# Preliminary imaging studies evaluating the vesicular acetylcholine transporter as a treatment target in major depressive disorder > **NIH NIH R21** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $438,625 ## Abstract The cholinergic hypothesis of major depressive disorder (MDD) is based on extensive evidence that excess brain acetylcholine (ACh) contributes to both the onset and worsening of MDD. However, the specific neurobiological cause of this dysregulated ACh has not been established in humans in vivo. Based on rodent data and our preliminary data in humans, one potential mechanism for increased ACh is through the vesicular ACh transporter (VAChT). For the first time we can visualize and quantify VAChT using the positron emission tomography (PET) tracer [18F]VAT. We have exciting preliminary data in humans without a diagnosis of MDD but with a range of depressed mood showing that hippocampal levels of VAChT are inversely correlated with depression severity. Furthermore, published literature demonstrate (1) decreased VAChT levels (which were associated with higher depression in our data) were associated with increased ACh levels and (2) increased ACh in individuals with depression, implying that low VAChT levels may underlie the increased ACh in MDD. VAChT is therefore a highly compelling candidate for driving cholinergic dysregulation and represents a completely novel target for treating depression. Thus, we propose a high-risk high-reward mechanistic R21 to validate this hypothesis and provide initial proof of concept to support larger investigations of the cholinergic system for potential therapeutic developments in MDD. To achieve this, we propose the following aims: Aim 1. Assess the role of VAChT in the pathophysiology of MDD by fully quantitative PET imaging using [18F]VAT. We hypothesize that lower VAChT underlies cholinergic alterations (higher acetylcholine) in MDD based on animal models of depression exhibiting lower 40% VAChT and our preliminary data indicating VAChT density is inversely correlated with depression severity. We hypothesize that VAChT density is lower in 7 individuals with MDD compared to 7 healthy volunteers without MDD. Aim 2. Demonstrate that acute nicotine challenge increases VAChT in those with MDD. Although its mechanism has not been fully elucidated, transdermal nicotine has been demonstrated to be an effective rapid-onset antidepressant in humans. And in rodents it was demonstrated to increase mRNA expression of VAChT by 54%. Depressed individuals from Aim 1 will be treated with nicotine. Based on animal models, we hypothesize that the 7-day nicotine challenge will increase hippocampal VAChT in 7 individuals suffering from MDD. Our proposed high- risk high-reward mechanistic R21 would be the first study to assess the role of VAChT in MDD pathophysiology in humans, determine how VAChT is regulated by nicotine, advance our understanding of the pathophysiology of MDD, stimulate development of novel cholinergic specific therapeutics, and provide proof of concept to support future larger studies. Our expected outcomes and positive impact at the end of our mechanistic study are to have demonstrated a first assessment of nicoti... ## Key facts - **NIH application ID:** 10950488 - **Project number:** 1R21MH137546-01 - **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK - **Principal Investigator:** Christine Delorenzo - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $438,625 - **Award type:** 1 - **Project period:** 2024-08-15 → 2026-08-14 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10950488 ## Citation > US National Institutes of Health, RePORTER application 10950488, Preliminary imaging studies evaluating the vesicular acetylcholine transporter as a treatment target in major depressive disorder (1R21MH137546-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10950488. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*