# Neuropharmacology Component - Martin-Fardon

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $222,125

## Abstract

Relapse vulnerability is a challenge for the successful treatment of alcohol use disorder (AUD), making relapse
prevention a central focus of treatment and medication development efforts. Stress is a major factor that
contributes to the chronic relapsing and compulsive nature of drug addiction. The hypocretin (Hcrt; orexin)
system regulates physiological processes including feeding, energy metabolism, arousal, and stress, and is
recruited by alcohol. Hypocretin neurons are only located in the hypothalamus (HYP) that includes the lateral
HYP (LH), dorsomedial HYP (DMH), and perifornical area (PFA) and project to major components of
neurocircuitry that mediates drug seeking including the medial prefrontal cortex (mPFC). Chronic drug use
dysregulates stress responses that are mediated by corticotropin-releasing factor (CRF) in both the
hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress areas outside the HPA axis (e.g.,
central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]). An Hcrt/CRF interaction
exists that could participate in chronic relapsing and negative affective states that characterize drug addiction.
Dynorphin (Dyn) promotes depressive-like behavior and mediates the aversive effects of stress via k opioid
receptors (KORs) signaling. Even though Hcrt and Dyn are co-localized and co-released, in the ventral tegmental
area (VTA) and the paraventricular nucleus of the thalamus (PVT), they play opposing roles in the mediation of
drug-directed behavior. The Martin-Fardon component will test whether Hcrt/CRF and Hcrt/Dyn interaction in the
infralimbic cortex (IL) -- a subregion of the mPFC that exerts inhibitory control over alcohol seeking and shows
long-term deficits in rats following a history of alcohol dependence -- changes following dependence and whether
these systems are pivotal in stress-induced reinstatement of alcohol-seeking behavior in male and female rats
at late (2 weeks) abstinence. This will be achieved by (1) exploring whether the Hcrt/CRF and Hcrt/Dyn
interactions in the IL mediate stress-induced reinstatement of alcohol-seeking behavior in alcohol-dependent
animals during abstinence; (2) establishing whether the IL Hcrt-r/CRF1/KOR signaling in the IL is upregulated
due to alcohol-dependence during abstinence; and (3) confirming the importance of the HYP(Hcrt)®IL circuit
during stress-induced reinstatement of alcohol-seeking behavior using an inhibitory Designer Receptor
Exclusively Activated by Designer Drugs construct selective for Orx cells in Orx-Cre rats. This project will provide
insights into the involvement of the IL Hcrt-r/CRF1/KOR signaling during pathological (alcohol-seeking) behavior
and may identify novel targets for alcohol craving and relapse prevention.

## Key facts

- **NIH application ID:** 10526267
- **Project number:** 2P60AA006420-40
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Remi Martin-Fardon
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $222,125
- **Award type:** 2
- **Project period:** 1983-12-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526267

## Citation

> US National Institutes of Health, RePORTER application 10526267, Neuropharmacology Component - Martin-Fardon (2P60AA006420-40). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10526267. Licensed CC0.

---

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