Abstract
Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.