Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area

Abstract

Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to modulate reward.

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

“…In general these studies demonstrate that inhibition can be potentiated by axoaxonic contacts without the need for somatic interneuron firing; such mechanism alters the weight between excitatory and inhibitory inputs and therefore alters the output of the neuronal circuit. The idea of a presynaptic control of GABA release is also supported by our PPPA results where pharmacological blockade of GluN2A NMDARs produced a similar enhancement in reward as the one observed in the control subjects and in previous studies (Bergeron and Rompré, 2013;Ducrot et al, 2013), whereas intra-VM downregulation of its mRNA remained without effect.…”

“…In accordance with previous results, ventral midbrain microinjection of the NMDA antagonist, PPPA, produced a leftward and upward shift of the pulse-frequency curve reflecting an enhancement of reward and performance (see Bergeron and Rompré, 2013;Ducrot et al, 2013). This shows that VM glutamate also exerts a negative modulation on Figure 5 Bar graphs representing the Averages of maximum change in stimulation threshold and maximum response rate after intra-VM injection of saline or PPPA (0.82 pmol per 0.5 ml per side) for all subject that received the different siRNA treatments.…”

“…Despite the fact that PPPA displays only a modest pharmacological selectivity for GluN2A-vs GluN2B-containing NMDARs, we have previously shown that enhancement of electrically evoked reward following a wide range of intra-VM PPPA infusion is associated with GluN2A-containing NMDA (Bergeron and Rompré, 2013;Ducrot et al, 2013). As expected, PPPA enhanced the rewarding effectiveness of the electrical stimulation and produced an increase in the maximum response rate.…”

The antero-posterior heterogeneity of the ventral tegmental area

“…The changes in reward threshold positively correlated with the VTA antero-posterior position of a NMDA antagonist injection, while it negatively correlated with the antero-posterior position of an AMPA antagonist injection (Ducrot et al, 2013). The influence of AMPA antagonism was thus stronger in the aVTA.…”

Editorial: Reward- and aversion-related processing in the brain: translational evidence for separate and shared circuits

“…In clever cross-species experiments, they revealed similar expression patterns and highlighted the importance of octopamine on the modulation of local GABAergic interneurons, which could help to clarify the mechanisms underlying food-odor reinforcement. Ducrot et al ( 2013 ) underscored the involvement of glutamatergic AMPA and NMDA receptors in electrical brain self-stimulation reinforced behavior in rats. Blocking AMPA receptor function in the anterior ventral tegmental area decreased appetitive responding, perhaps related to reduced excitatory input to dopaminergic cells, while NMDA receptor blockade in more posterior areas increased appetitive responding, which likely reflects GABAergic disinhibition.…”