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...

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Bibliographic Details
Published in:	Neuropsychopharmacology (New York, N.Y.) Vol. 39; no. 7; pp. 1635 - 1644
Main Authors:	LI, Jennifer, ISHIWARI, Keita, CONWAY, Michael W, FRANCOIS, Jennifer, HUXTER, John, LOWRY, John P, SCHWARZ, Adam J, TRICKJEBANK, Mark, GILMOUR, Gary
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-06-2014
Subjects:	Analysis of Variance Animals Antipsychotic Agents - therapeutic use Antipsychotics Area Under Curve Biological and medical sciences Brain - drug effects Brain - metabolism Clozapine - therapeutic use Disease Models, Animal Dissociative Disorders - chemically induced Dissociative Disorders - drug therapy Dose-Response Relationship, Drug Excitatory Amino Acid Antagonists - toxicity Haloperidol - therapeutic use Ketamine - toxicity Male Medical sciences Neuropharmacology Original Oxygen - metabolism Pharmacology. Drug treatments Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Tissue Distribution - drug effects Functional connectivity Rat coherence Neuroleptic Psychotropic Toxicity Rodentia Central nervous system Pharmacotherapy Glutamate receptor brain tissue oxygen Encephalon Vertebrata Mammalia Treatment Ketamine General anesthetic Animal constant potential amperometry antipsychotics Antipsychotic Drug of abuse Antagonist NMDA receptor
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 These authors contributed equally to this work.
ISSN:	0893-133X 1740-634X
DOI:	10.1038/npp.2014.10