The overall goal of this research program is to evaluate the therapeutic potential for buprenorphine and to use animal studies to support its development for depression and anxiety disorders. 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. Buprenorphine is medically available and used safely for the treatment of physical dependence to opioids but has received virtually no attention for the use of psychiatric disorders in nondependent populations. As a mu-opioid receptor (MOR) partial agonist and kappa-opioid receptor (KOR) antagonist, buprenorphine has been studied extensively in models of drug reward, physical dependence, and analgesia. Recent studies highlighting the role of dynorphin in stress have shown that KOR antagonists can produce antidepressant and anxiolytic effects in animal models. The pharmacological profile of buprenorphine as a potent MOR partial agonist and KOR antagonist supports the likelihood that buprenorphine would produce beneficial effects on stress-induced behaviors. Few published studies on the effects of buprenorphine in animal models of depression and anxiety exist to support clinical trials and development or to understand its potential mechanism of action. Taken together, these experiments will establish a basic foundation for considering the development of buprenorphine for new indications in psychiatric disorders and translate to prospective clinical treatment studies of depression and anxiety in treatment-resistant patients.

Public Health Relevance

This project examines whether buprenorphine is likely to be effective for the clinical treatment of depression and anxiety disorders using preclinical animal behavior tests predictive of clinical activity. A neural circuitry model is proposed to explain the effectiveness of buprenorphine for treating psychiatric disorders. Major depression is an important public health problem because of its severe economic impact and contribution to morbidity from other medical disorders. Many patients do not respond to current medications. The results of this project will determine whether buprenorphine should be developed for the clinical treatment of comorbid depression and anxiety that is especially refractory to treatment with current medications.

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)
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Hillefors, MI
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University of Pennsylvania
Schools of Medicine
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
Robinson, Shivon A; Erickson, Rebecca L; Browne, Caroline A et al. (2017) A role for the mu opioid receptor in the antidepressant effects of buprenorphine. Behav Brain Res 319:96-103
Erickson, Rebecca L; Browne, Caroline A; Lucki, Irwin (2017) Hair corticosterone measurement in mouse models of type 1 and type 2 diabetes mellitus. Physiol Behav 178:166-171
Browne, Caroline A; Erickson, Rebecca L; Blendy, Julie A et al. (2017) Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism. Neuropharmacology 117:401-407
Robinson, Shivon A; Brookshire, Bethany R; Lucki, Irwin (2016) Corticosterone exposure augments sensitivity to the behavioral and neuroplastic effects of fluoxetine in C57BL/6 mice. Neurobiol Stress 3:34-42
Falcon, Edgardo; Browne, Caroline A; Leon, Rosa M et al. (2016) Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors. Neuropsychopharmacology 41:2344-51
Browne, Caroline A; van Nest, Duncan S; Lucki, Irwin (2015) Antidepressant-like effects of buprenorphine in rats are strain dependent. Behav Brain Res 278:385-92
Falcon, Edgardo; Maier, Kaitlyn; Robinson, Shivon A et al. (2015) Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice. Psychopharmacology (Berl) 232:907-15
Browne, Caroline A; Lucki, Irwin (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:161