2026 Theses Doctoral

Developmental exposure to SSRIs induces motivational deficits in adolescent and adult mice that can be attenuated by pharmacological antagonism or viral knockdown of mu opioid receptors in the nucleus accumbens

Cambre, Emily C.

Major Depressive Disorder (MDD) is a common and debilitating mental illness that affects over 300 million people in the world and is primarily characterized by depressed mood and anhedonia. Anhedonia, which is composed of a collection of reward processing deficits, or the reduction of effort, ‘liking’, and reward learning, is a core symptom of this disorder. MDD can emerge as early as adolescence, and manifests with the same mood and behavioral impairments as seen in adults. The chances of developing MDD are influenced by many variables, including genetics, acute and/or chronic stressors, and other environmental factors such as drug exposures. A more recent advancement in our understanding of risk factors to MDD comes from a Finnish cohort study, which found that children of mothers who continued antidepressant treatment throughout their pregnancy had higher rates of MDD diagnoses beginning in adolescence and continued through adulthood. Specifically, the mothers in this study were chronically treated with a class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs.

This paradoxical finding, where exposure to SSRIs increases the risk of developing MDD later in life, has been replicated in a mouse model. Previous work with these mice, referred to as Dev FLX mice, has shown that behavioral impairments, such as increased avoidance and reduced motivation, cannot be corrected with further SSRI treatment. The Dev FLX mouse model reflects a major concern with the treatment of MDD; frontline therapies, such as SSRIs, have limited success. Notably, anhedonia, which commonly reflects more severe cases of MDD, is often not resolved with current pharmacotherapies. Because of this there is a need to develop or identify new pharmacotherapies that adequately resolve reward processing impairments. We undertook the current experiments to better understand 1) the particular reward processing impairments that manifest in a translationally relevant model of SSRI exposure, 2) whether or not the same behavioral impairments seen in adulthood of Dev FLX mice emerge during adolescence, and 3) which pharmacological target is best suited to ameliorate the identified behavioral impairments and the underlying changes in reward processing circuitry that give way to the identified treatment approach.

To measure changes in effortful behavior (motivation), researchers often use an operant box paradigm known as the progressive ratio (PR) task. While the PR task has been adapted for both adult and adolescent rat models , this behavioral paradigm has not been adjusted to be tested with adolescent mice. We began by designing an adolescent PR task that optimized the training and testing period to the abilities of smaller, younger mice, as well as accounting for the fluctuation of weight and hunger of a growing mouse. Once the task was refined for adolescence, we then tested adolescent Dev FLX mice in the PR task. We found that Dev FLX mice show impairments in motivation, as measured by reduced breakpoints and session times in the PR task, compared to adolescent mice controls.

We moved to experiments in adult Dev FLX mice, using the PR task, the lickometer task, and the Pavlovian conditioning task. The results from these experiments, which measure ‘wanting’, ‘liking’, and learning respectively, collectively suggested that while reward ‘liking’ and reward learning remained normal, Dev FLX mice showed major impairments in their motivation. Having identified the reward processing impairments in our mouse model, we then treated our mice with chronic SSRI administration. We confirmed that subsequent SSRI treatment in adulthood was ineffective at improving effortful behavior.

Previous work from collaborators had established that chronic administration of the mu-opioid receptor (MOR) agonist tianeptine (TIA) corrected anxiety-like behaviors in Dev FLX mice, whereas SSRI treatment was ineffective. Given that MOR agonists classically boost perception to rewards, we tested to see if chronic TIA administration would correct motivational impairments in our mice. To our surprise, we found that TIA did not improve effort. In contrast, the pseudo-irreversible MOR antagonist methocinnamox (MCAM) corrected motivational impairments in Dev FLX mice, both in acute and chronic dosing regimens. The improvements in the PR task were irrespective of changes to other components of reward processing; we found that chronic and acute treatment with MCAM reduced reward ‘liking’, as seen with reduced licking for reward in the lickometer task. The effects of MCAM treatment were also evaluated in control mice. We found that MCAM treatment had opposing results in control mice; PR task performance was unaffected whereas overall licking in the lickometer task was reduced. These results suggest that the beneficial effects of MCAM treatment are unique to Dev FLX mice.

Previous studies have identified the nucleus accumbens (NAc) and the ventral tegmental are (VTA) as two core regions that control reward processing behavior. Based on our previous findings, we assessed the effects of reduced MOR expression in one of these two brain regions on reward processing behaviors of Dev FLX mice. Using a viral knockdown approach, we found that MOR knockdown in the NAc restored motivation and had no effect on ‘liking’ behaviors. In contrast, MOR knockdown in the VTA resulted in reduced licking in the lickometer task, but no changes to performance in the PR task. This finding suggests that the effects of MCAM on motivation can be recapitulated with MOR knockdown in the NAc, and this is likely a site of altered endogenous opioid signaling. However, upon analysis of MOR distribution amongst cell types in the NAc, we did not find changes in the overall receptor population within this region. Our data argues that developmental exposure to SSRIs results in particular deficits in motivation that are corrected both pharmacologically and non-pharmacologically by reduced endogenous opioid signaling, suggesting a translationally relevant model of MDD with a unique treatment target.