κ-Opioid System Regulates the Long-Lasting Behavioral Adaptations Induced by Early-Life Exposure to Methylphenidate

Methylphenidate (MPH) is commonly prescribed in childhood and adolescence for the treatment of attention–deficit/hyperactivity disorders. In rodents, MPH exposure during preadolescence (postnatal days [PD] 20–35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for κ-opioid receptors (KOR). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the κ-agonist U-50,488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90+), these rats were divided into groups receiving saline, U-50,488 (5 mg/kg), or nor-Binaltorphimine (20 mg/kg), a κ-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus-maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50,488, while being normalized by nor-Binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/κ-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure. Moreover, these findings further support the idea of κ-antagonists as potential pharmacotherapy for the treatment of anxiety- and depression-related disorders.