title: Pharmacological MRI response to a selective dopamine transporter inhibitor, GBR12909, in awake and anesthetized rats.
abstract: Pharmacological magnetic resonance imaging (phMRI) is a powerful tool for imaging the effects of drugs on brain activity. In preclinical phMRI studies, general anesthesia used for minimizing head movements is thought to influence the phMRI responses to drugs. In this study we investigated the phMRI responses to a selective dopamine transporter (DAT) inhibitor, GBR12909, and a dopamine (DA) releaser, d-amphetamine (AMPH), in the isoflurane anesthetized and awake rats using a relative cerebral blood volume (rCBV) method. AMPH (1 mg/kg i.p.) caused an increase in rCBV in the dopaminergic circuitry in the both anesthetized and awake rats. The striatal rCBV change was correlated with the change of the striatal DA concentration induced by AMPH in the both anesthetized and awake rats. GBR12909 (10 mg/kg i.p.) caused a positive rCBV response and showed a similar regional pattern of rCBV response to AMPH in the awake rats, and the correlation between the change of the striatal rCBV and the striatal DA concentration was observed. However, in the anesthetized rats, GBR12909 induced a widespread negative rCBV response, whereas an increase in striatal DA concentration was observed. These findings indicate that phMRI responses to activation of DA neurotransmission by GBR12909 or AMPH are overall identical in the awake state, while the phMRI response to a DAT inhibitor, GBR12909 but not to AMPH was changed by isoflurane anesthesia. For the evaluation of neuroactive drugs using phMRI, isoflurane anesthesia might be complicated the interpretation of pharmacodynamic effects of drugs in preclinical studies.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi and Co., Ltd., Osaka, Japan; Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Kashiwagi
authors.forename: Takemi
authors.initials: T
authors.lastname: Rokugawa
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Obata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watabe
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects*; D001931:Brain Mapping; D015259:Dopamine Agents / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014851:Wakefulness / Q000502:physiology*
chemical_list: C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D000661:Amphetamine
keywords: DAT inhibitor; GBR12909; dopamine; isoflurane; pharmacological MRI