# Midbrain neural circuit mechanisms underlying addiction

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2022 · —

## Abstract

PROJECT SUMMARY
The opioid crisis has enormous consequences on the health and well-being of Veterans and their communities.
Opioid addiction is propelled by opioid-induced changes in brain circuits that control behavioral responses to
rewarding and aversive stimuli, and neuromodulatory therapies that reverse opioid-induced changes in these
circuits are sorely needed. The mesolimbic dopamine (DA) projection from ventral tegmental area (VTA) to
nucleus accumbens (NAc) is often described as the brain's reward circuit, and indeed much evidence points to
a central role for this projection in processes underlying behavioral reinforcement. But what controls activity of
VTA DA neurons? And where does NAc send signals that have been modulated by released DA? An answer
to both those questions is: the ventral pallidum (VP). Yet much less is known about VP. For example, it has
only recently become appreciated that VP contains heterogeneous populations of excitatory and inhibitory
projection neurons that regulate approach and avoidance behaviors in opposite directions. Further, Mu-opioid
receptors (MOR) mediate both the analgesic and addictive effects of abused opioid drugs, the VP is a MOR
hotspot, and MOR activation in VP can profoundly change behavior. Thus, we know that VP can potently
modulate approach and avoidance behaviors and that opioids can potently modulate VP. Yet we know
remarkably little about how VP cell types are connected to NAc and VTA cell types, how VP cell types and
synapses are modulated by MORs, or how opioid-induced plasticity in VP cell types and synapses modify
approach and avoidance behaviors that are perturbed in opioid dependence and withdrawal. This proposal will
systematically attack this knowledge gap using mouse genetics and both ex vivo and in vivo anatomical,
physiological and behavioral approaches to: i) characterize the cell types and synapses in VP that express
MOR, ii) define how VP cell types are connected to afferent NAc and efferent VTA cell types, iii) identify how
MOR activation modulates the function of these cell types and synapses, and iv) describe how their function is
perturbed in opioid dependence and withdrawal.

## Key facts

- **NIH application ID:** 10471102
- **Project number:** 1I01BX005782-01A1
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Thomas Hnasko
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471102

## Citation

> US National Institutes of Health, RePORTER application 10471102, Midbrain neural circuit mechanisms underlying addiction (1I01BX005782-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10471102. Licensed CC0.

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