The overall goal of this research program is to determine whether kappa opioid receptor antagonists have the potential to be developed as rapidly acting antidepressants. There is a clear medical need for new drugs that would expand the options for treating comorbid depression and anxiety, especially for the substantial number of patients refractory to current medications. Kappa opioid receptors and their endogenous ligand dynorphin are thought to be involved in the production of dysphoria and depression accompanying exposure to stress. Kappa opioid receptor antagonists can produce antidepressant and anxiolytic effects in animal models, but the pharmacological profile of existing compounds make them unsuitable for clinical development. The proposed studies would evaluate the effects of two novel kappa opioid receptors, LY2456302 and LY2444295, as potential antidepressant and anxiolytic drugs using animal behavior tests. Studies will determine whether the kappa opioid receptor antagonists produce their effects more rapidly than established antidepressants and similar to ketamine on tests such as the forced swim test, novelty-induced hypophagia and on acutely reversing the effects of chronic mild stress on anhedonia and anxiety. The mechanism of action of kappa opioid receptor antagonists will be confirmed using mice with constitutive deletion of kappa opioid receptors. Additional studies will identify the neural circuitry involved in producing these behavioral effects. Taken together, these experiments will strengthen a basic foundation for considering the development of a novel kappa opioid receptor antagonists as rapid acting antidepressants for eventual therapy in treatment-resistant depression.

Public Health Relevance

This project examines whether kappa opioid receptor antagonists are likely to be effective for the clinical treatment of depression and anxiety disorders using preclinical animal behavior tests predictive of clinical activity. Major depression is an important public health problem because of its severe economic impact and contribution to morbidity from other medical disorders. Current antidepressants generally have a slow onset and many patients do not respond to current medications. The results of this project will establish whether novel kappa opioid receptor antagonisst have the capacity to produce a rapid antidepressant and anxiolytic response that is similar to ketamine. The neural mechanisms underlying these effects will be elucidated and a neural circuit in brain will be identified. A rationale will be strengthened for developing kappa opioid receptor antagonists as a novel target for rapid therapy of comorbid depression and anxiety.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Winsky, Lois M
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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Browne, Caroline A; Hammack, Robert; Lucki, Irwin (2018) Dysregulation of the Lateral Habenula in Major Depressive Disorder. Front Synaptic Neurosci 10:46
Browne, Caroline A; Falcon, Edgardo; Robinson, Shivon A et al. (2018) Reversal of Stress-Induced Social Interaction Deficits by Buprenorphine. Int J Neuropsychopharmacol 21:164-174
Shepard, Ryan D; Langlois, Ludovic D; Browne, Caroline A et al. (2018) Ketamine Reverses Lateral Habenula Neuronal Dysfunction and Behavioral Immobility in the Forced Swim Test Following Maternal Deprivation in Late Adolescent Rats. Front Synaptic Neurosci 10:39