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Comparative Study
. 2010 Feb;35(3):752-63.
doi: 10.1038/npp.2009.183. Epub 2009 Nov 18.

Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats

Gregory V Carr  1 , Debra A Bangasser, Thelma Bethea, Matthew Young, Rita J Valentino, Irwin Lucki
Affiliations
Comparative Study

Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats

Gregory V Carr et al. Neuropsychopharmacology. 2010 Feb.

Abstract

The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.

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Figures

Figure 1
Figure 1
The effects of nor-binaltorphimine dihydrochloride (nor-BNI) in the forced swim test (FST) in Sprague–Dawley (SD) and Wistar Kyoto (WKY) rats. At baseline, WKY rats exhibit more immobility and less climbing behavior compared to SD rats. Systemic administration of nor-BNI (1, 5, or 10 mg/kg, s.c.) had no significant effects on any of the FST behaviors in SD rats. In contrast, nor-BNI (5 and 10 mg/kg) reduced immobility and increased swimming behavior in WKY rats. All data are depicted as the mean+SEM. n=8–10 per group. The number symbol represents significant differences between the saline-treated groups across strain, #p<0.001. Asterisks represent differences within strain from the saline-treated control group, *p<0.05 and **p<0.01.
Figure 2
Figure 2
The effects of DIPPA in the forced swim test (FST) in Sprague–Dawley (SD) and Wistar Kyoto (WKY) rats. (a) Systemic administration of DIPPA (5 and 10 mg/kg) did not produce antidepressant-like effects in SD rats. Both doses significantly decreased climbing behavior. n=9–11 per group. (b) DIPPA (5 and 10 mg/kg) significantly decreased immobility in WKY rats. The 10 mg/kg dose also significantly increased swimming behavior. n=12–16 per group. All data are depicted as the mean+SEM. Asterisks represent significant differences from the saline-treated control group. *p<0.05 and **p<0.01.
Figure 3
Figure 3
The effects of desipramine in the forced swim test (FST) in Sprague–Dawley (SD) and Wistar Kyoto (WKY) rats. WKY rats exhibited increased immobility and decreased climbing behavior at baseline compared to SD rats. Systemic administration of desipramine (20 mg/kg) significantly decreased immobility and also increased climbing behavior in both strains. All data are depicted as the mean+SEM. n=8–10 per group. The number symbol represents significant differences between the saline-treated groups across strain, #p<0.001. Asterisks represent significant differences from the saline-treated control group within strain. *p<0.05, **p<0.01, and ***p<0.001.
Figure 4
Figure 4
Localization of brain regions analyzed in c-fos studies. These schematics represent the approximate areas used for the quantification of c-fos profiles for each brain region. The images, from the top left image, correspond to Figures 20, 24, 35, 45, 47, 60, 94, and 115, respectively from Paxinos and Watson (2005). The numbers underneath each image represent the anterior/posterior distance from bregma. Abbreviations: AcbSh, nucleus accumbens shell; Cg1, cingulate cortex area 1; Cg2, cingulate cortex area 2; DG, dentate gyrus; DR, dorsal raphe; LC, locus coeruleus; LH, lateral habenula; Pir, piriform cortex; PaV, paraventricular nucleus of the hypothalamus; PVA, paraventricular thalamic nucleus; ST, bed nucleus of the stria terminalis.
Figure 5
Figure 5
Photomicrographs of the piriform cortex and nucleus accumbens shell. Representative photomicrographs from the four treatment groups in the c-fos activation experiment. (a) Piriform cortex; bar represents a distance of 200 μm. (b) Nucleus accumbens shell; bar represents a distance of 80 μm.
Figure 6
Figure 6
Western blot analysis of κ-opioid receptor (KOR) expression in the nucleus accumbens and piriform cortex. (a) Representative blots show the expression of KOR protein (MW=72 kDa), and β-actin (MW=42 kDa) in the piriform cortex. (b and c) Graphs show the mean ratio of the integrated intensity of each band of KOR protein to the corresponding band of β-actin from the same sample. KOR expression was greater in the piriform cortex, but not nucleus accumbens, of Wistar Kyoto (WKY) rats compared to Sprague–Dawley rats. All data are depicted as the mean+SEM. n=10–15 per group. Asterisks represent significant differences between groups, *p<0.05.
Figure 7
Figure 7
Dynorphin A expression levels in the nucleus accumbens and piriform cortex. (a) Wistar Kyoto (WKY) rats had higher baseline tissue content levels of dynorphin A in the nucleus accumbens. (b) There were no significant differences in dynorphin A content in the piriform cortex. All data are depicted as the mean+SEM. n=10 per group. Asterisks represent significant differences between groups, ***p<0.001.
Figure 8
Figure 8
The effects of local infusion of nor-binaltorphimine dihydrochloride (nor-BNI) into the piriform cortex in the forced swim test (FST) in Wistar Kyoto (WKY) rats. (a) Both doses tested (2.5 μg per side (n=4) and 10 μg per side (n=7)) produced significant decreases in immobility. The ‘misses' group (n=5), 10 μg per side dorsal with respect to the piriform cortex, did not exhibit any significant changes in behavior compared to the artificial cerebrospinal fluid (aCSF)-treated controls (n=7). (b) The location of the injections for the rats used in this study. Filled circles represent placements within the piriform cortex and open circles represent placements outside the region. All data depicted as the mean+SEM. Asterisks represent significant differences from the aCSF-treated control group, *p<0.05.
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