Abstract
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.