Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Abstract

Emerging evidence indicates that specific metabotropic glutamate receptors (mGluRs) modulate ethanol self-administration. In general, inhibition of glutamate transmission through blockade of postsynaptic mGluRs, or activation of presynaptic mGluRs, inhibits ethanol self-administration. The goal of this preclinical study was to further characterize mGluR regulation of ethanol self-administration by examining effects of AMN082, an allosteric positive modulator of presynaptic mGluR7 activity. Separate groups of C57BL/6J male mice were trained to self-administer ethanol or sucrose on a fixed-ratio 4 schedule of reinforcement during 1 h sessions. On test days, mice were pretreated with AMN082 (0, 1.0, 3.0, 5.6, or 10 mg/kg) 30 min prior to self-administration sessions. Functional specificity and activity was examined by testing the effects of AMN082 (0-10 mg/kg) on open-field locomotor activity and HPA axis function as measured by plasma corticosterone levels. AMN082 (10 mg/kg) produced a significant reduction in ethanol and sucrose reinforced responding, and inhibited locomotor activity. Plasma corticosterone levels were significantly increased following AMN082 (5.6 and 10 mg/kg) suggesting a dose-dependent dissociation between the behavioral and hormonal effects of the compound. These data suggest that activation of mGluR7 by AMNO82 produces nonspecific reductions in motivated behavior that are associated with negative effects on motor activity.

Figure 1

(A) Top panel shows ethanol intake (g/kg) plotted as a function of days during pre-testing, testing off-days, and post-testing phases of the 1-h ethanol (2% sucrose/9% ethanol) self-administration experiment. Values represent mean ±SEM from n=16 mice. Bottom panel shows percentage of ethanol and sucrose in the self-administered solution during each phase. (B) Linear regression of blood alcohol concentration (mg/dl) shown as a function of ethanol dose (g/kg) consumed. Blood samples were taken immediately following a single 1-hour self-administration session four days after AMN082 testing. Evaluated using Pearson’s correlation (n = 15).

Figure 2. Effects of AMN082 on sweetened ethanol self-administration during 1-h sessions by C57BL/6J mice

(A) Total responses on the ethanol and inactive lever, (B) ethanol dose consumed (g/kg), (C) percentage of responses on the ethanol lever, and (D) headpokes in the ethanol well plotted as a function of AMN082 dosage (mg/kg). AMN082 was administered intraperitoneally (ip) 30 minutes prior to testing. Values represent mean ±SEM from n=16 mice; * p<0.05 vs vehicle (veh) control (Dunnett’s test). Horizontal dashed lines represent mean performance under veh conditions.

Figure 3. Effects of AMN082 on sucrose self-administration during 1-h sessions by C57BL/6J mice

(A) Total responses on the sucrose and inactive lever, (B) total number of sucrose reinforcements, (C) percentage of responses on the sucrose lever, and (D) headpokes in the sucrose well plotted as a function of AMN082 dosage (mg/kg). AMN082 was administered intraperitoneally (ip) 30 minutes prior to testing. Values represent mean ±SEM from n=7 mice; * p<0.05 vs vehicle (veh) control (Dunnett’s test).

Figure 4. Effects of AMN082 on spontaneous locomotor activity in an open field

Horizontal distance traveled (m) plotted as a function of AMN082 dosage (mg/kg) for the (A) total 1-h session or (B) plotted as a function of 15-min intervals showing the time-course of AMN082 effects at each dose. AMN082 was administered intraperitoneally (ip) 30 minutes prior to testing. Values represent mean ±SEM for n=14 mice, * p<0.05, ** p<0.01 vs vehicle (veh) control group (Dunnett’s test).