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

Ventral midbrain (VM) neurons that project to limbic structures play a role in reward and incentive motivation. It has been suggested that a reward-related signal is transmitted when the firing rate of VM dopamine neurons shifts from a tonic to a phasic mode. Since glutamate is necessary for this transduction process, it is likely to play a role in reward signaling. This study was aimed at determining the effect of VM N-Methyl-D-Aspartate (NMDA) receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer an electrical stimulation in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and after bilateral VM injections of the following NMDA receptor antagonists: R-CPP, 3-(R-2-Carboxypiperazin-4-yl)-propyl-1 phosphonic acid, (0, 20.6, 41.2 and 82.5 pmol/0.5 μl/side), PPPA, (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid, (0, 0.825 and 1.65 nmol/0.5 μl/side) orRo04-5595, 1-[2-(4-Chlorophenyl)ethyl]-1,2,3,4-tetrqahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride (0, 0.825, 1.65 nmol/0.5 μl/side). R-CPP and PPPA produced a dose and time dependent decrease in reward threshold, an effect that was, at some doses and times after the injection, accompanied by an increase in maximum responses. These effects were not observed with Ro04-5595 over the range of doses tested. While previous studies suggest a role for glutamate in reward signaling, the present results show that VM glutamate exerts a tonic inhibition on the reward-relevant pathway. The selectivity of Ro04-5595 for NMDA receptors composed of GluN2B subunits and the higher affinity of R-CPP and PPPA for GluN2A suggest that the inhibition is mediated by receptors composed of GluN2A subunits.