Thiamine Mitigates Nicotine Withdrawal Effects in Adolescent Male Rats: Modulation of Serotonin Metabolism, BDNF, Oxidative Stress, and Neuroinflammation.

Adolescent nicotine use is particularly concerning due to increased susceptibility to long-term effects and dependence during this critical developmental period. This study investigates the therapeutic effects of thiamine on nicotine withdrawal-induced anxiety, anhedonia, and depression in rats. Adolescent rats received nicotine (2 mg/kg, s.c.) for 21 days, followed by 21 days of withdrawal. Thiamine (25 mg/kg or 50 mg/kg, i.p.) was administered during exposure and withdrawal. Behavioral assessments were used to evaluate anxiety- and depressive-like symptoms, and biochemical analyses measured oxidative stress markers, serotonin levels, MAO activity, BDNF, and GFAP as indicators of neuroinflammation in the prefrontal cortex (PFC). Nicotine withdrawal significantly elevated anxiety-, depression-, and anhedonia-like behaviors, increased oxidative stress, and upregulated MAO-A activity and GFAP expression, indicating neuroinflammatory effects. Notably, thiamine administration during both nicotine exposure and withdrawal effectively alleviated these behavioral impairments, restored serotonin levels, reduced oxidative stress markers, and mitigated the increase in GFAP expression. Additionally, thiamine alone has been shown to alleviate anxiety- and depressive-like behaviors. This study highlights thiamine's potential as a promising intervention for managing psychological distress associated with nicotine withdrawal. Given the high prevalence of adolescent nicotine use and its associated mental health challenges, further research on thiamine's mechanisms and therapeutic potential is warranted to improve treatment strategies during this critical developmental stage.Significance Statement Nicotine dependence remains a global health challenge, with withdrawal symptoms posing a significant barrier to cessation efforts, particularly in adolescents. This study explores the neuroprotective potential of thiamine in mitigating nicotine withdrawal in adolescent male rats by modulating key neurochemical pathways. Thiamine treatment was found to attenuate withdrawal-associated behavioral disturbances, while also restoring serotonin metabolism, upregulating brain-derived neurotrophic factor (BDNF), and reducing oxidative stress and neuroinflammation. These findings highlight thiamine's multifaceted role in alleviating nicotine withdrawal by addressing both neurochemical and inflammatory imbalances. This study suggests that thiamine could serve as an adjunct therapeutic approach for nicotine dependence, with implications for improving cessation outcomes during adolescence-a critical period for brain development and vulnerability to dependence.