Research & Innovation
Publications
Reversal of the motivational effects of tetrabenazine by NMDA receptor blockade
PMU Authors
Jana Lubec, Gert Lubec
All Authors
Artem Savchenko, Salim Tarchokov, Olga Dravolina, Jana Lubec, Gert Lubec, Ilya Sukhanov
Journal association
NEUROPHARMACOLOGY
Abstract
Background: Apathy is a syndrome of decreased goal-directed activity, one of the main features of different brain disorders. Despite its high prevalence and life-threatening potential, there are currently very few options for its pharmacological treatment, which may be related to the lack of valid animal models. Aims: The vesicular monoamine transporter 2 inhibitor tetrabenazine (TBZ) was used in this study to model apathy-related behavior in pathologies linked to a depletion of dopamine. The atypical dopamine transporter inhibitor CE-123 and the NMDA receptor antagonist MK-801 were evaluated for their effects on goal-directed activity in intact and TBZ-treated rats to compare dopamine and non-dopamine approaches. Methods: To assess goal-directed behavior, the progressive ratio 3 (PR3) operant schedule of food reinforcement was conducted in adult male rats. To assess the motivational changes underlying the schedule, a model analysis based on the mathematical principles of reinforcement was applied. Results: Treatment with TBZ (0.3 mg/kg) induced a decrease in response rate as the number of required responses increased. This effect was not accompanied by a decrease in the incentive value of the reinforcer or locomotor disturbances, suggesting that decreased tolerance to high effort demands was the underlying mechanism of the decrease in goal-directed activity. Treatment with MK-801 increased operant activity in both TBZ-treated and pharmacologically na & iuml;ve rats. Conclusions: Our results support the previously proposed view that the TBZ-treated rats can be a model of apathyrelated behavior in pathologies linked to a depletion of dopamine and suggest that NMDA receptors are a potential therapeutic target for the development of novel approaches to the treatment of apathy in both dopaminedepleted and dopamine-intact states.
Keywords
MOTIVATION, DOPAMINE, progressive ratio schedule of reinforcement, effort-based decision-making, Apathy, Tetrabenazine