Effect of Lithium Treatment on Homocysteic acid‐induced Manic/Depressive Behaviors in Sprague‐Dawley Rats
Authors: Felton Ryann , Goodman Ethan , Bierema Rebekah , Muloma Kathleen , Royer Jada , Wiles Lucas , Carrara Sarah , Berlin Julia , Barney Christopher C. , Chase Leah 
Published: November 2023

Bipolar disorder is a mood disorder for which the development of new treatments has been hindered by the lack of a reliable animal model. Previous studies in our lab have shown that daily injection of early postnatal rat pups (P3–P21) with homocysteic acid (HCA), a homocysteine metabolite, leads to a mixed manic/depressive phenotype that is observed after day 60. These results suggest that early HCA exposure may serve as a good model for bipolar disorder. To test the predictive validity of this model, we sought to determine if treatment of HCA‐exposed animals to lithium was effective in reducing the mixed manic/depressive behaviors observed in these rats. To test this hypothesis, we injected 20 female and 20 male rats with HCA or saline from P3–P21. The animals were then assessed for manic and depressive behaviors using saccharine preference, elevated plus maze, Morris water maze, forced swim and social interaction testing beginning at P60. As expected, we observed depressive behaviors in the HCA‐treated rats, specifically exhibited by reduced saccharine preference and reduced social interaction. We also observed a HCA‐induced increase in manic‐like behavior as evidenced by increased time spent in the open arms in the elevated plus. Finally, we observed that HCA‐treated rats exhibited reduced spatial learning in the Morris water maze. Following this initial behavior assessment, all rats were placed on a diet containing 2 g of lithium carbonate/kg rat chow. After 10 days, the behavior assessment was repeated. As predicted, lithium treatment resulted in diminished manic‐like behaviors in the HCA‐treated rats and restored spatial learning in the Morris water maze of female, HCA‐treated rats. Lithium also increased saccharine preference in female, HCA‐treated animals and social activity in male, HCA‐treated animals. Lithium also caused a reduction in saccharine preference and social behavior in the saline‐treated rats. Finally, to determine if the effects of lithium were reversible, we removed the lithium from the rats' diet for ten days and repeated the behavioral assessment for a third time. Removal of lithium resulted in the re‐establishment of manic behavior in the elevated plus maze and a reduction of spatial learning in HCA‐treated rats. However, the effects of lithium on the depression‐associated behaviors of HCA‐treated animals were not reversed, and all animals exhibited a strong increase saccharine preference and social behavior compared to when they were fed lithium. Thus, our results suggest that lithium is effective in treating the manic behavior, spatial learning deficits, anhedonia and reduced social interaction elicited by HCA as hypothesized. However, the effects of lithium on the HCA‐induced depressive behaviors appeared to persist after lithium treatment ended. Collectively, these data provide further evidence that early postnatal exposure to HCA may serve as model for the mixed manic/depressive phenotype associated with bipolar disorder.Support or Funding InformationThis project was funded by the Neuroscience Program at Hope College.