title: Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex.
abstract: Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet and Hospital, Stockholm, Sweden. nilsl@psyk.ks.se
authors.forename: N
authors.initials: N
authors.lastname: Lindefors
authors.forename: S
authors.initials: S
authors.lastname: Barati
authors.forename: W T
authors.initials: WT
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D004298:Dopamine