# Circuitry Progression of Cocaine-induced Cellular Adaptation

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $195,625

## Abstract

Abstract
Drug addiction has been conceptualized as the endpoint of cascades of transitions from initial voluntary and
limited drug use to habitual and escalated drug use, and eventually to compulsive use. Results from brain
region-specific studies lead to a prominent hypothesis that the initial cocaine use is primarily motivated by the
nucleus accumbens (NAc)-based reinforcing effects, and transitions to more persistent or habitual drug use by
recruiting the dorsal striatum (DS), resulting in escalated cocaine use and resistance to extinction. While the
behavioral transition from limited to escalated cocaine use has been observed in both humans and rodent
models, the key cocaine-induced cellular adaptations that progress from the NAc to DS to promote this
behavioral transition remain underexplored. Targeting this knowledge gap, we focus on the intrinsic membrane
excitability (IME) of NAc and DS medium spiny neurons (MSNs). IME determines the ability of neurons to fire
action potentials in response to excitatory inputs, and thus directly determines the output of the neurons.
Previous results demonstrate a critical IME adaptation—cocaine experience decreases IME of NAc MSNs, and
this cocaine-induced IME adaptation in the NAc contributes to psychomotor effects of cocaine, cocaine
withdrawal-associated general hypoactive state of the NAc, and cocaine seeking after drug withdrawal. The
preliminary results show that during a short-term (5d) cocaine self-administration procedure, mice exhibited
limited cocaine taking, and this cocaine procedure only induced the IME adaptation in NAc MSNs, but not DS
MSNs. After prolonged (21d) cocaine self-administration, mice exhibited escalated cocaine taking, and the IME
adaptation was observed in both NAc and medial/dorsal DS MSNs. Thus, cocaine-induced IME adaptation
progresses from the NAc to DS after prolonged cocaine self-administration, correlated to escalated cocaine
taking. Furthermore, experimentally preventing cocaine-induced IME adaptation in NAc MSNs prevented the
progression of IME adaptation to DS MSNs during prolonged cocaine self-administration, suggesting a critical
informational flow from the NAc to DS. This application will explore the anatomical basis mediating the NAc-to-
DS progression of cocaine-induced IME adaptation and the behavioral consequence of this progression. The
central hypothesis is that the NAc-to-DS progression of cocaine-induced IME adaptation after prolonged
cocaine self-administration is mediated, in part, by the striatonigrostriatal ascending spiral, a circuit complex
connecting the NAc and DS through reciprocal projections with the ventral tegmental area and substantia
nigra, and this NAc-to-DS progression of cocaine-induced IME adaptation promotes the behavioral transition
from limited to escalated cocaine use. The proposed experiments will characterize a critical form of cocaine-
induced cellular adaptation that progresses from the NAc to DS after prolonged cocaine self-adm...

## Key facts

- **NIH application ID:** 9982846
- **Project number:** 5R21DA047861-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yan Dong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982846

## Citation

> US National Institutes of Health, RePORTER application 9982846, Circuitry Progression of Cocaine-induced Cellular Adaptation (5R21DA047861-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982846. Licensed CC0.

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