Endogenous κ Opioid Activation Mediates Stress-Induced Deficits in Learning and Memory

We hypothesized that mice subjected to prolonged stress would demonstrate decreased performance in a learning and memory task attributable to the endogenous activation of the kappa opioid receptor (KOR). C57BL/6J mice were tested using the novel object recognition (NOR) assay at various time points after exposure to repeated forced swim stress (FSS). Unstressed mice demonstrated recognition of the novel object at the end of a procedure using three 10-min object interaction phases, with a recognition index (RI) for the novel object of 71.7 +/- 3.4%. However, 1 h after exposure to FSS, vehicle-pretreated mice displayed a significant deficit in performance (RI = 58.2 +/- 4.1%) compared with unstressed animals. NOR was still significantly reduced 4 but not 24 h after FSS. Treatment with the KOR-selective antagonist norbinaltorphimine (10 mg/kg, i.p.) prevented the decline in learning and memory performance. Moreover, direct activation of the KOR induced performance deficits in NOR, as exogenous administration of the KOR agonist U50,488 [(+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide] (0.3 mg/kg, i.p.) suppressed NOR (RI = 56.0 +/- 3.9%). The effect of FSS on NOR performance was further examined in mice lacking the gene for the endogenous KOR agonist dynorphin (Dyn). Dyn gene-disrupted mice exposed to FSS did not show the subsequent learning and memory deficits (RI = 66.8 +/- 3.8%) demonstrated by their wild-type littermates (RI = 49.7 +/- 2.9%). Overall, these results suggest that stress-induced activation of the KOR may be both necessary and sufficient to produce subsequent deficits in novel object recognition.