Blockade of ventral midbrain NMDA receptors enhances brain stimulation reward: A preferential role for GluN2A subunits

Bergeron, Sabrina; Rompré, Pierre‐Paul

doi:10.1016/j.euroneuro.2012.12.005

Cited by 17 publications

(37 citation statements)

References 63 publications

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“…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.…”

Section: Resultsmentioning

confidence: 72%

“…Because other siRNA manipulations produced a significant reduction of GluN2A without any reliable change in self-stimulation behavior, we are forced to conclude that the NMDARs mediating the reward signal are not composed of GluN2A subunits. They are also unlikely composed of GluN2B, since no reward enhancement was observed in a previous pharmacological study with a selective GluN2B antagonist injected into the VM (Bergeron and Rompré, 2013). One hypothesis then is that the relevant NMDARs are heterodimers composed of GluN1 and GluN3 subunits.…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of VM NMDARs also acts as a positive reinforcer and sustains self-administration behavior (David et al, 1998). Furthermore, VM microinjections of the PPPA and R-CPP, NMDAR antagonists for GluN2A-D subunits, potentiate the rewarding effect of electrical brain stimulation; such a potentiation was not seen with Ro 04-5595, a selective GluN2B antagonist, hence suggesting that glutamate exerts an inhibitory modulation on VM reward-relevant neurons by acting on NMDARs composed of GluN2A and/or GluN2D (Bergeron and Rompré, 2013). The present study was thus aimed at further characterizing the NMDARs that is/are responsible for this inhibitory modulation of reward.…”

Section: Introductionmentioning

confidence: 98%

“…After a minimum 7 days period of acclimation to the housing environment rats were anesthetized with isoflurane (2.5-3.5% O 2 , 0.6 l/min) and stereotaxically implanted according to Paxinos and Watson (2007) coordinates with 26-gauge guided cannulae (Model C315G HRS Scientific, Montreal, Canada) aimed bilaterally above the VM ( À 5.5 mm AP, 3.2 mm ML at a 181 angle, 6.5 mm DV from the skull surface) and a movable monopolar electrode aimed at the dorsal raphe ( À 7.6 mm AP, 0.0 mm ML, 6.6 mm DV from the skull surface). See Bergeron and Rompré (2013) for further surgery details. All procedures were carried out in accordance with established practices as described in the NIH Guide for Care and Use of Laboratory Animals.…”

Section: Subjects and Surgerymentioning

confidence: 99%

“…For a detailed shaping procedure see Bergeron and Rompré (2013). Once the rat nose-poked consistently for currents between 125 and 400 mA, 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.…”

Section: Self-stimulation Trainingmentioning

confidence: 99%

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

Hernández

Khodami-Pour

Lévesque

et al. 2015

Neuropsychopharmacol

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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.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%