title: Altered prefrontal dopaminergic function in chronic recreational ketamine users.
abstract: 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.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. rn2012@columbia.edu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
authors.forename: W Gordon
authors.initials: WG
authors.lastname: Frankle
authors.forename: Richard
authors.initials: R
authors.lastname: Keefe
authors.forename: Roberto
authors.initials: R
authors.lastname: Gil
authors.forename: Diana
authors.initials: D
authors.lastname: Martinez
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kegeles
authors.forename: Peter S
authors.initials: PS
authors.lastname: Talbot
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Leyla
authors.initials: L
authors.lastname: Khenissi
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Cooper
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
mesh_terms: 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
chemical_list: 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