DIFFERENTIAL-EFFECTS OF SINGLE AND REPEATED KETAMINE ADMINISTRATION ON DOPAMINE, SEROTONIN AND GABA TRANSMISSION IN RAT MEDIAL PREFRONTAL CORTEX

Cognitive functions regulated by the prefrontal cortex are sensitive t o changes in dopaminergic and serotoninergic transmission. The non-com petitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine infl uences dopaminergic transmission and induces psychotic symptoms in nor mal and schizophrenic individuals. This study examined the effect of s ingle and repeated ketamine (25 mg/kg, i.p.) administration on extrace llular levels of dopamine, GABA and the serotonin metabolite 5-hydroxy indoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vi vo microdialysis in conscious rat. In line with earlier studies, we ob served a transient five-fold increase in dopamine release following si ngle ketamine administration in drug naive animals. However, we also o bserved a two-fold increase in basal dopamine levels and an almost com plete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracell ular 5-HIAA levels were increased by ketamine in both drug naive and e ven 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 dif ferential effect of single and repeated ketamine administration on dop amine, serotonin and GABA transmission in the medial prefrontal cortex . We provide new evidence for a complex adaptation of neurotransmissio n following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopa mine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of d opaminergic transmission in the prefrontal cortex and may possibly alt er the balance between dopamine and serotonin transmission. (C) 1997 E lsevier Science B.V.