Actigraphy-based sleep parameters during the reinstatement of methamphetamine self-administration in rhesus monkeys

Abstract

The objective of this study was to investigate nighttime activity of nonhuman primates during extinction and cue- and drug-primed reinstatement of methamphetamine self-administration. Adult rhesus monkeys (Macaca mulatta; n = 5) self-administered methamphetamine (0.01 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement. Saline infusions were then substituted for methamphetamine and stimulus light (drug-conditioned stimulus presented during drug self-administration) withheld until subjects reached extinction criteria. Drug- and cue-induced reinstatement effects were evaluated after i.v. noncontingent priming injections of methamphetamine (0.03, 0.1, or 0.3 mg/kg). Activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline nighttime activity parameters) and throughout the protocol. Although methamphetamine self-administration did not significantly affect nighttime activity compared to baseline, sleeplike parameters were improved during extinction compared to self-administration maintenance. Priming injection of 0.1 mg/kg methamphetamine, but not 0.03 or 0.3 mg/kg, induced significant reinstatement effects. These behavioral responses were accompanied by nighttime outcomes, with increased sleep fragmentation and decreased sleep efficiency in the night following 0.1 mg/kg methamphetamine-induced reinstatement. In the absence of both drug and drug-paired cues (extinction conditions), nighttime activity decreased compared to self-administration maintenance. Additionally, effective reinstatement conditions impaired sleeplike measures. Our data indicate that the reintroduction of the stimulus light as a drug-paired cue increased nighttime activity.

Figure 1

Response rates during extinction and reinstatement after priming injections of methamphetamine (METH, 0.03, 0.1 or 0.3 mg/kg, IV). Data points represent mean±SEM. *p<0.05 compared to Extinction(Saline); Δ p<0.05 compared to 0.1 METH Reinstatement. One-way repeated measures ANOVA followed by Bonferroni’s post-hoc test.

Figure 2

(A) Sleep efficiency and (B) sleep fragmentation at baseline, methamphetamine self-administration maintenance (0.01 mg/kg/infusion), extinction, or reinstatement test sessions conducted with three different doses of methamphetamine (METH, 0.03, 0.1 or 0.3 mg/kg, IV). Nighttime activity data for baseline and self-administration maintenance were combined across a 5-day span of time. Nighttime activity data for extinction were recorded as the night after the first effective extinction session. Data are expressed as mean±SEM. *p<0.05 compared to Maintenance (0.01 METH); Δ p<0.05 compared to Extinction(Saline). One-way repeated measures ANOVA followed by Bonferroni’s post-hoc test.

Figure 3

Correlation between methamphetamine intake (0.01 mg/kg/injection self-administration) and sleep (A) efficiency or (B) fragmentation following self-administration days. Pearson‘s Correlation.

Figure 4

Correlation between response rates and sleep (A) efficiency or (B) fragmentation following effective reinstatement conditions (reinstatement effects induced by priming injection of 0.1 mg/kg methamphetamine). Pearson‘s Correlation.