Rationale: Dextromethorphan (DM), an over-the-counter cough suppressant, has been recently used as a drug of abuse by teenage groups in some countries, such as the United States, Canada, and Korea. We previously showed that repeated administration of DM, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, impairs spatial learning performance in adolescent rats.

Objectives: In the present study, long-term adverse effects of repetitive DM use at adolescence were examined in rats.

Methods: Male and female Sprague-Dawley rat pups received either intraperitoneal DM (40 mg/kg) or saline daily during postnatal days 28-37, and were then subjected to the Morris water maze task at the age of 18 months. Expression levels of NMDAR1, functional subunit of NMDA receptors, in the prefrontal cortex and the hippocampus were examined by Western blot analysis. Changes in plasma corticosterone levels responding to stress were determined by radioimmunoassay.

Results: DM-experienced male rats exhibited deficits in the probe trial, and female rats in the initial learning and the reversal training, in water maze performance. Expression levels of NMDAR1 in the brain regions were significantly increased in DM-experienced rats, compared to control rats. Stress-induced increases in plasma corticosterone levels were blunted both in male and female DM rats.

Conclusions: The results suggest that repeated administration of DM at high doses during adolescent period may induce permanent deficits in cognitive function and that increased expression of NMDAR1 in the prefrontal cortex and the hippocampus may take a role in DM-induced memory deficits.