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

Abstract

Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward. Blockade of VM NMDAR, however, enhances brain stimulation reward (BSR), the results can be explained by a reduction in the inhibitory drive on DA neurons that is also under the control of glutamate. In this study, we used fast-scan cyclic voltammetry (FSCV) in anesthetized animals to determine whether this enhancement is associated with a change in phasic DA release in the nucleus accumbens. Rats were implanted with a stimulation electrode in the dorsal-raphe (DR) and bilateral cannulae above the VM and trained to self-administer trains of electrical stimulation. The curve-shift method was used to evaluate the effect of a single dose (0.825 nmol/0.5 μl/side) of the NMDAR antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA), on reward. These animals were then anesthetized and DA release was measured during delivery of electrical stimulation before and after VM microinjection of the vehicle followed by PPPA. As expected, phasic DA release and operant responding depended similarly on the frequency of rewarding electrical stimulation. As anticipated, PPPA produced a significant reward enhancement. Unexpectedly, PPPA produced a decrease in the magnitude of DA transients at all tested frequencies. To test whether this decrease resulted from excessive activation of DA neurons, we injected apomorphine 20 min after PPPA microinjection. At a dose (100 μg s.c.) sufficient to reduce DA firing under control conditions, apomorphine restored electrical stimulation-induced DA transients. These findings show that combined electrical stimulation and VM NMDARs blockade induce DA inactivation, an effect that indirectly demonstrates that VM NMDARs blockade enhances reward by potentiating stimulation-induced excitation in the mesoaccumbens DA pathway.

Dorsal raphe stimulation relays a reward signal to the ventral tegmental area via GluN2C NMDA receptors

“…Both effects could be associated with a reduction in the release of DA from the nucleus accumbens since this decrease can affect both reward and motor function [ 51 ]. It has been shown that electrical and optical stimulation of DR neurons produces an increase in DA cell firing and DA phasic release [ 2 , 15 , 52 ] via glutamatergic DR efferents to the VTA [ 1 , 2 , 20 ]. Substantial reduction in the GluN2C input likely decreases glutamatergic excitability in DA neurons, reducing the overall DA release in terminal areas.…”

Oxycodone-induced dopaminergic and respiratory effects are modulated by deep brain stimulation

“…One further possibility is that continuous electrical stimulation of the VTA may induce a relatively rapid depolarization block (DB) similar to chronic antipsychotic treatments that, in turn, decrease tonic DA levels in the NAcc ( Lane and Blaha, 1987 ; Grace et al, 1997 ; Boye and Rompre, 2000 ; Hernandez et al, 2016 ). These hypotheses can be investigated by further studies using other pharmacological tests and measuring techniques such as amperometry.…”

Dorsal raphe stimulation relays a reward signal to the ventral tegmental area via GluN2C NMDA receptors

“…Both effects could be associated with a reduction in the release of DA from the nucleus accumbens since this decrease can affect both reward and motor function [45]. It has been shown that electrical and optical stimulation of DR neurons produces an increase in DA cell firing and DA phasic release [2,15,46] via glutamatergic DR efferents to the VTA [1,2,20]. Substantial reduction in the GluN2C input likely decreases glutamatergic excitability in DA neurons, reducing the overall DA release in terminal areas.…”