Long-Term Propranolol Treatment Induces Anxiolytic-like Effects and Alters Hypothalamic Noradrenergic, Serotonergic and GABAergic Neurotransmission

Propranolol is a non-selective β-adrenergic receptor antagonist widely used in cardiovascular medicine and anxiety-related conditions; however, its central neurochemical mechanisms remain incompletely understood. This study investigated the effects of long-term propranolol administration on anxiety-like behavior and hypothalamic neurotransmission in rats. Adult male Sprague–Dawley rats received propranolol in drinking water at doses of 1, 2.5, or 5 mg/kg b.w./day for 33 days. Behavioral effects were assessed using the Open Field Test (OF) and Elevated Plus Maze (EPM). Hypothalamic concentrations of amino acids, e.g., γ-aminobutyric acid (GABA) as well as monoamines, and their metabolites were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Long-term propranolol treatment induced a significant anxiolytic-like effect, reflected by increased exploration of open arms in the EPM, without affecting locomotor activity in the OF. Neurochemical analyses revealed a significant increase in hypothalamic GABA levels and a marked reduction in noradrenergic turnover, as indicated by decreased MHPG/NA ratios. Propranolol also increased hypothalamic serotonin concentrations, whereas dopaminergic turnover remained unchanged. These findings demonstrate that long-term propranolol administration produces neurochemical changes within the hypothalamus involving noradrenergic, serotonergic, and GABAergic signaling pathways. The results suggest that the anxiolytic-like effects of propranolol extend beyond β-adrenergic receptor blockade and may be mediated by coordinated modulation of multiple neurotransmitter systems involved in stress regulation and emotional processing. The study provides new evidence linking chronic propranolol exposure to selective hypothalamic neurochemical remodeling associated with reduced anxiety-like behavior.