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

Marie-Pierre Cossette,Giovanni Hernandez,Peter Shizgal,Pierre-Paul Rompré

doi:10.3389/fnbeh.2016.00161

Marie-Pierre Cossette, Giovanni Hernandez + Show 2 more

Open Access

https://doi.org/10.3389/fnbeh.2016.00161

Copy DOI

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.

Highlights

Glutamate, the major excitatory neurotransmitter in the brain, plays a major role in behavioral, cognitive and motivational functions
The injection sites were located within the ventral part of the ventral midbrain (VM) (Figures 2B,B ), a region that contains neurons activated by rewarding electrical stimulation (Wise and Rompre, 1989; Marcangione and Rompré, 2008)
Drugs that boost DA release enhance brain stimulation reward (BSR); whereas the opposite behavioral effect is obtained with drugs that decrease DA availability (Wise and Rompre, 1989)

Summary

Introduction

The major excitatory neurotransmitter in the brain, plays a major role in behavioral, cognitive and motivational functions. Through its direct action on DA neurons, glutamate switches DA neural activity from a slow, irregular, firing pattern to a phasic burst-firing mode that is associated with enhanced DA release (Grace and Bunney, 1984; Charara et al, 1996; Geisler et al, 2007; Omelchenko et al, 2009). This mode of neural activity is associated with the acquisition of appetitive and aversive tasks (Zweifel et al, 2009). It has been proposed that DA burst firing encodes reward prediction errors (Montague et al, 1996) and conveys motivationally relevant signals to anterior forebrain regions that control executive functions (Overton and Clark, 1997)

Methods

Results

Conclusion