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

Abstract

Glutamate is a major component of the reward circuitry and recent clinical studies suggest that new molecules that would target glutamate neurotransmission are most likely to constitute more effective medications for mood disorders. It is well known that activation of N-methyl-D-aspartate glutamate receptors (NMDARs) initiates dopamine burst firing, a mode associated with reward signaling; but NMDARs also contribute to the maintenance of an inhibitory drive to dopamine neurons. Such opposite modulatory functions imply that different subtypes of NMDARs are expressed on different ventral midbrain (VM) neurons and/or afferent inputs to dopamine neurons. By using the small interfering RNA (siRNA) technique, we studied the effects of VM downregulation of NMDAR subunits GluN1, GluN2A, and GluN2D on reward induced by dorsal raphe electrical stimulation. Reward thresholds were measured before and 24 h after each of three consecutive daily bilateral microinjections of siRNA for the targeted receptor subunit(s) or non-active RNA sequence. After the last measurement, reward thresholds were reassessed following a bilateral microinjection of the preferred GluN2A-NMDA antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA). Western-blot analysis showed that siRNAs reduced GluN1-and GluN2A-containing receptors whereas behavioral tests showed that only a reduction in GluN1 produced reward attenuation. Despite NMDAR reduction, reward-enhancing effect of PPPA remained unchanged. We conclude that VM glutamate relays the reward signal initiated by dorsal raphe electrical stimulation by acting on NMDARs devoid of GluN2A/2D subunits and exerts an inhibition on this reward signal by acting on GluN2A-containing NMDARs most likely located on afferent terminals.

Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation

“…In contrast to the vehicle, PPPA produced a significant 25.3% (SEM = 6.3) reduction in M50 value [ t (5) = 3.43; p < 0.05] and a significant 39.7% (SEM = 11.7) increase in nose-poke responses [ t (5) = 3.27; p < 0.05]. The observed potentiation of DR reward is very similar to what has been previously observed and described (Bergeron and Rompré, 2013 ; Ducrot et al, 2013 ; Hernandez et al, 2015 ).…”

“…Once the rat nose poked consistently at current intensities between 125 and 400 μA, a rate vs. pulse-frequency curve was obtained by varying the stimulation frequency across trials over a range that drove the number of rewards earned from maximal to minimal levels. A detailed shaping and training procedure can be found in Hernandez et al ( 2015 ).…”

“…A first saline test was performed to habituate the animals to the microinjection procedure. The detailed bilateral injections procedure can be found in Hernandez et al ( 2015 ). Immediately after the microinjection, rats were allowed to self-stimulate for an hour.…”

“…Empirical evidence for such an arrangement comes from experiments in which systemic or local injection of either N-methyl-D-aspartate receptor (NMDAR) agonists or antagonists increases DA burst firing (French et al, 1993 ), terminal DA release (Westerink et al, 1996 ; Mathé et al, 1998 ; Kretschmer, 1999 ), and forward locomotion (Kretschmer, 1999 ; Cornish et al, 2001 ). Furthermore, VM microinjections of short inhibitory RNA that reduces the number of NMDAR on VM neurons results in an attenuation of reward induced by dorsal-raphe (DR) electrical stimulation, while VM microinjection of (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA) and 2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), NMDAR antagonists that display a high affinity for receptor composed of the GluN2A subunits, produces the opposite effect (Bergeron and Rompré, 2013 ; Hernandez et al, 2015 ). The most likely mechanism for the reward-attenuating effect is a reduction in the NMDARs that control DA burst firing, whereas a likely mechanism for the reward-enhancing effect is a blockade of a different subtype of NMDARs that maintain the inhibitory drive on DA neurons.…”

To Act or Not to Act: Endocannabinoid/Dopamine Interactions in Decision-Making

“…This reduction would have a dual effect; it would diminish the excitatory inputs to DA neurons (Melis et al, 2004 ), which would curtail burst firing, but it could also reduce GABAergic inhibitory drive onto DA neurons. Indeed, glutamate plays a major role in the maintenance of DA inhibitory drive by acting on NMDA receptors located in GABA neurons most likely through GluN2A receptors (Bergeron and Rompré, 2013 ; Hernandez et al, 2015 ). A reduction in glutamate release probability, therefore, adds to an overall decrease in DA inhibitory drive.…”