Neurobehavioral and reinforcing effects of pregabalin in mice

Pregabalin misuse is increasing, but its psychostimulant and rewarding properties remain unclear, especially regarding sex differences and interactions with opioids. The objectives of this study are to investigate pregabalin's behavioral and neurochemical effects in male and female mice, including its impact on cognition, social interaction, reinforcement, and cross-sensitization with morphine. CD-1 mice received pregabalin (30-90 mg/kg, i.p.) acutely or for 5 days. Locomotor activity, Y-maze performance, social behavior, and conditioned place preference (CPP) were assessed. Brain monoamine levels were quantified by HPLC. A D1 dopamine receptor antagonist (SCH 23390) was used to explore dopaminergic involvement. Morphine CPP was tested after pregabalin pretreatment. Results showed that in male mice, acute pregabalin induced transient hyperlocomotion and rewarding effects in CPP test, both associated with increased dopamine in the prefrontal cortex and striatum. No psychostimulant or reinforcing effects were observed in female mice. Pregabalin had no impact on memory or general social behavior, though a subset of males displayed aggression, coinciding with elevated serotonin and norepinephrine. Repeated pregabalin dosing produced tolerance without sensitization. Blocking D1 receptors abolished pregabalin-induced CPP. Importantly, pregabalin pretreatment enhanced morphine-induced CPP, suggesting cross-sensitization. Conclusions indicate that pregabalin exerts sex-specific stimulant and rewarding effects in mice, driven by dopaminergic signaling. Its ability to potentiate morphine's rewarding properties raises concern about abuse potential, particularly in opioid-exposed individuals. These findings highlight the need to consider sex as a biological variable when assessing the addictive risk of pregabalin.