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Molecular and electrophysiological studies have indicated that HINT1<jats:sup>\u2212\/\u2212<\/jats:sup> mice exhibit increased PKC, PKA, and GSK3\u03b2 activities, as well as glutamate <jats:italic>N<\/jats:italic>-methyl-D-aspartate receptor (NMDAR)\/\u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B\/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3\u03b2 inhibitors and valproate directly attenuated the expression of the manic-like symptoms, whereas PKC inhibition, lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors that counterbalanced the preexisting manic-like symptoms. Na\u00efve HINT1<jats:sup>\u2212\/\u2212<\/jats:sup> mice exposed to stressful paradigms rapidly manifested depressive-like behaviors in subsequent stressful situations, a capacity that persisted for a couple of weeks thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 precipitated manic-like behaviors in stressed HINT1<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Notably, the antagonism of NMDARs prevented HINT1<jats:sup>\u2212\/\u2212<\/jats:sup> mice from alternating behaviors in response to stress. A comparison with \u201cmanic\u201d Black Swiss mice indicated that in HINT1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, PKC supports manic-like symptoms and reduces the expression of depressive-like behaviors via activation of GSK3\u03b2 and regulation of NR2B-enriched NMDARs. 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