# Investigating the mechanistic contribution of Cav1.2 channels in extinction of cocaine-associated memories

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $519,447

## Abstract

Project Summary
Cocaine addiction exerts a high cost on society and individuals and to date no pharmacotherapies exist.
Behavioral therapies are not effective at preventing relapse; indeed, 70-80% of cocaine users will experience
relapse following therapy. Preventing relapse to cocaine use represents the primary challenge that exists for
the treatment of cocaine dependent individuals. One of the many factors that contribute to relapse is the
exceptionally strong associations that drugs of abuse, such as cocaine make between environmental contexts
and the rewarding properties of the drug. Thus, understanding the neural mechanisms that are responsible for
these drug-context associations and ways in which we can override them, is critical for the development of
improved treatment options. The dorsal hippocampus (dHPC), well known for its role in learning and memory,
is an important anatomical region involved in cocaine-context associations. Despite this knowledge, the role of
this brain region in cocaine addiction remains understudied. Work from our laboratory has identified a novel role
for the Cav1.2 L-type Ca2+ channel (LTCC) in the dHPC in extinction of cocaine-associated contextual memories,
consistent with their well-known role in hippocampal-dependent synaptic plasticity underlying certain forms of
learning/memory. Extinction learning involves a new form of learning that is capable of overriding original
memories, particularly maladaptive memories. Thus Cav1.2 channels serve as a promising candidate for
overriding drug-context associations. Using the cocaine conditioned place preference (CPP), a preclinical model
used to study cocaine-associated contextual memories, we find that extinction of cocaine CPP increases
synaptic levels of Cav1.2 and its phosphorylated form in the dorsal dentate gyrus (dDG), a hippocampal
subregion, in a dopamine D1 receptor cell type-dependent manner. This is consistent with growing evidence for
a role of dHPC dopamine for learning/memory mechanisms including cocaine contextual memories. Our
molecular studies have identified that extinction increases key signaling molecules in the dDG. These include
AKAP150 anchoring protein, PKA, NFATc3 and the GluA1 subunit of AMPA receptors. Thus, in this application
we aim to capitalize on this knowledge to further explore dDG Cav1.2 channel mechanisms in extinction of
cocaine-associated memories. We will test the central hypothesis that contextual extinction learning recruits
Cav1.2 channel mechanisms at dDG synapses via recruiting dopamine D1R signaling. We will use a combination
of genetic, pharmacological, electrophysiological, and in vivo calcium imaging techniques with behavioral testing
for the proposed studies. Aim 1 will test the involvement of AKAP-PKA-Cav1.2 signaling. Aim 2 will address the
involvement of AKAP-CaN-NFAT signaling and Aim 3 will examine the contribution of D1R signaling, in cocaine
CPP extinction and dDG cell activity.

## Key facts

- **NIH application ID:** 11011395
- **Project number:** 7R01DA053261-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Anjali M Rajadhyaksha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $519,447
- **Award type:** 7
- **Project period:** 2020-07-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11011395

## Citation

> US National Institutes of Health, RePORTER application 11011395, Investigating the mechanistic contribution of Cav1.2 channels in extinction of cocaine-associated memories (7R01DA053261-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11011395. Licensed CC0.

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