Dissociable effects of antipsychotics on ketamine-induced changes in regional oxygenation and inter-regional coherence of low frequency oxygen fluctuations in the rat.
Typical and atypical antipsychotics have been shown to alleviate N-methyl-D-aspartate (NMDA) receptor antagonist-induced BOLD signals in healthy humans and animals to differing degrees; factors that might relate to their different molecular mechanisms and clinical profiles. Recent studies have also extended these investigations to the analysis of resting state functional connectivity measures of BOLD signals in different brain regions. Using constant potential amperometry, we examined the effects of the NMDA receptor antagonist S-(+)-ketamine on tissue oxygen levels in medial prefrontal cortex (mPFC) and medial ventral striatum (mVS), and temporal coherence of low-frequency oxygen fluctuations between these regions in freely moving rats. Furthermore, we assessed the extent to which the atypical antipsychotic clozapine and the typical antipsychotic haloperidol could modulate the effects of S-(+)-ketamine on these measures. Acute S-(+)-ketamine (5-25 mg/kg) produced dose-dependent increases in both tissue O2 levels and coherence. Although effects of clozapine and haloperidol alone were relatively minor, their effects on ketamine-induced signals were markedly more distinct. Clozapine dose-dependently attenuated the absolute S-(+)-ketamine (25 mg/kg) O2 signal in both regions, and also attenuated ketamine-induced increases in regional coherence. Haloperidol had no effect on the absolute ketamine O2 signal yet potentiated increases in regional coherence. The dissociable effects of haloperidol and clozapine on ketamine-induced hyperoxygenation and mPFC-mVS coherence elucidate potentially important mechanistic differences between these classes of pharmacology. This study demonstrates for the first time that in vivo amperometry can measure both regional brain tissue O2 levels and inter-regional coherence, advancing BOLD-like measurements of functional connectivity into awake, unconstrained animals.
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
Jennifer
J
Li
1] Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK [2] Department of Chemistry, National University of Ireland, Maynooth, Co. Kildare, Ireland.
Keita
K
Ishiwari
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
Michael W
MW
Conway
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
Jennifer
J
Francois
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
John
J
Huxter
Department of Chemistry, National University of Ireland, Maynooth, Co. Kildare, Ireland.
John P
JP
Lowry
Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA.
Adam J
AJ
Schwarz
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
Mark
M
Tricklebank
Centre for Cognitive Neuroscience, Eli Lilly and Co. Limited, Windlesham, Surrey, UK.
Gary
G
Gilmour
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004213:Dissociative Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D006220:Haloperidol / Q000627:therapeutic use; D007649:Ketamine / Q000633:toxicity; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution / Q000187:drug effects
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D003024:Clozapine; D006220:Haloperidol; D010100:Oxygen