Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats - PubMed (original) (raw)

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats

Xiaohu Xie et al. Psychopharmacology (Berl). 2010 Jan.

Abstract

Rationale: The functional integrity of the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine seeking. However, the neuropharmacological mechanisms of this phenomenon are poorly understood.

Objectives: Given the known significance of group I metabotropic glutamate receptors (mGluRs), including the mGluR1 subtype, in drug-induced behaviors, the present study was designed to evaluate the contribution of mGluR1s in the DH to drug context-induced reinstatement of extinguished cocaine-seeking behavior.

Methods: Sprague-Dawley rats were trained to lever press for unsignaled cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different environmental context (extinction context). Using a counterbalanced partial within-subjects testing design, rats were re-exposed to the cocaine-paired context or the extinction context while cocaine-seeking behavior (nonreinforced active lever pressing) was assessed. Prior to each test session, rats received bilateral microinfusions of the highly potent mGluR1-selective antagonist JNJ16259685 (0.6, 30, or 120 pg/0.5 microl per hemisphere) or vehicle into the DH or the overlying somatosensory cortex trunk region (SStr; anatomical control).

Results: Intra-DH, but not intra-SStr, JNJ16259685 infusions dose dependently attenuated drug context-induced reinstatement of cocaine seeking relative to vehicle treatment, without attenuating instrumental behavior in the extinction context, general motor activity, or food-reinforced instrumental behavior in control experiments.

Conclusions: Stimulation of mGluR1s in the DH is necessary for incentive motivational and/or memory processes that contribute to drug context-induced cocaine-seeking behavior. These findings indicate that the mGluR1 is an interesting target from an addiction treatment perspective.

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Conflict of interest statement

The authors do not have any conflicts of interest to disclose.

Figures

Fig. 1

Fig. 1

Schematic and photographic representation of injection cannula placements within the dorsal hippocampus (DH) and trunk region of the somatosensory cortex (SStr). Arrows identify the most ventral point of the infusion cannula tracts on each photomicrograph of representative cresyl violet-stained brain sections. Filled circles, open triangles, and open circles represent the most ventral point of the cannula tracts for rats in the DH-cannulated cocaine-trained, DH-cannulated food-trained, and SStr-cannulated cocaine-trained groups, respectively, on schematics from the rat brain atlas of Paxinos and Watson (1997). Numbers indicate the distance from bregma in millimeters.

Fig. 2

Fig. 2

Non-reinforced active and inactive lever responses (mean/1 h ± SEM) during testing in the extinction (EXT) and previously cocaine-paired contexts (COC). JNJ16259685 or vehicle was infused bilaterally into the DH (A, B: N = 10–14/group) or the SStr (C, D: N = 12) before testing. The Asterisks represent a significant difference relative to responding in the extinction context (Panel A: ANOVA context simple main effect, Tukey test, p < 0.05; Panels B, C, D: ANOVA context main effect, p < 0.05). The Dagger represents a significant difference relative to the vehicle treatment (ANOVA treatment simple main effect, Tukey test, p < 0.05).

Fig. 3

Fig. 3

Locomotor activity (A; mean photobeam breaks/1 h ± SEM) in a novel context as well as

preprandial

food-reinforced instrumental behavior (B; mean lever presses/1 h ± SEM) and

postprandial

food-reinforced instrumental behavior (C; mean lever presses/1 h ± SEM) in contexts 1 or 2. JNJ16259685 or vehicle was administered bilaterally into the DH (Panel A: N = 10–14/group; Panel B: N = 10; Panel C: N = 8) before testing. Rats in the postprandial condition received 100 45-mg food pellets 1 h before each behavioral session. The Plus sign represents a significant difference relative to all other time points (ANOVA time simple main effect, Tukey test, p < 0.05).

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