The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression. Deficit in the levels or function of the glucocorticoid receptor (GR) found in depressed patients has been causally implicated in depression, as this deficit is normalized by antidepressant treatments. Baseline levels of amygdalar Nor-1 and GR mRNA were higher in the WKYs compared to the comparison control Sprague-Dawley rats (SD). Prolonged treatment with the antidepressant desipramine (DMI) decreased the expression of both transcripts in the WKY strain concomitantly with decreased immobility in the forced swim test (FST) of depressive behavior. Using short hairpin RNA (shRNA) targeted against Nor-1, we investigated the direct contribution of elevated Nor-1 expression in the amygdala of WKY to their exaggerated depressive behavior in the FST. After validating the shRNA targeting of Nor-1 in vitro, Nor-1 shRNA containing vector was infused intracerebroventricularly, using a linear polyethylenimine (PEI)-containing in vivo gene delivery system. Repeated administration of Nor-1 shRNA ameliorated the depressive behavior of WKYs in the FST and decreased amygdalar Nor-1 mRNA levels without affecting GR mRNA levels. These data demonstrate that brain region-specific changes in GR expression in response to DMI are strain dependent and that elevated amygdalar Nor-1 expression can contribute to depressive behavior in the WKY model of depression.