Chronic ketamine abuse causes dysfunctions of different brain areas relevant to neurodevelopmental psychiatric disorders: evidence from fMRI in a primate model

Abstract

OBJECTIVE: Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, and illegal use of it as a recreational drug among adolescence and young adult is rapidly growing. Many studies have showed that prefrontal dopaminergic system is particularly vulnerable to the toxic effects on cognitive functions. This suggests that chronic ketamine abuse in young people may cause a severe disruption of different brain areas relevant to psychiatric disorders. METHODS: We established a chronic ketamine abuse model using the adolescent cynomoglus monkeys administrated with ketamine once a day (1 mg/kg, i.v.) for 6 months. Blood oxygenation level dependent (BOLD) contrast images were generated through stimulating the function of somatosensory area using functional magnetic resonance imaging (fMRI). Parallel and successive behavioral were observed. RESULTS: Chronic ketamine abuse in younger monkeys caused obvious deficits in the ventral tegmental area (VTA)/substantial nigra (SN), parietal cortex, and cingulate cortex. Besides, some increased activities were observed in striatum (lentiform nucleus, LN), fusiform gyrus (FG) and entorhinal cortex (Ent) on the right side of the brain in the chronic ketamine administrated monkeys. Behaviour results showed significant differences of the movement in both control and ketamine groups with general and consistent decreased trend with time periods of ketamine administration. CONCLUSION: Dysfunction of a projection from Ent to LN could play a role in ketamine abuse or induce epilepsy. We also found that deficit of cortical visual area in ketamine abuse model might cause a ‘positive schizophrenic syndrome’. Moreover, hypofunction of mesocortical dopamine pathway may induce a negative symptom in psychosis, or attention deficit disorder (ADD).