Biomedical subjects

Y Iris Chen

Publications and source records attributed to Y Iris Chen.

6 recordsLinked to original sources

PubMed2006

Brain hemodynamic changes mediated by dopamine receptors: Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling.

The coupling between neurotransmitter-induced changes in neuronal activity and the resultant hemodynamic response is central to the interpretation of neuroimaging techniques. In the present study, MRI experiments showed that dopamine transporter blockers such as cocaine and dopamine releasers such as amphetamine and D1 receptor agonists induced large positive increases in relative cerebral blood volume (rCBV) that were not sensitive to nitric oxide synthase inhibition. However, D1/D5 receptor antagonism with SCH-23390 prevented or blocked the hemodynamic response without any concomitant effect on dopamine release. Dopamine D2/D3 receptor agonists, in contrast, induced negative changes in rCBV in brain regions corresponding largely to those endowed with these receptors. D1 and D5 receptor mRNAs were expressed in microvessels of responsive brain areas, while D2 and D3 receptors were not consistently associated with the microvascular bed. D3 receptors had an astroglial localization. Together, these experiments show that direct effects of dopamine upon the vasculature cannot be ignored in measuring the hemodynamic coupling associated with dopaminergic drugs. These results further suggest that this coupling is partially mediated through D1/D5 receptors on the microvasculature leading to increased rCBV and through astroglial D3 receptors leading to decreased rCBV. These data provide additional support for the role of local post-synaptic events in neurovascular coupling and emphasize that the interpretation of fMRI signals exclusively in terms of neuronal activity may be incomplete.

Animals↗

PubMed2006

High resolution spatial mapping of nicotine action using pharmacologic magnetic resonance imaging.

Nicotine is one of the most addictive substances known. To better understand the mechanisms of action, we mapped the regional brain response to nicotine administration using pharmacologic magnetic resonance imaging (phMRI) in rats. We measured the regional response of relative cerebral blood volume (rCBV) in rats to a challenge of 0.07 mg/kg (0.43 micromol/kg) of nicotine. The areas of the brain with significant and reproducible changes in the rCBV response were (in descending order of magnitude) infralimbic cortex, hippocampus (subiculum), agranular insular/pyriform cortex, visual cortex, interpeduncular area, nucleus accumbens, cingulate cortex, thalamus, and septum. This pattern of response is consistent with stimulation of both cholinergic and dopaminergic neuronal pathways and is consistent with the known behavioral properties of nicotine. The peak CBV response to nicotine occurred between 9 and 13 min depending upon brain region, and the average full width half-maximum of the rCBV response was 27 min. The high spatial and temporal resolution of the phMRI technique lends itself well to further, more detailed, studies of nicotine dynamics.

Acetylcholine↗

PubMed2005

Mapping interactions between dopamine and adenosine A2a receptors using pharmacologic MRI.

Adenosine receptors in the basal ganglia are implicated in regulation of dopamine function and release. We investigated the interactions between dopamine receptors and adenosine receptors in the basal ganglia using pharmacologic MRI (phMRI) in rats. Stimulation of dopamine receptors was achieved using administration of 2 mg/kg of amphetamine. Then we investigated the antagonism of these changes using the selective A2a receptor antagonist 3,7-dimethyl-1-propargylaxanthine (DMPX). Amphetamine alone caused large increases (10-30%) in relative cerebral blood volume (rCBV) in caudate/putamen (CPu), nucleus accumbens (NAcc), thalamus, and frontal and cingulate cortices with changes that persisted for 70-80 min. DMPX alone (5 mg/kg) induced decreases in rCBV (approximately 8-10%) in NAcc, CPu, and olfactory tubercule, with smaller changes in thalamus (-6%) consistent with the regional distribution of A2a receptors. We examined the interactions between amphetamine and DMPX by assessing the effects of DMPX (5 mg/kg) administration 20 min after injection of 3 mg/kg amphetamine. These experiments showed that DMPX immediately decreased the rCBV increase induced by amphetamine in NAcc, CPu, and thalamus but not in cingulate or sensorimotor cortex. Companion microdialysis experiments showed that dopamine release in CPu was decreased in a similar manner. These experiments demonstrate the utility of phMRI for probing, in a noninvasive manner, the temporal and spatial dynamics of neurotransmitter interactions.

Adenosine A2 Receptor Antagonists↗

PubMed2004

3-Nitropropionic acid-induced neurotoxicity--assessed by ultra high resolution positron emission tomography with comparison to magnetic resonance spectroscopy.

To explore acute and long-term effects of 3-nitropropionic acid (3-NP)-induced neurotoxicity, longitudinal positron emission tomography (PET) studies of energy metabolism and magnetic resonance spectroscopic (MRS) studies of neurochemicals were conducted in a rat model. The first injection of 3-NP (20 mg/kg i.p.) was followed by MRS study of neurochemicals and PET study of glucose utilization using [(18)F]2-fluorodeoxy-D-glucose ((18)F-FDG). After that, 3-NP administration was done two times a day with a dose of 10 mg/kg i.p. until animals were symptomatic or for a maximum of 5 days combined with daily PET studies. Long-term effects were investigated 4 weeks and 4 months after cessation of 3-NP. These studies showed a significant inter-animal variation in response of 3-NP toxicity. Animals that developed large striatal lesions had decreased glucose utilization in the striatum and cortex 1 day after starting 3-NP injections. Similarly succinate and lactate/macromolecule levels were enhanced; these changes being, however, reversible. Progressive degeneration was observed by decreasing striatal glucose utilization and N-acetylaspartate (NAA) and increasing choline. These observations paralleled with weight loss and deficits in behavior. Animals that did not develop lesions showed reversible enhancement in cortical glucose utilization and no change in striatal glucose utilization or neurochemicals or locomotor activity.

Acute Disease↗

PubMed2003

Radiolabeling and biodistribution of methyl 2-(methoxycarbonyl)-2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate, a potential neuroprotective drug.

Methyl 2-(methoxycarbonyl) -2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate (MMMHC) is developed as a potential neuroprotective drug. It was labeled with C-11 from the desmethyl precursor methyl 2-(methoxycarbonyl)-2-amino bicyclo[2.1.1]-hexane-5-carboxylate with [11C]methyl triflate in acetone solution at 60 degrees C with labeling yield of 69% and with radiochemical purity of >99%. Positron Emission Tomography (PET) studies in a normal rat showed that Methyl 2-(methoxycarbonyl)-2-([11C]methylamino)bicyclo[2.1.1]-hexane-5-carboxylate ([11C] MMMHC) accumulated mainly in the cortical brain areas after iv administration. Frontal cortex/cerebellum ratios in a rat brain were 8.0/6.0, 6.8/4.2, 6.3/4.3, 5.5/4.2 and 5.2/4.5 percent of the injected dose in 100 ml at 2 min, 5 min, 10 min, 20 min and 40 min respectively after i.v. injection. During 20-40 min, 2.9+/-0.4% of the total activity stayed in the brain. These results showed that MMMHC could be labeled with C-11 with high yield, and it passed the brain-blood barrier and accumulated in several brain regions.

Animals↗

PubMed2003

Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model.

Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗