Chronic stress persistently upregulates hippocampal histamine H1 and H2 receptors: dissociation from behavioral recovery with fluoxetine and exercise

Chronic stress induces neurobiological alterations within limbic circuits. The contribution of hippocampal histaminergic signaling to stress-related behavioral dysfunction remains insufficiently characterized. This study examined the comparative and combined effects of fluoxetine and treadmill exercise on anxiety- and depression-like behaviors and ventral hippocampal histamine H1 and H2 receptor expression in a chronic unpredictable mild stress (CUMS) rat model. Male Wistar rats were exposed to four weeks of CUMS and allocated to seven groups: Control, CUMS, Exercise (EXC), Fluoxetine (FLX), CUMS+EXC, CUMS+FLX, and CUMS+FLX+EXC. Anxiety-like behavior was assessed using the elevated plus maze (EPM) and open field test (OFT), while depressive-like behavior was evaluated using the forced swim test (FST). Hippocampal H1 and H2 receptor mRNA levels were quantified by real-time PCR. CUMS induced significant anxiety- and depression-like behaviors, evidenced by reduced central zone exploration and increased FST immobility. Fluoxetine significantly attenuated depressive-like behavior, while combined fluoxetine and exercise increased open-arm exploration in the EPM. CUMS significantly upregulated hippocampal H1 and H2 receptor mRNA expression relative to controls. Neither fluoxetine nor exercise alone significantly reversed these stress-induced elevations. Combined treatment produced partial attenuation of H1 receptor upregulation, whereas H2 receptor expression remained elevated across treatment conditions. These findings demonstrate that chronic stress induces robust hippocampal histaminergic remodeling that persists despite behavioral improvement, suggesting that histaminergic signaling is a stress-responsive molecular substrate only partially sensitive to conventional antidepressant strategies. The dissociation between behavioral recovery and receptor normalization identifies the hippocampal histaminergic system as a potential target for future therapeutic intervention in stress-related disorders.