Operant sensation seeking requires metabotropic glutamate receptor 5 (mGluR5)

Abstract

Pharmacological and genetic studies have suggested that the metabotropic glutamate receptor 5 (mGluR5) is critically involved in mediating the reinforcing effects of drugs of abuse, but not food. The purpose of this study was to use mGluR5 knockout (KO), heterozygous (Het), and wildtype (WT) mice to determine if mGluR5 modulates operant sensation seeking (OSS), an operant task that uses varied sensory stimuli as a reinforcer. We found that mGluR5 KO mice had significantly reduced OSS responding relative to WT mice, while Het mice displayed a paradoxical increase in OSS responding. Neither KO nor Het mice exhibited altered operant responding for food as a reinforcer. Further, we assessed mGluR5 KO, Het and WT mice across a battery of cocaine locomotor, place preference and anxiety related tests. Although KO mice showed expected differences in some locomotor and anxiety measures, Het mice either exhibited no phenotype or an intermediate one. In total, these data demonstrate a key role for mGluR5 in OSS, indicating an important role for this receptor in reinforcement-based behavior.

Figure 1. Operant sensation seeking (OSS) and operant responding for food on fixed and progressive ratio schedules.

(A, B) Active lever pressing during 11 daily FR-1 OSS (A) or food (B) operant sessions. (C, D) Inactive lever pressing during the same sessions. (E, F) Progressive ratio responding following FR-1 sessions (bars represent mean of PR days 4 and 5± SEM). OSS: n = 8–12, Food: n = 5–6. *p<0.05, ***p<0.001.

Figure 2. Place conditioning for cocaine.

Preference scores (post-test minus pre-test time spent on cocaine-paired side) following place conditioning with 5 mg/kg (top) or 1 mg/kg (bottom) cocaine. Individual pre- and post-test values are shown for each genotype on the right of each preference graph. Bars represent mean ± SEM.

Figure 3. Locomotor response to novel environment and cocaine.

(A) Total distance traveled and (B) distance in 6 min bins during a 60 min novel open field (NOF) test. (C) Center time during the NOF test. (D) Timeline of locomotor testing. Day 1 included the NOF test, then the first habituation injection of saline followed by 30 min more time in the open field. S denotes a saline injection, C denotes a cocaine injection (10 mg/kg i.p). (E) Locomotor data from the mice on day 3. Mice were placed into the open field chambers, allowed one hour to habituate, injected with saline at min 60, then with cocaine at min 90. (F) Distance traveled following cocaine injection (day 3, min 90–120). Bars and symbols represent mean ± SEM n = 6–9 per genotype. **p<0.01.

Figure 4. Anxiety-like Behavior as Measured by Elevated Plus Maze (EPM) and Light-Dark Exploration test.

(A) Open arm time as a function of total arm time on the EPM. (B) Locomotor activity during the same test. (C) Time spent on the light side and (D) transitions between light and dark sides during a 5 min light-dark exploration test. Bars represent mean ± SEM. n = 9–13 per genotype.