Mapping the central effects of ketamine in the rat using pharmacological MRI

Littlewood, Clare L.; Jones, Nicholas; O’Neill, Michael; Mitchell, Stephen N.; Tricklebank, Mark D.; Williams, Steven

doi:10.1007/s00213-006-0344-0

Cited by 92 publications

(41 citation statements)

References 87 publications

(93 reference statements)

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“…Although phMRI has been frequently used in preclinical and clinical settings, the number of examples in which phMRI responses are translated between rodents and humans is limited to a few cases. Of interest, ketamine phMRI infusion responses have been measured in naive rats (Littlewood et al, 2006;Chin et al, 2011) and healthy human subjects (De Simoni et al, 2012); robust responses were detected in the cingulate, frontal cortex, and hippocampal formation in both species (Bifone and Gozzi, 2012). Similarly, a highly convergent phMRI signature has been observed between rodents (Liu et al, 2007) and humans (Leppa et al, 2006) after acute remifentanil administration, in which activation was present in brain structures, such as the striatum, thalamus, hippocampus, and cingulate cortex.…”

Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial m-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

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Section: Discussionmentioning

confidence: 99%

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Becerra

Upadhyay

Chang

et al. 2013

J Pharmacol Exp Ther

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“…Few studies have used SPM techniques in rats with different imaging modalities: autoradiographic iodoantipyrine [30][31][32][33][34], fMRI [35][36][37][38][39][40], and FDG-PET [20,41,42]. Two PET studies used a standardization according to a custom digital template matched to a highresolution microMRI image in Paxinos orientation [41,42].…”

Section: Discussionmentioning

confidence: 99%

Detection of Visual Activation in the Rat Brain Using 2-deoxy-2-[18F]fluoro-d-glucose and Statistical Parametric Mapping (SPM)

et al. 2008

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Purpose: This study was designed to assess changes in brain glucose metabolism in rats after visual stimulation. Materials and methods: We sought to determine whether visual activation in the rat brain could be detected using a small-animal positron emission tomography (PET) scanner and 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG). Eleven rats were divided into two groups: (a) five animals exposed to ambient light and (b) six animals stimulated by stroboscopic light (10 Hz) with one eye covered. Rats were injected with FDG and, after 45 min of visual stimulation, were sacrificed and scanned for 90 min in a dedicated PET tomograph. Images were reconstructed by a threedimensional ordered subset expectation maximization algorithm (1.8 mm full width at half maximum). A region-of-interest (ROI) analysis was performed on 14 brain structures drawn on coronal sections. Statistical parametric mapping (SPM) adapted for small animals was also carried out. Additionally, the brains of three rats were sliced into 20-μm sections for autoradiography. Results: Analysis of ROI data revealed significant differences between groups in the right superior colliculus, right thalamus, and brainstem (p≤0.05). SPM detected the same areas as the ROI approach. Autoradiographs confirmed the existence of hyperactivation in the left superior colliculus and auditory cortex. Conclusions: To our knowledge, this is the first report that uses FDG-PET and SPM analysis to show changes in rat brain glucose metabolism after a visual stimulus.

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“…In fact, N-methyl-D-aspartate (NMDA) antagonists, such as phencyclidine (PCP) or ketamine, can induce symptoms that mimic psychosis in healthy volunteers and exacerbate symptoms in schizophrenic patients (Krystal et al, 1994;Lahti et al, 1995). Using in vivo imaging, Littlewood et al (2006) demonstrated that ketamine increased BOLD signals in the frontal, hippocampal, cortical, and limbic areas with the largest activations observed in the retrosplenial cortex and hippocampus. In addition, it was found that pretreatment of glutamatergic agents seemed to globally modulate rCBV changes in rats challenged with PCP (Gozzi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it was found that pretreatment of glutamatergic agents seemed to globally modulate rCBV changes in rats challenged with PCP (Gozzi et al, 2008). It is intriguing that ketamine, which can induce psychomimetic symptoms or behavioral aberrations (Moghaddam et al, 1997;Nishizawa et al, 2000;Becker and Grecksch, 2004), produced significant changes of brain activity in several cortical, hippocampal, and midbrain regions in animals and humans (Lång-sjö et al, 2003;Holcomb et al, 2005;Honey et al, 2005;Littlewood et al, 2006). A central translational perspective is to conduct the preclinical studies in a way that would allow the study in humans.…”

Section: Introductionmentioning

confidence: 99%

Awake Rat Pharmacological Magnetic Resonance Imaging as a Translational Pharmacodynamic Biomarker: Metabotropic Glutamate 2/3 Agonist Modulation of Ketamine-Induced Blood Oxygenation Level Dependence Signals

Chin¹,

Upadhyay²,

Marek³

et al. 2010

J Pharmacol Exp Ther

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Neuroimaging techniques have been exploited to characterize the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on brain activation in humans and animals. However, most preclinical imaging studies were conducted in anesthetized animals and could be confounded by potential drug-anesthetic interactions as well as anesthetic agents' effect on brain activation, which may affect the translation of these basic research findings to the clinical setting. The main aim of the current study was to examine the brain activation elicited by the infusion of a subanesthetic dose of ketamine using blood oxygenation level dependence (BOLD) pharmacological magnetic resonance imaging (phMRI) in awake rats. However, a secondary aim was to determine whether a behaviorally active metabotropic glutamate 2/3 receptor agonist, (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY379268), could modulate the effects of ketamine-induced brain activation. Our data indicate that ketamine produces positive BOLD signals in several cortical and hippocampal regions, whereas negative BOLD signals were observed in regions, such as periaqueductal gray (PAG) (p Ͻ 0.05). Furthermore, pretreatment of LY379268 significantly attenuated ketamine-induced brain activation in a region-specific manner (posterior cingulate, entorhinal, and retrosplenial cortices, hippocampus CA1, and PAG). The region-specific brain activations observed in this ketamine phMRI study may afford a method of confirming central activity and dose selection in early clinical trials for novel experimental therapeutics.

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Mapping the central effects of ketamine in the rat using pharmacological MRI

Cited by 92 publications

References 87 publications

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

Detection of Visual Activation in the Rat Brain Using 2-deoxy-2-[18F]fluoro-d-glucose and Statistical Parametric Mapping (SPM)

Awake Rat Pharmacological Magnetic Resonance Imaging as a Translational Pharmacodynamic Biomarker: Metabotropic Glutamate 2/3 Agonist Modulation of Ketamine-Induced Blood Oxygenation Level Dependence Signals

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