Effect of Delay on Self-Administration of Remifentanil under a Drug Versus Drug Choice Procedure in Rhesus Monkeys

Abstract

Drug abuse can be conceptualized as excessive choice of drug over other reinforcers, and factors that affect drug taking can be examined experimentally using choice procedures. This study examined the impact of reinforcer delay on self-administration of the m-opioid receptor agonist remifentanil in rhesus monkeys (n 5 4) lever pressing under a concurrent fixed-ratio 30 schedule. Responding on either lever delivered an intravenous infusion of either remifentanil or saline. Dose-effect curves were first determined when responding on one lever delivered remifentanil and responding on a second lever delivered saline. Monkeys then chose between two doses of remifentanil, and delay to delivery of the large dose was varied systematically. Responding for remifentanil (0.01-1.0 mg/kg/infusion) increased dose-dependently when the alternative was saline or a dose of remifentanil. Delaying delivery of the large dose of remifentanil by 30, 60, 120, or 240 seconds increased responding for smaller, immediately available doses (0.01-0.1 mg/kg/infusion) and, in some cases, increased responding for doses of remifentanil that did not maintain responding when the alternative was saline. These data demonstrate that delaying the delivery of an opioid receptor agonist can significantly affect its reinforcing effectiveness. The imposition of a delay reduces the effectiveness of large doses of drug to maintain responding and increases the effectiveness of immediately available commodities, including smaller doses of drug. Increased reinforcing effectiveness of smaller doses of drug in the context of other delayed reinforcers might contribute to the development and maintenance of opioid abuse.

Delay discounting of the μ-opioid receptor agonist remifentanil in rhesus monkeys

“…Consistent with earlier studies using cocaine (e.g., Anderson and Woolverton, 2006; Woolverton et al, 2007), delaying delivery of a large dose of the mu opioid receptor agonist remifentanil increases choice of small immediately available doses of remifentanil in rhesus monkeys (Maguire et al, 2013a). While that previous study extended the generality of the findings by Woolverton and colleagues to another drug class (mu opioid receptor agonists), the rate at which remifentanil is discounted has not been assessed.…”

“…Thus, understanding how delay impacts opioid self-administration could help to identify behavioral factors that contribute to opioid abuse. Recent studies indicate that delay can substantially impact self-administration of drugs, including the mu opioid receptor agonist remifentanil (Maguire et al, 2013a), insofar as delaying delivery of a large dose of drug increases responding for small immediately available doses of drug. The current study extends those results by assessing the rate of delay discounting of remifentanil in rhesus monkeys choosing between two doses of remifentanil under a similar, but not identical, choice procedure.…”

“…Four adult rhesus monkeys ( Macaca mulatta ), 2 females (SO and OL) and 2 males (GI and MO), were used in this study; SO and MO participated in a previous study (Maguire et al, 2013a). Body weight (6-10 kg) was maintained by post-session feeding (Harlan Teklad, High Protein Monkey Diet, Madison, WI, USA).…”

“…infusions of remifentanil as described previously (Maguire et al, 2013a). Daily sessions were divided into 3 blocks, each comprising 2 forced trials followed by 6 choice trials.…”

Delay discounting of food by rhesus monkeys: Cocaine and food choice in isomorphic and allomorphic situations.

“…In most of these studies, choice was examined in isomorphic situations (i.e., choice between qualitatively identical reinforcers; Anderson and Woolverton, 2003; Harvey-Lewis et al, 2014; Maguire et al, 2013b; Newman et al, 2008; Perry et al, 2007; Woolverton et al, 2007). Because delay discounting has been conceptualized as impulsive choice of immediate drug effects, it is important to understand delay discounting of non-drug reinforcers when drugs are immediately available as a fundamental component of the drug abuse process.…”