title: Different dosing regimens of repeated ketamine administration have opposite effects on novelty processing in rats.
abstract: Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects.
authors.affiliation: Department of Psychology (Scarborough), University of Toronto, Canada.
authors.forename: Anett
authors.initials: A
authors.lastname: Schumacher
authors.affiliation: Department of Psychology (Scarborough), University of Toronto, Canada.
authors.forename: Brindan
authors.initials: B
authors.lastname: Sivanandan
authors.affiliation: Department of Psychology (Scarborough), University of Toronto, Canada.
authors.forename: Edgor Cole
authors.initials: EC
authors.lastname: Tolledo
authors.affiliation: Department of Psychology (Scarborough), University of Toronto, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Woldegabriel
authors.affiliation: Department of Psychology (Scarborough), University of Toronto, Canada; Department of Cell and Systems Biology, University of Toronto, Canada. Electronic address: rutsuko.ito@utoronto.ca.
authors.forename: Rutsuko
authors.initials: R
authors.lastname: Ito
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001288:Attention / Q000187:drug effects*; D001307:Auditory Perception / Q000187:drug effects; D019422:Dietary Sucrose; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D046709:Pattern Recognition, Physiological / Q000187:drug effects*; D011581:Psychological Tests; D011619:Psychotropic Drugs / Q000008:administration & dosage*; D020318:Rats, Long-Evans; D055697:Taste Perception / Q000187:drug effects; D014796:Visual Perception / Q000187:drug effects
chemical_list: D019422:Dietary Sucrose; D011619:Psychotropic Drugs; D007649:Ketamine; D000661:Amphetamine
keywords: Animal model; Depression; Dopamine; Ketamine; Novelty detection; Schizophrenia