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Reversibility of dopamine receptor antagonist-induced hyperprolactinemia and associated histological changes in Tg
Gopala Krishna1, Shivaputhrappa Ganiger2, Kamala Kannan2
1Supernus Pharmaceuticals Inc., Rockville, MD 20850, United States.
Abstract:
The purpose of this study was to better understand the biological effects of increased prolactin levels induced in mice by dopamine D2 receptor antagonist molindone treatment. Toxicokinetics, prolactin levels, and reproductive tissue histology were evaluated in Tg rasH2 wild-type mice treated orally with molindone at 0, 5, 15, and 50mg/kg/day for 6 months, followed by a 2-month posttreatment recovery period. A greater than dose-proportional increase in molindone exposure ([AUC]0‒24) was observed on Day 180 for both sexes. Statistically significant (P<0.01) increases in prolactin levels were observed in most treatment groups compared with controls at 0.5h postdose on Days 1 and 180. Prolactin levels returned to baseline levels during the recovery period. Microscopic changes attributable to hyperprolactinemia, including corpora lutea enlargement and interstitial cell atrophy in the ovaries, and atrophy of the uterus and vagina were observed on Day 180. These changes were reversed during the recovery period in the 5- and 15-mg/kg/day treatment groups. Mice receiving molindone at 50mg/kg/day also showed signs of reversal on histologic examination.
Insights
Molindone treatment in mice significantly increased prolactin levels and caused temporary reproductive tissue changes. These effects, including hyperprolactinemia, reversed after molindone cessation, indicating potential reversibility of drug-induced endocrine disruption.
Area of Science:
- Endocrinology
- Toxicology
- Reproductive Biology
Background:
- Dopamine D2 receptor antagonists can elevate prolactin levels.
- Understanding the biological effects of hyperprolactinemia is crucial for drug safety assessment.
Purpose of the Study:
- To investigate the biological effects of molindone-induced hyperprolactinemia in mice.
- To evaluate the toxicokinetics, prolactin levels, and reproductive tissue histology following chronic molindone administration.
Main Methods:
- Tg rasH2 wild-type mice were orally administered molindone (0, 5, 15, 50 mg/kg/day) for 6 months.
- Toxicokinetics, prolactin levels, and reproductive organ histology were assessed during treatment and a 2-month recovery period.
Main Results:
- Molindone exposure increased with dose and was greater than dose-proportional.
- Significant prolactin level increases were observed post-treatment, returning to baseline during recovery.
- Histological changes in reproductive tissues (ovaries, uterus, vagina) due to hyperprolactinemia were noted and largely reversed post-treatment.
Conclusions:
- Molindone induces dose-dependent hyperprolactinemia and associated reproductive tissue alterations in mice.
- These drug-induced changes are reversible upon cessation of molindone treatment.
- The study highlights the importance of monitoring prolactin levels and reproductive health during dopamine D2 antagonist therapy.
