procedure in rats

Abstract

Intravenous (i.v.) drug self-administration remains the "gold standard" for assessing abuse potential of drugs. Failure of a drug to maintain self-administration might indicate merely the absence of positive reinforcing effects but might also indicate presence of aversive effects. Sensitivity to aversive effects is thought to affect the initiation and maintenance of drug use as well as relapse. Choice procedures are used to study positive reinforcing effects of drugs and to a much lesser extent to study punishing effects of drugs. Experiment 1 compared the mu opioid receptor agonist remifentanil (0.001-0.01 mg/kg/infusion), the kappa receptor agonist spiradoline (0.0056-0.056 mg/kg/infusion), and histamine (1.0 mg/kg/infusion) in rats choosing between a food pellet only and an intravenous (i.v.) infusion + a food pellet. To test whether a history with one punishing drug affects the punishing effects of a second drug, Experiment 2 compared sensitivity to spiradoline in rats with and without a history of histamine punishment. All rats predominantly chose a pellet alone when histamine + a pellet was the alternative, and they predominantly chose remifentanil + a pellet over a pellet alone. In Experiment 2, spiradoline was punishing in rats with a history of histamine punishment but not drug-naïve rats. This food choice procedure is sensitive to reinforcing and punishing effects of different drugs in the same subjects, suggesting that the procedure is well-suited for studying drug mixtures (e.g., mu and kappa agonists) and the impact of different physiological conditions (e.g., pain) on reinforcement and punishment.

Effects of remifentanil/histamine mixtures in rats responding under a choice procedure

“…Conversely, rats progressively decreased their choice of histamine + a pellet, instead choosing a pellet alone, as the dose of histamine increased from 0.1 to 3.2 mg/kg/infusion, demonstrating robust and dose-related punishing effects of histamine. Reinforcement with remifentanil and punishment with histamine replicated previous work, from our laboratory and others, in adult male rats tested with similar dose ranges (Podlesnik et al, 2010;Holtz and Carroll, 2015;Mayer et al, 2018;Maguire et al, 2019;Minervini et al, 2019).…”

“…Side biases are known to be unmasked when choosing between functionally equivalent reinforcers that are available concurrently on ratio schedules (e.g. Mazur, 1988; Belke, 2010; Lagorio and Hackenberg, 2012; Freeman et al ., 2014) and likely represent a specific type of indifference among alternatives.…”

“…A drug with reinforcing effects that maintains responding under typical self-administration procedures would be expected to shift choice away from a food pellet alone and towards a pellet plus an infusion. Rhesus monkeys respond predominantly for cocaine plus food over food alone (Woolverton, 2003) and rats respond predominantly for remifentanil plus food over food alone (Minervini et al, 2019), reflecting positive reinforcing effects of cocaine and remifentanil in choice procedures. Since choice procedures are exquisitely sensitive to punishing and reinforcing effects of drugs, they might be useful for screening drug mixtures that have therapeutic effects, such as analgesia.…”

“…The present study used a choice procedure to compare the effects of remifentanil (mu opioid receptor agonist with positive reinforcing effects) and histamine (H 1-4 receptor agonist with punish effects), alone and in mixtures, to test the hypothesis that remifentanil/histamine mixtures are less reinforcing compared with remifentanil alone and less punishing compared with histamine alone. Remifentanil and histamine were selected because they each have a short duration of action (Bovet et al, 1958;Halpern et al, 1959;Egan, 1995;Patel and Spencer, 1996) as well as robust and well-established reinforcing or punishing effects under a broad range of conditions, including choice procedures (Woolverton, 2003;Negus, 2005;Cooper et al, 2008;Podlesnik et al, 2010;Woolverton et al, 2012;Podlesnik and Jimenez-Gomez, 2013;Freeman et al, 2014;Sukhtankar et al, 2014;Holtz and Carroll, 2015;Maguire et al, 2019;Minervini et al, 2019).…”

Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats

“…All animals used in these studies were maintained in accordance with Surgery. Briefly, a chronic indwelling catheter (CNC-3H-30-6/6.5; Access Technologies, Skokie, IL, USA) was implanted in the left femoral vein of rats anesthetized with 2% isoflurane as described previously (Minervini et al 2019). The catheter was attached to a 22-G access port (VAB95BS; Instech Laboratories Inc.) anchored in a s.c. pocket.…”