Metformin pharmacokinetics in the rat brain: dose- and time-dependent concentrations in reward-relevant regions and differential effects on cocaine locomotor sensitization
Abstract
Background and Purpose: Metformin (1,1-demythlbiguanide, MET), typically prescribed to treat type 2 diabetes (T2D), has shown promise for treating substance use disorders (SUD). Preclinical studies report therapeutic value in reducing cocaine, nicotine, alcohol, and opioid-related behaviors. While MET crosses the blood-brain-barrier (BBB), few studies have examined brain levels. Experimental Approach: Liquid chromatography tandem mass spectrometry was used to measure MET in the serum and relevant brain regions associated with reward behavior (dorsal and ventral striatum and prefrontal cortex). Adult male and female Sprague Dawley rats were provided MET treated drinking water (1, 1.75, and 2.5 mg/ml) for 7, 15, or 30+ days before blood and brain tissue was collected. Controls were exposed to untreated drinking water for 30 days. Food/water intake and body weight were measured daily. Separately, MET behavioral effects (1.75 mg/ml) were assessed via cocaine-induced locomotor sensitization. Key Results: Water intake was reduced with increasing MET concentrations. Dose-dependent effects of MET on body weight were evident in female rats but did not coincide with changes in food intake. Measured MET levels were comparable across all brain regions sampled in males and females. Free access to MET-treated drinking water prevented cocaine locomotor sensitization selectively in male rats, suggesting significant sex differences in biodistribution across the BBB. Conclusions and…
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