Ketamine Exposure during Adolescence Increases Sensitivity to Cocaine in Adulthood

RM 217

Pediatric depression was not well recognized until relatively recent. Today, however, major depressive disorder (MDD) is commonly diagnosed in children and adolescents, and when left untreated, may result in negative consequences that extend into adulthood. It is estimated that children and adolescents who suffer from MDD are likely to develop conduct and anxiety disorders, and that up to 25% eventually develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of antidepressants prescribed to populations below 20 years of age. Recently, the non-competitive N-methyl-D- aspartate (NMDA) receptor antagonist, ketamine, has been shown to alleviate symptoms of MDD in individuals that suffer from treatment-resistant depression. However, little is known about the potential long-term consequences of exposure to ketamine during early development. This is particularly important to examine, given ketamine’s abuse potential. To address this issue at the preclinical level, we examined whether ketamine exposure during adolescence results in longlasting changes in sensitivity to the rewarding effects of cocaine. Specifically, male c57BL/6 mice were exposed to ketamine (0 or 20 mg/kg) during adolescence (postnatal days [PD] 35-49) and were later assessed in adulthood (PD 70+) on behavioral responsivity to cocaine (0, 5, or 10 mg/kg) place conditioning (CPP). Here we show that adult mice pre-treated with ketamine during adolescence displayed enhanced preference for environments previously paired with moderately low doses of cocaine, when compared to saline pre-treated controls. Together, our findings suggest that exposure to ketamine during adolescence increases drug liability, later in life.