Bicuculline-induced brain activation in mice detected by functional magnetic resonance imaging.
Dynamic measurements of local changes in relative cerebral blood volume (CBV(rel)) during a pharmacological stimulation paradigm were performed in mice. Using magnetite nanoparticles as an intravascular contrast agent, high-resolution CBV(rel) maps were obtained. Intravenous administration of the GABA(A) antagonist bicuculline prompted increases in local CBV(rel) as assessed by MRI with a high spatial resolution of 0.2 x 0.2 mm(2) and a temporal resolution of 21 s. Signal changes occurred 20-30 s after the onset of drug infusion in the somatosensory and motor cortex, followed by other cortical and subcortical structures. The magnitudes of the CBV(rel) increases were 18% +/- 4%, 46% +/- 14%, and 67% +/- 7%, as compared to prestimulation values for the cortex, and 9% +/- 3%, 25% +/- 4%, and 36% +/- 7% for the caudate putamen for bicuculline doses of 0.6, 1.25, and 1.5 mg/kg, respectively. On-line monitoring of transcutaneous carbon dioxide tension PtcCO(2) reflecting arterial PaCO(2) did not show any alteration during the stimulation paradigm. One of five of the mice receiving the highest bicuculline dose, and three of seven receiving the intermediate dose displayed a different cortical response pattern. After a CBV(rel) increase of 40% lasting for approximately 1 min, significant CBV(rel)reductions by 80% have been observed. Subcortical structures did not display this behavior. The present study suggests that this noninvasive approach of functional MRI (fMRI) can be applied to study drug-induced brain activation by central nervous system (CNS) drugs in mice under normal and pathological situations.
Mueggler
T
T
Core Technologies Area, Novartis Pharma Ltd, Basel, Switzerland.
Baumann
D
D
Rausch
M
M
Rudin
M
M
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003287:Contrast Media / Q000008:administration & dosage; D003911:Dextrans; D004305:Dose-Response Relationship, Drug; D052203:Ferrosoferric Oxide; D018756:GABA Antagonists / Q000494:pharmacology*; D006439:Hemodynamics; D007091:Image Processing, Computer-Assisted; D007501:Iron / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008815:Mice, Inbred Strains; D010087:Oxides / Q000008:administration & dosage
D003287:Contrast Media; D003911:Dextrans; D018756:GABA Antagonists; D058185:Magnetite Nanoparticles; D010087:Oxides; D002245:Carbon Dioxide; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide; D001640:Bicuculline