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Receptor modulators chart new courses out of depression

Posted by on Tuesday, February 4, 2020 in Discoveries, News & Discoveries .

By Amanda N. Johnson

A teal piece of paper in the shape of a downcast head sits on top of torn black paper. The torn paper is arranged in concentric circles with the head in the center.
“Major depression is one of the most common mental disorders in the U.S. According to the National Institute of Mental Health, approximately 7% (17.3 million) of American adults had at least one major depressive episode in 2017.” (Tadamichi,

Existing drug treatments relieve mental illness for some people, but fall short of providing a full recovery for many others. One goal of neuroscience research is to find new ways to modulate brain activity so that more patients experience freedom from poor mental health. The laboratories of Craig Lindsley (Pharmacology), Danny Winder (Molecular Physiology and Biophysics), and Jeffrey Conn (Pharmacology) recently published research in Neuron that furthers this aim. The work provides direction for the development of new drug therapies for the more than two-thirds of major depressive disorder (MDD) patients who are unsuccessfully treated with conventional antidepressants.

The investigation, led by postdoc Max Joffe, focuses on the prefrontal cortex (PFC), a region of the brain that regulates the management of one’s self and resources toward achieving a goal. In MDD patients, PFC functioning is reduced. As a result, patients struggle to actively manage their lives and lose interest in activities they normally find enjoyable.

Prior research indicates that an inhibitor of two receptors of the neurotransmitter glutamate, mGlu2 and mGlu3, which regulate nervous system excitation in the PFC, successfully treated depression in animal models. Inhibiting only one of these receptors, however, would be a preferable therapy as targeting both is more likely to trigger undesirable side effects. In spite of the sparsity of distinguishing features, the Lindsley, Winder, and Conn labs previously generated inhibitors capable of discriminating between these receptors. They used these inhibitors to investigate if targeting each receptor individually could still effectively combat depression.

Treatment with an inhibitor designed against either mGlu2 or mGlu3 reversed depression symptoms, including those that are poorly managed by current therapies, in multiple animal models of chronic stress. Both inhibitors achieved these effects by directly increasing excitatory signaling in a subset of brain cells within the PFC that communicates with the thalamus, a region of the brain that relays motor and sensory signals to the cortex. They also found that each inhibitor altered the communication pattern between the PFC and thalamus in distinct ways.

These modes of action contrast with that of conventional antidepressants, which indirectly enhance excitatory signaling by decreasing inhibitory signaling. Directly targeting the mGlu2 and/or mGlu3 receptors thus provides promising new routes out of depression that may be selected based on which of the many depression symptoms a particular MDD patient experiences.

Funding for this research was provided by the NIH, the Pharmaceutical Research and Manufacturers of America Foundation, and the Searle Undergraduate Research Program.