Are AMPA receptor positive allosteric modulators potential pharmacotherapeutics for addiction?

Abstract

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.

Figures

Figure 1

Male Sprague-Dawley rats were placed into 2 h daily methamphetamine IVSA-administration sessions for 10 days. Presses on an active lever produced methamphetamine infusions (0.05 mg/kg/infusion) on an FR1 schedule of reinforcement with a simultaneous 2 s light-tone stimulus complex. Following stable acquisition of methamphetamine IVSA, rats were placed into daily 2 h extinction sessions for 10 days during which active-lever presses no longer produced drug infusions or presentation of the stimulus complex. Twenty min prior to being placed into each extinction session, rats received intraperitoneal (i.p.) administration of either vehicle (Veh, 30% w/v 2-hydroxypropyl-β-cyclodextrin), CX1837 0.1 mg/kg (N = 6) CX1837 1 mg/kg (N = 12) CX1739 0.1 mg/kg (N = 7), 1 mg/kg (N = 7), or 10 mg/kg (N = 9). Vehicle treated rats (N = 20) were used for comparison for both CX1739 and CX1837. Data points represent the mean percent change (± SEM) from self-administration (mean of the final 2 days of self-administration procedures) for active lever presses. For CX1837, a mixed ANOVA analysis revealed a significant main effect of extinction session, F(9,306) = 5.78, p < 0.001, a significant extinction session x dose interaction, F(18, 306) = 2.77, p < 0.001, but no main effect of dose, F(2,34) = 1.32, p > 0.05. Post-hoc analyses revealed a significant reduction in responding on extinction day one by the 1 mg/kg dose of CX1837 versus vehicle, F(2,34) = 4.86, p < 0.05. No other measures were significantly different. For CX1739, a significant main effect of extinction session, F(9,351) = 15.180, p < 0.001, a significant extinction session X dose interaction, F(27,351) = 1.94, p < 0.004, but not a significant main effect of dose, F(3,39) = 2.60 p > 0.05. Post-hoc analyses revealed a significant reduction in responding on extinction day one by the 10 mg/kg dose of CX1739 vs. vehicle F(3,39) = 5.476, p < 0.003. No other measures were significantly different. All experimental procedures were conducted with the approval of the Institutional Animal Care and Use Committee at Arizona State University and according to the Guide for Care and Use of Laboratory Animals as adopted by the National Institutes of Health (NIH).

Figure 2

Following extinction sessions, rats were placed into cue-primed reinstatement procedures to assess the retention of extinction learning. Data points represent the mean percent change (±SEM) from self-administration (mean of the final 2 days of self-administration procedures) for active lever presses. A one-way ANOVA did not reveal significant differences between vehicle or any CX1837 doses (0.1 or 1 mg/kg, i.p.), F(3,39) = 0.161, p = 0.922, nor any significant differences between vehicle and of the doses of CX1739 tested (0.1, 1, or 10 mg/kg, i.p.), F(2,35) = 0.294, p = 0.747.