# Role of the serotonin transporter and organic cation transporter 3 in serotonergic modulation of emotion-regulating circuitry

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $731,502

## Abstract

Dysfunctional serotonergic neuromodulation in mood-regulating circuits underlies many psychiatric diseases, thus
understanding regulation of serotonin (5-HT) transmission is of fundamental importance. The 5-HT transporter
(SERT) clears 5-HT from extracellular fluid with high-affinity, and is considered a primary controller of the strength
and duration of 5-HT signaling. Our studies have revealed that organic cation transporter 3 (OCT3), a low-affinity,
but high-capacity transporter of monoamines, plays a critical role in 5-HT clearance as well. Though circuits
modulating arousal and emotion are highly complex, processing within the basolateral amygdala (BLA) is
considered essential, especially for fear conditioning. The BLA receives dense input from 5-HT neurons in dorsal
raphe nucleus (DRN), and BLA principal neurons have numerous fear-regulatory outputs, including dense
projections to medial entorhinal cortex (mEC), which serves as a gateway for fear memory information flow into
and out of hippocampus. Like SERT, OCT3 is highly expressed in BLA, ideally positioning these transporters to
powerfully control extracellular 5-HT and its local neuro-modulatory efficacy. Proposed studies test the hypothesis
that 5-HT clearance by OCT3 and SERT in BLA facilitates acquisition and consolidation of fear memory by buffering
the rise of 5-HT that normally restrains BLA-mEC neuronal activation by excitatory fear memory-promoting limbic
inputs. We posit that fear conditioning stimuli, which lead to fear memory, co-activate limbic and DRN 5-HT inputs
to BLA along with activating the hypothalamic-pituitary-adrenal stress axis. OCT3 is potently inhibited by
corticosterone, indicating that diminished OCT3 clearance allows 5-HT to rise high enough during fear conditioning
to activate 5-HT receptors and effectively buffer limbic excitation of BLA-mEC neurons, decreasing their output and
reducing fear memory. We will use state-of-the-art conditional gene deletion strategies to separately and
collectively deplete SERT and OCT3 from DRN neurons, combined with optogenetic activation and inhibition of
DRN 5-HT neurons projecting directly to BLA. AAV shRNA will be used to knockdown SERT and/or OCT3 on all
cell types in BLA. These approaches will be used to determine the relative contributions of SERT and OCT3 to 1)
5-HT clearance in BLA in vivo using high-speed chronoamperometry; 2) 5-HT modulation of BLA-mEC neuronal
activity using in vivo single neuron and whole-cell patch clamp recording in brain slices; 3) fear conditioning
behavior. Because of their important roles in fear conditioning and 5-HT signaling in BLA, we will interrogate the
functional contributions of 5-HT2A and 5-HT1A receptors in this circuit. Serotonergic neurotransmission potently
modulates behavior, and its dysregulation is strongly implicated in psychiatric diseases. Proposed, discovery
driven, studies will provide unprecedented mechanistic insights into the role 5-HT, and its regulation by SERT an...

## Key facts

- **NIH application ID:** 10489359
- **Project number:** 5R01MH093320-09
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** LYNETTE C DAWS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $731,502
- **Award type:** 5
- **Project period:** 2012-03-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489359

## Citation

> US National Institutes of Health, RePORTER application 10489359, Role of the serotonin transporter and organic cation transporter 3 in serotonergic modulation of emotion-regulating circuitry (5R01MH093320-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10489359. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*