The ventral striatum (VS) is characterized by a distinctive neural architecture in which multiple corticolimbic glutamatergic (GLUergic) and mesolimbic dopaminergic (DAergic) afferents converge on the same output cell type (the medium-sized spiny neuron, MSN). However, despite the gateway function attributed to VS and its involvement in action selection and spatial navigation, as well as the evidence of physical and functional receptor-receptor interaction between different members of ionotropic GLUergic and DAergic receptors, there is no available knowledge that such reciprocal interaction may be critical in shaping the ability to learn novel spatial and non-spatial arrangement of stimuli. In this study, it was evaluated whether intra-VS bilateral infusion of either N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-selective antagonists may suppress the ability to detect spatial or non-spatial novelty in a non-associative behavioral task. In a second set of experiments, we further examined the hypothesis that VS-mediated spatial information processing may be subserved by some preferential receptor-receptor interactions among specific GLUergic and DAergic receptor subtypes. This was assessed by concomitant intra-VS infusion of the combination between subthreshold doses of either NMDA or AMPA receptor antagonists with individual D1 or D2 receptor blockade. The results of this study highlighted the fact that NMDA or AMPA receptors are differentially involved in processing of spatial and non-spatial novelty, and showed for the first time that preferential NMDA/D1 and AMPA/D2 receptor-receptor functional communication, but not NMDA/D2 and AMPA/D1, is required for enabling learning of novel spatial information in the VS.