Subanaesthetic Ketamine Treatment Alters Prefrontal Cortex Connectivity With Thalamus and Ascending Subcortical Systems

Acute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the...

Full description

Saved in:
Bibliographic Details
Published in:Schizophrenia bulletin 2013-03, Vol.39 (2), p.366-377
Main Authors: DAWSON, Neil, MORRIS, Brian J, PRATT, Judith A
Format: Article
Language:English
Subjects:
Adult and adolescent clinical studies
Anesthetics, Dissociative - pharmacology
Animals
Biological and medical sciences
Carbon Radioisotopes
Deoxyglucose
Disease Models, Animal
Ketamine - pharmacology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Neural Pathways - diagnostic imaging
Neural Pathways - drug effects
Neural Pathways - physiopathology
Positron-Emission Tomography
Prefrontal Cortex - diagnostic imaging
Prefrontal Cortex - drug effects
Prefrontal Cortex - physiopathology
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Psychoses
Radiopharmaceuticals
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Regular
Schizophrenia
Schizophrenia - physiopathology
Thalamic Nuclei - diagnostic imaging
Thalamic Nuclei - drug effects
Thalamic Nuclei - physiopathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Acute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the functional deficits associated with this disorder and shows reduced activity (hypofrontality) in schizophrenia patients. Chronic NMDA antagonist treatment in rodents can also induce hypofrontality, although paradoxically acute NMDA receptor antagonist administration induces metabolic hyperfrontality. In this study, we use 2-deoxyglucose imaging data in mice to characterize acute ketamine-induced alterations in regional functional connectivity, a deeper analysis of the consequences of acute NMDA receptor hypofunction. We show that acute ketamine treatment increases PFC metabolic activity while reducing metabolic activity in the dorsal reticular thalamic nucleus (dRT). This is associated with abnormal functional connectivity between the PFC and multiple thalamic nuclei, including the dRT, mediodorsal (MDthal), and anteroventral (AVthal) thalamus. In addition, we show that acute NMDA receptor blockade alters the functional connectivity of the serotonergic (dorsal raphe [DR]), noradrenergic (locus coeruleus [LC]), and cholinergic (vertical limb of the diagonal band of broca [VDB]) systems. Together with other emerging data, these findings suggest that the reticular nucleus of the thalamus, along with the diffusely projecting subcortical aminergic/cholinergic systems, represent a primary site of action for ketamine in reproducing the diverse symptoms of schizophrenia. Our results also demonstrate the added scientific insight gained by characterizing the functional connectivity of discrete brain regions from brain imaging data gained in a preclinical context.
ISSN:0586-7614
1745-1701
DOI:10.1093/schbul/sbr144