title: Ketamine produces lasting disruptions in encoding of sensory stimuli.
abstract: The current study analyzed the acute, chronic, and lasting effects of ketamine administration in four inbred mouse strains (C3H/HeHsd, C57BL/6Hsd, FVB/Hsd, and DBA/2Hsd) to evaluate vulnerability to ketamine as a drug of abuse and as a model of schizophrenia. Serum half-life of ketamine was similar between all strains (approximately 13 min). Also, the ratio of brain-to-serum ketamine levels was 3:1. Examination of multiple phases of auditory processing using auditory-evoked potentials (AEPs) following acute ketamine (0, 5, and 20 mg/kg) treatment revealed C3H/HeHsd mice to be most vulnerable to ketamine-induced alterations in AEPs, whereas FVB/Hsd mice exhibited the least electrophysiological sensitivity to ketamine. Overall, the precortical P1-evoked potential component increased in amplitude and latency, whereas the cortically generated N1 and P2 components decreased in amplitude and latency following acute ketamine across all strains. Brain catecholamine analyses indicated that ketamine decreased hippocampus epinephrine levels in C3H/HeHsd but elevated hippocampus epinephrine levels in FVB/Hsd, suggesting one potential mechanism for AEP vulnerability to ketamine. Based on results of the acute study, the immediate and lasting effects of chronic low-dose ketamine on AEPs were examined among C3H/HeHsd (sensitive) and FVB/Hsd (insensitive) mice. We observed a decrement of the N1 amplitude that persisted at least 1 week after the last exposure to ketamine across both strains. This lasting deficit in information processing occurred in the absence of acute changes among the FVB/Hsd mice. Implications for both ketamine abuse and N-methyl-D-aspartate hypofunction models of schizophrenia are discussed.
authors.affiliation: Division of Neuropsychiatry and Stanley Center for Experimental Therapeutics in Psychiatry, Clinical Research Bldg., Rm. 145a, 415 Ci Blvd., University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Maxwell
authors.forename: Richard S
authors.initials: RS
authors.lastname: Ehrlichman
authors.forename: Yuling
authors.initials: Y
authors.lastname: Liang
authors.forename: Danielle
authors.initials: D
authors.lastname: Trief
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kanes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Karp
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
mesh_terms: D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006207:Half-Life; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics; D012677:Sensation / Q000187:drug effects*; D013045:Species Specificity
chemical_list: D000778:Anesthetics, Dissociative; D002395:Catecholamines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine