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Ethanol affects many functions of the brain and peripheral organs. Here we show that ethanol opens G-protein-activated, inwardly rectifying K + (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate. At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK1/2 and cardiac-type GIRK1/4 channels without interaction with G proteins or second messengers. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol.

SummaryMechanism of central actions of antidepressants were studied in experimental animals.Tests were made on general behavior, anticonvulsant activity in maximal electroshock seizure, antireserpinic action, antagonistic action to methamphetamine‐excitation, anesthesia induced by hexobarbital, hypertension due to noradrenalin, hypotension induced by acetylcholine, anti‐tremorine action and antagonism for physostigmine in unanesthetized mice and rabbits. In these tests, it seemed that the mechanism of antidepressants is related to the changes of biogenic amines in the brain and to the central autonomic functions. Namely, imipramine, amitriptyline and nialamide were related intimately to the changes of biogenic amine and to the inhibitory effects of parasympathetic functions. Diazepam was connected with the tranquilizing effects and the inhibitory effects of parasympathetic functions, and dimethylaminoethanol had no relation to the autonomic functions.

(R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.

AbstractOromandibular dystonia is a focal dystonia involving the masticatory and tongue muscles, causing difficulties in speech or mastication. We treated 13 patients with this condition by injecting diluted lidocaine and alcohol intramuscularly. This method is aimed at reducing muscle spindle afferent activity. The symptoms had been resistant to other therapies such as pharmacotherapy or dental treatment. All patients showed clinical improvement after this therapy with reduced EMG activities in the affected muscles, whereas control injection of normal saline gave no changes in EMG activities. The overall subjective improvement was 57.7 ± 25.1% (mean ± standard deviation) in a self‐rating scale. The mean response of the jaw elevator muscles (70 ± 13.1%) was significantly higher (p < 0.02, t test) than that of the depressor muscles (38 ± 28.4%). Despite the precise mechanism being unknown, this difference might be related to the smaller number of muscle spindles in the depressor than the elevator muscles. This therapy is useful for the treatment of drug‐resistant oromandibular dystonia.

11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

Most CNS diseases begin with inflammation with subsequent neural damage eventually occurring; however, the process leading from the onset of inflammation to neural damage remains obscure. We used an artificial brain injury mouse model and examined how neural damage occurred in the brain parenchyma. The damaged area in each mouse was clearly observed by magnetic resonance imaging (MRI), and the progression of damage was observed to occur in a biphasic manner (acute damage, within 1 week; delayed damage, after 2 weeks). We found that the delayed neural damage was absent in iNOS-deficient mice (iNOS-KO mice). Then, we analyzed brain tissues and determined that delayed neural damage was accompanied by an increase in the levels of NO end products and iNOS expression, with accumulation of iNOS-expressing microglia around the injured area. In addition, the expression of IL-1beta mRNA was increased in areas affected by acute damage, but not in those affected by delayed damage. These findings suggest that delayed neural damage might arise from NO production by iNOS-expressing activated microglia and that such activated microglia might become a therapeutic target for many CNS diseases.

The amygdaloid complex (AMY) is implicated in emotional and motivational aspects of behavior, including the formation of positive reinforcement association. AMY may also associated with brain rewarding circuitry. In the present study, the effect of ethanol (EtOH) on the release of dopamine (DA) and serotonin (5-HT) was studied in the central amygdaloid nucleus (CeAMY), and projecting excitatory afferents to the ventral tegmental area (VTA), of freely moving Wistar rats by brain microdialysis. Within 20 min of i.p. injection of EtOH (2 g/kg), the levels of DA and 5-HT in the CeAMY dialysate increased over the baseline value by 270 and 160% (N = 6-7), respectively. Addition of EtOH (25, 50 and 100 mM) to the microdialysis perfusion medium for 1 h caused a 115-150% dose-related increase in the extracellular level of DA in the CeAMY. 100 mM EtOH-induced CeAMY DA release continued to increase for 1 h after the perfusion medium was returned to normal perfusion medium. In contrast, the CeAMY 5-HT level was increased only by the addition of 100 mM EtOH for 1 h to 130% for 80 min. The stimulation of the CeAMY by EtOH through the microdialysis membrane showed delayed responses of DA and 5-HT compared with the i.p. injection of EtOH. Overall, the present findings are not sufficient to conclude whether EtOH acts directly or indirectly on the major monoamine nerve cells in the CeAMY, but the degree of acute EtOH action affected the differences in time at the peak response on EtOH-induced DA and 5-HT releases in the CeAMY via VTA.

The purpose of this study was to evaluate the effects of alcohol on hemodynamic changes induced by visual stimulation. Ten healthy human subjects were examined using Optical Topography((R)) (Hitachi Medical Corporation: ETG-100). Each subject gradually drank 0.4 ml/kg alcohol over 10 min. Changes in oxy-hemoglobin (Hb), deoxy-Hb and total-Hb concentration were measured five times: 20 min before alcohol intake, immediately after alcohol intake, and at 20, 40 and 60 min after alcohol intake. A questionnaire was used to assess subjective feelings of alcohol. Blood-alcohol concentration (BAC) was estimated from ethanol concentration in expired air four times: immediately after alcohol intake and at 20, 40 and 60 min after alcohol intake. The visual stimulation tool was a checkerboard. It showed alternations of black and red patterns at a frequency of 8 Hz. The stimulus was displayed for 10 s after a rest of 30 s. The stimulus was repeated 10 times. Oxy-Hb concentration increased and deoxy-Hb concentration decreased during visual stimulation before and after alcohol intake, despite changes in the score of subjective feelings of alcohol and BAC. Alcohol intake does not significantly affect hemodynamic changes caused by visual stimulation in the visual cortex.