Naltrexone maintenance fails to alter amphetamine effects on intracranial self-stimulation in rats

Abstract

Pharmacotherapy to treat stimulant use disorders continues to be an unmet medical need. Some evidence supports both the role of opioids in mediating abuse-related amphetamine effects and the potential utility of opioid antagonists as therapeutic candidates for treating amphetamine abuse. This study used intracranial self-stimulation (ICSS) to evaluate effects of exposure to and termination of naltrexone maintenance on rewarding amphetamine effects in an ICSS procedure in rats. Morphine and cocaine were included as positive and negative controls, respectively. Male Sprague-Dawley rats (N = 40) were trained to lever press for electrical brain stimulation to the medial forebrain bundle via an implanted electrode. Rats were then implanted with osmotic pumps delivering naltrexone (0.001 mg/kg/h, SC, 0.01 mg/kg/h, SC, or 0.1 mg/kg/h, SC) or saline for 14 days. Cumulative dose-effect curves were determined for amphetamine (0.032 mg/kg to 0.32 mg/kg), cocaine (1 mg/kg to 10 mg/kg), and morphine (1 mg/kg to 10 mg/kg) during the 2nd week of naltrexone maintenance. Additionally, dose-effect curves for morphine and amphetamine were determined again 24 hr after pump removal. Our results suggest that (a) exposure to and termination of naltrexone maintenance do not affect baseline ICSS responding, (b) naltrexone doses sufficient to antagonize morphine did not alter amphetamine or cocaine effects, and (c) termination of naltrexone treatment produced weak evidence for increased morphine sensitivity but no change in amphetamine effects. Our results do not support naltrexone as a pharmacotherapy for amphetamine and cocaine abuse and also suggest that termination from chronic naltrexone does not increase sensitivity to abuse-related morphine or amphetamine effects in ICSS. (PsycINFO Database Record

Figure 1

Diagram of experimental timeline.

Figure 2

Effects of morphine (A–D), amphetamine (E–H), or cocaine (I–L) on ICSS frequency-rate curves during maintenance on saline or naltrexone (0.001–0.1 mg/kg/hr). Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: reinforcement rate expressed as percentage of maximum control reinforcement rate (% MCR). All data are mean+/−SEM for N=14 (saline, 0.1 mg/kg/h NTX) or N=6 (0.001 and 0.01 mg/kg/h NTX). Filled points indicate signficantly different from “Test day Baseline” as indicated by a significant two-way ANOVA followed by the Holm-Sidak post hoc test, p<0.05.

Figure 3

Naltrexone blocked the effects of morphine but not of amphetamine or cocaine on the summary measure of ICSS performance. Abscissae: drug dose (mg/kg). Ordinates: percentage of baseline number of stimulations per component delivered across all brain stimulation frequencies (% Baseline total stimulations). All data are mean+/−SEM for N=14 (saline, 0.1 mg/kg/h NTX) or N=6 (0.001 and 0.01 mg/kg/h NTX). Filled points indicate signficantly different from “Saline” as indicated by a significant two-way ANOVA followed by the Holm-Sidak post hoc test, p<0.05.

Figure 4

Effects of morphine (A–B) or amphetamine (C–D) on ICSS frequency-rate curves after removal of saline or 0.1 mg/kg/hr naltrexone minipumps. Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: reinforcement rate expressed as percentage of maximum control reinforcement rate (% MCR). All data are mean+/−SEM for N=6 (morphine) or N=8 (amphetamine). Filled points indicate signficantly different from “Test day Baseline” as indicated by a significant two-way ANOVA followed by the Holm-Sidak post hoc test, p<0.05.

Figure 5

Termination of naltrexone treatment did not alter morphine or amphetamine effects on the summary measure of ICSS performance. Abscissae: drug dose (mg/kg). Ordinates: percentage of baseline number of stimulations per component delivered across all brain stimulation frequencies (% Baseline total stimulations). All data are mean+/−SEM for N=6 (morphine) or N=8 (amphetamine).