Altered prefrontal dopaminergic function in chronic recreational ketamine users

Objective: Ketamine is a noncompetitive antagonist at the glutamatergic N- methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopa-minergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D-1 receptor availability was assessed by using positron emission tomography and the selective D-1 receptor radio-ligand [C-11] NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects. Method: History of ketamine abuse was confirmed in subjects by hair analysis. [C-11] NNC 112 binding potential was measured with kinetic analysis using the arterial input function. Results: Dorsolateral prefrontal cortex D-1 receptor availability was significantly up-regulated in chronic ketamine users ([C-11] NNC 112 binding potential: mean = 1.68 ml/g, SD = 0.40) relative to comparison subjects (mean = 1.35 ml/g, SD = 0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [C-11] NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week. Conclusions: Chronic ketamine users exhibited a regionally selective up-regulation of D-1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.