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 dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D1 receptor availability was assessed by using positron emission tomography and the selective D1 receptor radioligand [11C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects.


METHODS
History of ketamine abuse was confirmed in subjects by hair analysis. [11C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function.


RESULTS
Dorsolateral prefrontal cortex D1 receptor availability was significantly up-regulated in chronic ketamine users ([11C]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 [11C]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 D1 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.
Narendran
Rajesh
R
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. rn2012@columbia.edu
Frankle
W Gordon
WG
Keefe
Richard
R
Gil
Roberto
R
Martinez
Diana
D
Slifstein
Mark
M
Kegeles
Lawrence S
LS
Talbot
Peter S
PS
Huang
Yiyun
Y
Hwang
Dah-Ren
DR
Khenissi
Leyla
L
Cooper
Thomas B
TB
Laruelle
Marc
M
Abi-Dargham
Anissa
A
D000328:Adult; D000700:Analgesics / Q000009:adverse effects*; D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D006197:Hair / Q000737:chemistry; D006801:Humans; D013287:Illicit Drugs / Q000009:adverse effects / Q000378:metabolism; D007649:Ketamine / Q000009:adverse effects* / Q000032:analysis / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000502:physiology*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D014018:Tissue Distribution; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D013287:Illicit Drugs; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; C077123:NNC 112; D007649:Ketamine; D004298:Dopamine