Estradiol regulates L‐type calcium channel‐dependent social behavior deficits during cocaine abstinence in female rats

Abstract Social withdrawal during cocaine abstinence is a significant predictor of relapse, yet the neuroendocrine mechanisms underlying this vulnerability remain poorly understood, particularly in females. Estradiol, a potent neuromodulator of mesocorticolimbic circuitry, regulates dopamine‐dependent processes that encode social motivation. L‐type calcium channels (LTCCs) similarly regulate neuronal excitability and plasticity in corticolimbic regions implicated in addiction and affective regulation, and estradiol interacts with LTCC signaling through both membrane‐initiated and transcriptional mechanisms. However, whether estradiol and LTCCs functionally converge to regulate social behavior during cocaine abstinence is unknown. Here, we used a preclinical behavioral pharmacology approach to examine this interaction in female Sprague–Dawley rats. Ovariectomized (OVX) rats with or without 17β‐estradiol replacement underwent jugular catheterization and self‐administered cocaine (0.5 mg/kg/inf, FR1) or saline for 10 days, followed by 17 days of forced abstinence. Social preference was assessed using a three‐chamber social interaction test, with systemic isradipine (1.2 mg/kg, i.p.) administered 15 min prior to testing. Cocaine abstinence significantly reduced social preference in intact females. LTCC blockade with isradipine restored social preference, but this effect was dependent on ovarian hormone status: isradipine normalized social behavior in sham‐operated and OVX + E2 rats but not in OVX rats lacking estradiol. Multiple linear regression confirmed that ovarian hormone status and isradipine treatment, but not total cocaine intake, significantly predicted social preference, with a robust hormone × isradipine interaction explaining 44.6% of behavioral variance. These findings demonstrate that estradiol does not simply protect against abstinence‐related social deficits but rather biases neural signaling such that social behavior becomes sensitive to LTCC‐dependent mechanisms. This work identifies a functional estradiol–LTCC interaction regulating social motivation during cocaine abstinence and highlights the importance of hormonal state in shaping sex‐specific addiction vulnerability.