Metformin reverses oxandrolone-induced anxiety-like behavior and amygdalar neurochemical dysregulation in male rats.

Oxandrolone, a synthetic anabolic androgenic steroid, is widely used for its muscle-building effects but has been associated with anxiety and mood disturbances. We hypothesized that chronic oxandrolone exposure disrupts inhibitory, excitatory, monoaminergic, and neuromodulatory signaling within the amygdala, a brain region critical for emotional regulation, and that metformin may attenuate these effects due to its reported neuroprotective properties.

methodsAdult male rats were treated daily with oxandrolone for 14 days, with or without metformin co-administration. Anxiety-like behavior was assessed, followed by targeted neurochemical analysis of the dissected amygdala. Levels of GABAergic, glutamatergic, cholinergic, and monoaminergic neurotransmitters, along with key endocannabinoids and the neuropeptide oxytocin, were quantified using liquid chromatography mass spectrometry to comprehensively evaluate systems implicated in anxiety and affective regulation.

resultsOxandrolone treatment induced pronounced anxiety-like behavior and was associated with reduced levels of GABA, acetylcholine, serotonin, anandamide, 2-arachidonoylglycerol, and oxytocin, alongside increased glutamate, glutamine, and dopamine. Norepinephrine levels were unchanged. Metformin co-treatment mitigated both behavioral and neurochemical alterations. These findings indicate that oxandrolone shifts amygdala neurochemistry toward an excitatory and anxiogenic state, while metformin partially counteracts these effects.

conclusionThe study provides mechanistic insight into the neuropsychiatric risks of anabolic steroid exposure and highlights potential therapeutic targets.