Sex-specific effects of chronic caffeine on impulsive choice and serotonergic markers in an ADHD rat model

RATIONALE: Caffeine had been proposed as an adjuvant therapy for Attention Deficit and Hyperactivity Disorder (ADHD). Although caffeine can ameliorate some ADHD-related behaviors, its effects on impulsivity (more prevalent in boys) and potential sex differences, remains unclear. OBJECTIVES: To assess sex differences in responsiveness to chronic caffeine on impulsive choice, brain cell composition and serotonergic markers in an ADHD rat model. METHODS: Male and female Spontaneously Hypertensive Rats (SHR, ADHD model) and Wistar-Kyoto rats (WKY, control strain) received caffeine (0.3 g/L in drinking water) from postnatal day (PND) 15. Impulsive-like behavior was assessed with delayed discounting task (DDT) from PND 28-56. In frontal cortex and hippocampus, we quantified 5-HT2A and 5-HT1B serotonin receptors, the serotonin transport (SERT) and neuronal and non-neuronal nuclei. RESULTS: In SHR of both sexes, caffeine reduced trials needed to reach criterion in the DDT. Effects on impulsive choice were sex dependent in SHR: caffeine increased choices of the large, delayed reward (reducing impulsive-like behavior) in males, but decreased such choices (promoting impulsive-like behavior) in females. In female SHR, caffeine increased the proportion of non-neuronal nuclei in frontal cortex and hippocampus. In the hippocampus of both sexes, caffeine lowered 5-HT2A receptor and SERT levels; females showed lower 5-HT2A than males. Effects in WKY were minimal. CONCLUSIONS: Chronic caffeine exerts sex-specific behavioral and cellular effects in an ADHD model and modulates hippocampal serotonergic markers. These findings underscore the need to consider sex in caffeine-based adjunctive strategies for ADHD and motivate mechanistic studies to explain divergent responses.