# Transgenerational inheritance of a Cocaine resistance phenotype

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2021 · $477,424

## Abstract

The focus of this research program is the influence of paternal cocaine taking on the physiology and behavior
of subsequent generations (i.e. offspring and grandoffspring). Human epidemiological data indicates that
cocaine addiction is often accompanied by cognitive decline including episodic memory impairments. Our
working hypothesis is that paternal cocaine exposure elicits learning and synaptic plasticity impairments in
male offspring and grandoffspring by reducing D-serine levels/NMDA receptor signaling in the hippocampus. In
Specific Aim 1, learning and memory as well as long term potentiation (LTP), a generally accepted
physiological learning correlate, will be assessed in the offspring of sires that self-administered cocaine.
Preliminary findings from object-based memory assays indicate that male, but not female, offspring and
grandoffspring of cocaine-exposed sires have impaired hippocampus-dependent object location memory.
Paternal cocaine exposure also impairs hippocampal LTP in male offspring. In Specific Aim 2 we will evaluate
the hypothesis that these learning and synaptic plasticity deficits in the adult descendants of cocaine-
experienced sires are due to decreased dorsal hippocampal D-serine/NMDA receptor signaling, which are
critically involved in spatial learning and synaptic plasticity. Preliminary data indicate that D-serine levels are
decreased in the dorsal hippocampus of cocaine-sired male rats. The enzyme D-amino acid oxidase (DAAO)
catalyzes the oxidative deamination of D-serine. Preliminary data indicate that daao1 mRNA levels are
increased in the dorsal hippocampus of cocaine-sired male rats. To examine potential epigenetic mechanisms
underlying the increase in daao1 mRNA, histone posttranslational modifications associated with daao1 will be
examined in F1 and F2 generations. Finally, D-serine, D-cycloserine or a DAAO inhibitor will be administered
into the dorsal hippocampus or onto hippocampal slices of cocaine-sired or cocaine-grandsired rats, which we
predict will rescue spatial learning and plasticity deficits. In Specific Aim 3 we will evaluate how information is
transferred between generations by assessing miRNA changes in the sperm of cocaine-experienced sires and
their offspring. Preliminary data indicate that cocaine self-administration significantly altered four miRNAs (miR-
1-3p, miR-206-3p, miR-1b, miR-362-3p) in sire sperm. In order to determine if the CNS is required for the
effect of cocaine on sperm miRNAs we will compare self-administered cocaine to yoked cocaine methiodide,
which does not cross the blood-brain barrier. We also will assess the duration of cocaine-induced changes in
sperm by evaluating miRNAs 1 or 90 days following cocaine self-administration. Collectively, these
experiments will determine changes in hippocampal function in the descendants of cocaine-experienced sires
that contribute to learning deficits in these animals. We also will examine cocaine-induced changes in sperm
that may ca...

## Key facts

- **NIH application ID:** 10183208
- **Project number:** 5R01DA033641-10
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Robert Christopher Pierce
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,424
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183208

## Citation

> US National Institutes of Health, RePORTER application 10183208, Transgenerational inheritance of a Cocaine resistance phenotype (5R01DA033641-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183208. Licensed CC0.

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