# Cocaine-induced axon migration in the nucleus accumbens

> **NIH NIH R21** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $195,000

## Abstract

Summary
It is now well established that repeated cocaine exposure results in persistent increases in spine density in
nucleus accumbens GABAergic medium spiny neurons (MSNs), which account for over 90% of neurons in the
accumbens). A critical unanswered question is whether these new spines form functional synapses. Our
preliminary data suggest that this may indeed be the case as cocaine self-administration induces lasting
increases in systems that influence axon guidance in both the nucleus accumbens and VTA. Thus, following
prolonged abstinence after cocaine self-administration there are increases in the Slit-Robo system, which
repels axon guidance, and Netrin-DSCAM, which promotes axon extension, in the nucleus accumbens. The
fact that the Slit-Robo and Netrin-1-DSCAM systems produce opposing effects on axon extension suggests
differential cocaine-induced synaptogenesis in accumbens MSNs, which are divided into two categories: D1- or
D2-dopamine receptor expressing. Repeated cocaine produces opposing effects in these classes of neurons
such that transmission through D1 dopamine receptor (D1DR)-expressing MSNs is favored. Therefore, our
over-arching hypothesis is that cocaine self-administration increases dopamine synaptogenesis in D1DR-
containing MSNs (through Netrin-DSCAM), while the formation of new dopamine synapses in MSNs
expressing D2 dopamine receptors (D2DRs) is suppressed via Slit-Robo.
In Specific Aim 1 we will assess cocaine-induced changes in Robo2 and DSCAM mRNA specifically in
dopaminergic neurons in the VTA. Similarly, cocaine-mediated alterations in Slit2 and Netrin-1 mRNA will be
assessed selectively in D1DR- and D2DR-expressing MSNs in the nucleus accumbens (core and shell
subregions). Accumbens core and shell protein levels also will be assessed for Robo2 and DSCAM in
dopaminergic terminals as well as Slit2 and Netrin-1 protein levels in D1DR- and D2DR-expressing MSNs. We
also will determine the functional effect of Netrin-1 knockdown in the accumbens, which we expect to reverse
the incubation of craving (i.e. the time-dependent increase in cocaine cue-evoked drug seeking).
Specific Aim 2 focuses on synapse formation in the nucleus accumbens after cocaine self-administration and
an extended period of forced abstinence using the new mGRASP technique. We predict cocaine-induced
synapse formation selectively in dopaminergic projections to D1DR-expressing MSNs in the nucleus
accumbens.

## Key facts

- **NIH application ID:** 10148155
- **Project number:** 7R21DA046760-02
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Robert Christopher Pierce
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,000
- **Award type:** 7
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148155

## Citation

> US National Institutes of Health, RePORTER application 10148155, Cocaine-induced axon migration in the nucleus accumbens (7R21DA046760-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148155. Licensed CC0.

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