Frontal Cortical Monoamine Release, Attention, and Working Memory in a Perinatal Nicotine Exposure Mouse Model Following Kappa Opioid Receptor Antagonism

Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI’s effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate’s effects were evident at 0.5 h but not at 2.5 h. norBNI’s effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement.