Rapid-acting antidepressants are urgently required to treat the ever-increasing number of individuals suffering from major depressive disorder (MDD) and the growing incidence of treatment resistance to conventional antidepressant medications.


There are several ongoing drug development projects in the lab. One of these research programs investigates the antidepressant potential of kappa opioid receptor (KOR) antagonists as novel therapeutics for psychiatric disorders. Activation of KORs by their endogenous ligand dynorphin produces dysphoria, aversion, and depression in response to stressful stimuli in humans and rodents. Importantly, KOR antagonists have been shown to produce antidepressant and anxiolytic activity in rodent tests that are sensitive to the effects of antidepressant compounds.

Determining the underlying mechanisms mediating the immediate and protracted behavioral effects of the putative antidepressant ketamine is another primary focus of the lab. Unlike conventional antidepressants which may take weeks to months to exert their therapeutic effects, a single infusion of ketamine produces rapid (within hours) relief from depressive symptoms that is sustained for up to one week in some patients. Elucidating the mechanisms that mediate the different stages of ketamine’s behavioral effects is a critical component in developing more effective and rapid acting therapeutics for psychiatric disorders such as MDD.


Dr. Lucki

Behavioral pharmacology

Behavioral screening tests are used to identify potential candidates and determine the basic pharmacological underlying their mechanism of action. Next candidate drugs are evaluated using models of chronic stress, such as chronic mild stress and chronic social defeat. Rats and mice are used in the laboratory to fully exploit the benefits that these species offer to researchers. Often these studies utilize mice with genetic knockout of specific genes globally or within a specific cell population and their wild type controls to address critical questions of mechanism.

Mechanism of action of antidepressant and antianxiety medications

Underlying substrates of antidepressant activity: In vivo microdialysis enables measurement of extracellular concentrations of monoamines in conscious rats and mice. Current studies focus on the role of specific neurotransmitters, such as serotonin (5-HT) and dopamine (DA), in the behavioral effects of antidepressant and anxiolytic drugs. Animal tests used to evaluate the potential efficacy of different neurotransmitter and peptide receptors for clinical therapeutic effects are employed to identify brain regions associated with behavioral responses to drugs.

Stress neurobiology and psychiatric disorders

Molecular correlates of behavioral responses: Various molecular biology techniques are used to identify brain regions that are associated with stress and drug responses. Techniques included in vitro ligand binding; histology; quantification real time PCR,  ELISA and western blot techniques and HPLC analysis of brain monoamines. Typically, tissue is obtained from rodents following exposure to stressors with or without systemic or central injection of compounds of interest.



Numerous clinical studies have shown that low doses of buprenorphine, a mixed opioid analgesic, can produce therapeutic effects within one week of treatment onset in populations of MDD patients that are treatment-resistant. Additional indications for low doses of buprenorphine include the reduction of severe suicidal ideation and PTSD. A central goal of our studies is to better understand the basic neuropharmacology of buprenorphine as it relates to behavior in mice and mental health disorders in humans. Our studies have elucidated the mechanisms underlying the effects of buprenorphine in experimental models that are relevant to human mental health disorders (i.e. the behavioral changes induced by buprenorphine treatment in rodent tests that are sensitive to the effects of antidepressant compounds). This includes determining that KORs mediate the antidepressant like activity of buprenorphine in rodent tests and that MOR blockade produces the anxiolytic activity produced by buprenorphine. Following exposure to chronic stressors, mice exhibit significant physiological changes attributed to stress and several deficits across a battery of behavioral tests. Critically, 1 week of buprenorphine treatment is sufficient to reverse stress induced physiological and behavioral changes. At a molecular level buprenorphine normalized the stress induced changes in the mRNA expression of opioid peptides and receptors within the cortex, striatum, hippocampus and amygdala.


Combining behavior and in vivo microdialysis: The participation of central DA neurotransmission in depression, anxiety and neuroendocrine regulation associated with behavioral stress is a central mechanism proposed to underlie the immediate effects of rapid-acting antidepressants. Microdialysis procedures are used to measure the release of neurotransmitters in discrete regions of awake freely-moving rats or mice. We developed an analog of the novelty induced hypophagia (NIH) test that could be used to measure the response of DA release in the nucleus accumbens (NAc) in awake behaving mice.  Mice trained to consume a palatable food (peanut butter chips) in the dialysis apparatus exhibit an increase of DA release in the NAc. This effect is observed even when mice are prevented from consuming the food, demonstrating that DA was released in response to the expectation of the reward and not by its consumption. Untrained mice do not exhibit this increase in DA release despite consuming the food, as they novel environment suppresses this response. Similarly, trained mice exposed to novelty stress (bright lights, odor) showed increased latency to approach the food and did not exhibit increased DA release.  Pretreatment of mice exposed to novelty stress with buprenorphine reduced approach latencies and restored the increase of DA release, suggesting that this may be the mechanisms through which buprenorphine restores reward processing under stressful conditions.


After establishing that MORs do not play a role in mediating the behavioral effects of the novel KOR agonists LY2456302 and LY2444295, our studies moved on to incorporate the important consideration of sex differences in sensitivity to KOR ligands. This is important because sex-specific differences in sensitivity to KOR agonist and antagonists is required to adequately inform drug dosing in humans. Utilizing nest building, an innate behavioral indicative of self-care, we have demonstrated decreased sensitivity to KOR ligands in females. This hypothesis is supported by the clinical literature demonstrating higher KOR availability in healthy human males compared with females. Studies are ongoing in the laboratory to develop this hypothesis.


Prolonging the antidepressant activity of rapid-acting antidepressants: Ketamine has demonstrated robust antidepressant effects in treatment-resistant patients at subanesthetic doses within hours of a single infusion. However, clinical evidence now suggests that in more severely ill patients, multiple doses, twice or three weekly, are required to achieve optimal remission from depressive symptoms. To enhance the translational value of our preclinical data, the utility of the thrice weekly dosing regimen was evaluated using the forced swim test (FST) in mice. We have demonstrated a prolonged sensitization to the behavioral effects of ketamine that are sustained for up to 2 weeks following the last injection. Utilizing this paradigm, we can now contrast the molecular and neurochemical substrates engaged by single or multiple ketamine treatments at designated time points.