2025 Theses Doctoral

Investigating the utility and mechanism of action of the atypical antidepressant tianeptine

Pekarskaya, Elizabeth

Major depressive disorder is a significant contributor to worldwide disability. Unfortunately, current treatments are ineffective for approximately half of patients and often have intolerable side effects. An atypical antidepressant and mu-opioid receptor agonist, tianeptine, shows promise as a treatment for the sensory and emotional symptoms of multiple etiologies of depression.

Here, we investigated the utility of tianeptine in several mouse models of depression. In a chronic stress mouse model, we demonstrated that tianeptine is effective and distinct in terms of time to efficacy, neurobiological impact, and underlying neural circuit from the standard SSRI fluoxetine. In a developmental exposure to fluoxetine mouse model, we showed that tianeptine is effective at normalizing disrupted behaviors in adulthood, unlike adult treatment with fluoxetine. In the spared nerve injury mouse model of neuropathic pain, we find that tianeptine successfully reduces allodynia (increased sensitivity/painful response to what should be a non-painful touch) without causing broad analgesia in both males and females. We also find that tianeptine normalizes behaviors commonly associated with mouse models of anxiety and depression in male neuropathic pain mice.

Chronic pain and depression often result in changes in mu-opioid receptor expression or availability in multiple brain areas. We find preliminary evidence that expression decreases in the habenula, the brain region with the most mu-opioid receptors. This area often becomes dysregulated during chronic pain and depression in human patients, possibly due to this decrease in mu-opioid receptors. When we chronically treat mice with methocinnamox, a drug that prevents the mu-opioid receptor from activating (mimicking a reduction in expression or availability), we find many of the same pain-related and affective behavioral changes observed in the SNI model. This suggests that endogenous opioid dysregulation may underlie several of these symptoms and that normalization of endogenous opioid signaling may be a goal for future treatment options.

Finally, we identified significant changes in cerebral blood volume (CBV) in SNI mice in several brain areas associated with pain and reward behaviors. Most notably, a decrease in CBV in the medial forebrain bundle, a region associated with pleasurable states, and an increase in the medial habenula, a region associated with aversive states. These CBV differences are normalized to control levels after tianeptine treatment. We also discovered that relative levels of GABA and glutamine, but not glutamate, are decreased in the habenula in SNI mice, consistent with previous literature in other brain areas showing a decreased glutamine-to-glutamate ratio in depressed patients.

Taken altogether, we find tianeptine shows promise as a novel alternative treatment for several subtypes of depression, alleviating a variety of pain and negative affect-associated symptoms, and that further investigations in the medial habenula and medial forebrain bundle may reveal relevant circuits for understanding tianeptine’s mechanism of action.