Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

•Slc6a8−/y mice have increased striatal, hippocampal 5-hydroxyindoleacetic acid and hippocampal tryptophan hydroxylase and monoamine oxidase.•Slc6a8−/y mice and female mice heterozygous for Slc6a8 (Slc6a8+/−) mice are resilient to learned helplessness induction.•Minor alterations in anxiety-like and native-depression-like measures were discovered in Slc6a8−/y and Slc6a8+/− mice.•The results of this study suggest that creatine plays a role in serotonin metabolism, which may manifest as changes in induced depressive-like behaviors. Approximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8−/y) and female mice heterozygous for Crt expression (Slc6a8+/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8−/y and Slc6a8+/- mice had faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Slc6a8−/y had decrease latency to immobility in the tail-suspension test and Slc6a8+/- had increased open entries in elevated zero maze, but all other variables matched those of wildtype mice, however. Slc6a8−/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while 5-HT levels are unchanged. This indicates an alteration to the 5-HTergic system in Cr deficient mice. Our results indicate that Cr plays a complex role in affective disorders and 5-HT, warranting further investigation.