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

Many people with comorbid depression and anxiety do not achieve full remission through treatment with currently available options. Treatment resistance in patients with both depression and anxiety highlights the need for novel antidepressant and anxiolytic treatments that could better address the specific therapeutic needs of this population. Rodents are widely used in depression and anxiety drug discovery programs. The rodent strains used often lack face validity for the disorders of interest. The experiments in this thesis utilized the Wistar Kyoto (WKY) rat, a strain that exhibits multiple behaviors similar to the core symptoms of depression and anxiety, in experiments designed to assess the effects of kappa-opioid receptor (KOR) antagonists in tests of depression-like and anxiety-like behavior. WKY rats were compared to Sprague Dawley (SD) rats, a commonly used strain in depression and anxiety research, in all experiments. Depression-like behavior was assessed in the modified forced swim test (FST) and anxiety-like behavior was assessed in the novelty-induced hypophagia (NIH) and defensive burying (DB) tests. WKY rats displayed more depression-like behavior in the FST compared to SD rats. Systemic administration of KOR antagonists produced antidepressant-like effects in WKY rats, but did not significantly alter the behavior of SD rats. C-fos immunohistochemistry identified the nucleus accumbens shell and piriform cortex as potential neural substrates for the antidepressant-like effects of the KOR antagonist nor-binaltorphimine (nor-BNI) in WKY rats. Additional experiments demonstrated that WKY rats had higher KOR tissue content levels in the piriform cortex and higher dynorphin A tissue content levels in the nucleus accumbens. Furthermore, local injection of nor-BNI into the piriform cortex of WKY rats produced antidepressant-like effects in the FST. WKY rats also display more anxiety-like behavior in the NIH and DB tests. In the NIH and DB tests, the KOR antagonist DIPPA produced clear anxiolytic-like effects in WKY rats, and partial anxiolytic-like effects in SD rat. These experiments highlight the WKY rat strain as a unique model of aspects of comorbid depression and anxiety characterized by increased dynorphin-KOR tone. These experiments also support the continued development of KOR antagonists as novel treatments for depression and anxiety.