Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity

Yael Toren, Yarden Ziv, Shlomo Sragovich, R. Anne McKinney, Segev Barak, Shula Shazman, Illana Gozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cocaine use disorder (CUD) is a chronic neuropsychiatric disorder estimated to effect 1–3% of the population. Activity-dependent neuroprotective protein (ADNP) is essential for brain development and functioning, shown to be protective in fetal alcohol syndrome and to regulate alcohol consumption in adult mice. The goal of this study was to characterize the role of ADNP, and its active peptide NAP (NAPVSIPQ), which is also known as davunetide (investigational drug) in mediating cocaine-induced neuroadaptations. Real time PCR was used to test levels of Adnp and Adnp2 in the nucleus accumbens (NAc), ventral tegmental area (VTA), and dorsal hippocampus (DH) of cocaine-treated mice (15 mg/kg). Adnp heterozygous (Adnp+/−)and wild-type (Adnp+/−) mice were further tagged with excitatory neuronal membrane-expressing green fluorescent protein (GFP) that allowed for in vivo synaptic quantification. The mice were treated with cocaine (5 injections; 15 mg/kg once every other day) with or without NAP daily injections (0.4 µg/0.1 ml) and sacrificed following the last treatment. We analyzed hippocampal CA1 pyramidal cells from 3D confocal images using the Imaris x64.8.1.2 (Oxford Instruments) software to measure changes in dendritic spine density and morphology. In silico ADNP/NAP/cocaine structural modeling was performed as before. Cocaine decreased Adnp and Adnp2 expression 2 h after injection in the NAc and VTA of male mice, with mRNA levels returning to baseline levels after 24 h. Cocaine further reduced hippocampal spine density, particularly synaptically weaker immature thin and stubby spines, in male Adnp+/+) mice while increasing synaptically stronger mature (mushroom) spines in Adnp+/−) male mice and thin and stubby spines in females. Lastly, we showed that cocaine interacts with ADNP on a zinc finger domain identical to ketamine and adjacent to a NAP-zinc finger interaction site. Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD.

Original languageEnglish
Article number76
JournalJournal of Molecular Neuroscience
Volume74
Issue number3
DOIs
StatePublished - Sep 2024

Funding

FundersFunder number
Anne and Alex Cohen
Naomi Foundation
Eldee Foundation
Marie Skłodowska-Curie TClock4AD
Sagol School of Neuroscience, Tel Aviv University
Ministry of Science and Technology, Israel
Elton Laboratory for Molecular Neuroendocrinology
Miriam and Sheldon G. Adelson Graduate School, Faculty of Medical and Health Sciences
Exonavis Therapeutics Ltd
Tel Aviv University
European Research Council
AAMN Foundation101072895

    Keywords

    • Addiction
    • ADNP
    • Cocaine
    • NAP
    • Sex differences
    • Structural plasticity

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