METABOLIC MAPPING OF THE RAT-BRAIN AFTER SUBANESTHETIC DOSES OF KETAMINE - POTENTIAL RELEVANCE TO SCHIZOPHRENIA

Subanesthetic doses of ketamine have been shown to exacerbate symptoms in schizophrenia and to induce positive, negative, and cognitive schi zophrenic-like symptoms in normal subjects. The present investigation sought to define brain regions affected by subanesthetic doses of keta mine, using high resolution autoradiographic analysis of C-14-2-deoxyg lucose (2-DG) uptake and immunocytochemical staining for Fos-like immu noreactivity (Fos-LI). Both functional mapping approaches were used be cause distinct and complementary information is often obtained with th ese two mapping methods. Ketamine, at a subanesthetic dose of 35 mg/kg , substantially increased 2-DG uptake in certain limbic cortical regio ns, including medial prefrontal, ventrolateral orbital, cingulate, and retrosplenial cortices. In the hippocampal formation, the subanesthet ic dose of ketamine induced prominent increases in 2-DG uptake in the dentate gyrus, CA-3 stratum radiatum, stratum lacunosum moleculare, an d presubiculum. Increased 2-DG uptake in response to 35 mg/kg ketamine was also observed in select thalamic nuclei and basolateral amygdala. Ketamine induced Fos-LI in the same limbic cortical regions that exhi bited increased 2-DG uptake in response to the subanesthetic dose of t he drug. However, no Fos was induced in some brain regions that showed increased 2-DG uptake, such as the hippocampal formation, anteriovent ral thalamic nucleus, and basolateral amygdala. Conversely, ketamine i nduced Fos in the paraventricular nucleus of the hypothalamus and cent ral amygdala, although no effect of the drug on 2-DG uptake was appare nt in these regions. In contrast to the increase in 2-DG uptake observ ed in select brain regions after the subanesthetic dose, an anesthetic dose of ketamine (100 mg/kg) produced a global suppression of 2-DG up take. By contrast, a robust induction of Fos-LI was observed after the anesthetic dose of ketamine that was neuroanatomically identical to t hat produced by the subanesthetic dose. Results of the present investi gation show that anesthetic and subanesthetic doses of ketamine have p ronounced effects on regional brain 2-DG uptake and induction of Fos-L I. The alterations in regional brain metabolism induced by the subanes thetic dose may be relevant to effects of ketamine to induce schizophr enic-like symptoms. (C) 1998 Elsevier Science B.V.