Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer

Abstract

To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S(D)) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S(D) and SCM S(D). MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.

Fig. 1.

Effects of MTEP on reinstatement induced by discriminative stimuli associated with cocaine. A, left, active lever responses during conditioning sessions in the presence of stimuli paired with cocaine (COC/S⁺) versus nonavailability of cocaine (SAL/S^-). ***, paired Student's t test, t₃₀ = 10.6; p < 0.001 versus COC/S⁺. Center, extinction (EXT) responses at criterion and responses during an initial reinstatement test in the presence of the stimulus paired with reward nonavailability (S^-). &, p < 0.01 versus S⁺. Right, reinstatement responses in the presence of the stimuli previously associated with cocaine availability (S⁺) in vehicle-treated rats (0) and modification of conditioned reinstatement across doses of MTEP. *, p < 0.05 versus vehicle. B, cumulative number of responses (per 10-min intervals) throughout the 60-min reinstatement periods (error bars omitted for clarity). Simple effects: *, p < 0.05 vehicle versus 1, 3, and 10 mg/kg (for details, see Results).

Fig. 2.

Effects of MTEP on reinstatement induced by discriminative stimuli associated with SCM. A, left, active lever responses during conditioning sessions in the presence of stimuli paired with cocaine SCM (SCM/S⁺) versus nonavailability of the reinforcer (non-SCM/S^-). ***, paired Student's t test, t₃₉ = 91.4; p < 0.001 versus SCM/S⁺. Center, extinction (EXT) responses at criterion and responses during an initial reinstatement test in the presence of the stimulus paired with reward nonavailability (S^-). &, p < 0.001 versus S⁺. Right, reinstatement responses in the presence of the stimuli previously associated with SCM availability (S⁺) in vehicle-treated rats (0) and modification of conditioned reinstatement across doses of MTEP. **, p < 0.01 versus vehicle; †, p < 0.05 versus MTEP 0.3 mg/kg. B, cumulative number of responses (per 10-min intervals) throughout the 60-min reinstatement periods (error bars omitted for clarity). Simple effects: *, p < 0.05 vehicle versus 0.3, 1, 3, and 10 mg/kg (for details, see Results).

Fig. 3.

Effects of MTEP on cocaine self-administration. A, cocaine-reinforced responses after vehicle (0) versus MTEP administration (*, p < 0.05 versus vehicle). B, cumulative number of responses throughout the 2-h self-administration session (error bars omitted for clarity). Simple effects: *, p < 0.05 vehicle versus 3 and 10 mg/kg (for details, see Results).

Fig. 4.

Effects of MTEP on SCM self-administration. A, SCM-reinforced responses after vehicle (0) versus MTEP administration. B, cumulative number of responses (per 10-min intervals) during the 30-min self-administration session (error bars omitted for clarity).

Fig. 5.

Spontaneous locomotor activity during the 3-h monitoring period after MTEP injection (A) and cumulative number of beam breaks (B; per 10-min intervals) during the 3-h monitoring period (error bars omitted for clarity). Simple effects: 10 mg/kg versus vehicle, *, p < 0.05 (for details, see Results).