# Corticostriatal-hypothalamic circuits and opioid seeking

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2023 · $14,603

## Abstract

PROJECT SUMMARY
Opioid use disorder (OUD) is characterized by excessive motivational drive to seek drugs and/or a loss of
inhibitory top-down control of drug seeking, resulting in relapse and recurrent drug seeking. Preliminary data
from our lab show two opposing circuits originating from the infralimbic (IL) cortex, one that ‘drives’ heroin
seeking behavior and one that ‘limits’ heroin seeking behavior. These ‘driver’ and ‘limiter’ pathways project from
the IL to subcortical reward and motivational hubs, such as the nucleus accumbens shell (NAsh) and the lateral
hypothalamus (LH). Our lab has shown that the ILLH circuit drives heroin seeking and relapse, while the
ILNAsh pathway limits heroin seeking. The functional downstream outputs of the ILNAsh limiter pathway
are, however, currently unknown. The LH is well characterized as a driver of motivated behavior, and the
GABAergic inhibitory projection from the NAshLH projection has been implicated in the suppression of drug
seeking behavior after extinction, suggesting inhibition of the LH is a mechanism for decreasing drug
seeking. In Aim 1, I will investigate the NAshLH pathway as a potential limiter of heroin seeking, using
chemogenetic manipulations to alter activity in this circuit and measure behavioral outcomes on drug seeking in
a preclinical model of OUD. I propose that this pathway is an extension of the previously identified ILNAsh
limiter pathway, involving an ensemble of neurons in the NAsh that both receive input from the IL and project
to the LH. I hypothesize this unique neuronal population will ultimately be responsible for limiting heroin-seeking
behavior. The disynaptic ILNAshLH limiter pathway interposes a GABAergic relay between the IL and LH,
providing a potential mechanism by which the limiter pathway function is actualized. Thus, it is possible that the
disynaptic ILNAshLH limiter circuit and the ILLH driver circuit converge on the LH, where the inhibitory
projection from the NAsh may compete with the excitatory projection from the IL to control heroin seeking.
Preliminary data from the Peters lab has shown that LH orexin neuron number correlates with metrics of heroin
motivation, and systemic blockade of orexin receptors with a dual orexin receptor antagonist (DORA) decreases
heroin relapse, strongly implicating the LH orexin neuron population in controlling heroin-seeking
behaviors. Further, these LH orexin neurons project to the IL cortex, and blockade of orexin receptors within
the IL cortex dampens motivated behaviors. In Aim 2, I will use chemogenetics to determine whether the LHIL
pathway drives drug seeking. I will then determine whether intra-IL orexin receptor activation is required for
heroin seeking, using brain-site specific pharmacology. If indeed the limiter and driver pathways are competing
within the LH, this orexinergic feedback to the IL cortex might be expected to strengthen the driver, leading
to an imbalance in heroin seeking. The proposed e...

## Key facts

- **NIH application ID:** 10750717
- **Project number:** 1F31DA059203-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Robin D Vareed
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $14,603
- **Award type:** 1
- **Project period:** 2023-09-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750717

## Citation

> US National Institutes of Health, RePORTER application 10750717, Corticostriatal-hypothalamic circuits and opioid seeking (1F31DA059203-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10750717. Licensed CC0.

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