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We compared the modulation of GABA (gamma-aminobutyric acid)-activated currents by benzodiazepines in recombinant GABAA receptors containing either one of two alpha subunits, alpha 1 or alpha 6. Lüddens et al. (Nature, 346 (1990) 648-651) have previously demonstrated that the alpha 6 subunit is part of a cerebellar receptor subtype which selectively binds Ro15-4513, an antagonist of alcohol-induced motor ataxia. Here we report that the imidazobenzodiazepine Ro15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-(1,5-a) (1,4)benzodiazepine-3-carboxylate) reduced GABA-activated currents in recombinant alpha 6 beta 2 gamma 2 and alpha 1 beta 2 gamma 2 receptors, thus acting consistently as an inverse agonist. Moreover, another well characterized negative modulator, DMCM (methyl-4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate), also reduces GABA activated-currents in both receptors. In contrast, flunitrazepam (FNZM), a benzodiazepine agonist, increases GABA-activated currents in alpha 1 beta 2 gamma 2 receptors, but not in alpha 6 beta 2 gamma 2 receptors. This study lends further support to the hypothesis that the binding sites of full and partial inverse agonists are different.

Maximal L-glutamate/glycine-evoked currents were inhibited by ethanol in Xenopus laevis oocytes expressing recombinant heteromeric NMDA receptors consisting of NR1-NR2A, NR1-NR2B, and NR1-NR2C subunit combinations. Concentration-dependent inhibition was observed at ethanol concentrations of > or = 50 mM both in Ca(2+)-containing and Ca(2+)-deficient, Ba(2+)-containing Mg(2+)-free media. The NR1-NR2C channels were slightly less sensitive to ethanol inhibition than the other heteromeric channels in Ca(2+)-deficient, Ba(2+)-containing medium. The inhibition was unaffected by the clamping-voltage and by a mutation [NR1-NR2A(N595Q)] that prevents the Mg(2+)-blockade of the channels, indicating that the mechanism of action of ethanol differs from that of Mg2+. The results are consistent with the hypothesis that the NMDA receptor subtypes can mediate many behavioural actions of ethanol.

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1-/- mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1-/- mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1-/- mice did not differ significantly from wild-type mice in ethanol's sedative or incoordinating effects. However, the GluR1-/- mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1-/- mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1-/- mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1-/- mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.

PurposeTo explore the use of PINS radiofrequency (RF) pulses to reduce RF power deposition in multiband/simultaneous multislice imaging with the RARE/turbo spin echo (TSE) sequence at 3T and 7T.MethodsA PINS‐TSE sequence was implemented and combined with blipped CAIPI to improve the reconstruction of superposed slices. Whole brain imaging of healthy volunteers was performed at both 3T and 7T using a 32‐channel coil for signal reception.ResultsA considerable reduction in power deposition was achieved compared with a standard sequence of the manufacturer. At 3T, the reduction in specific absorption rate (SAR) made short pulse repetition times (TRs) possible, however, in order to obtain a good T2 contrast, it is advisable to maintain TR while extending the echo train length. At 7T, whole brain coverage with a spatial resolution of 1 × 1 × 2 mm3 was achieved in an acquisition time of 150 s. Furthermore, it could be shown that pulse sequences that use PINS pulses do not suffer from having additional magnetization transfer contrast.ConclusionPINS RF pulses combined with multiband imaging reduce SAR sufficiently to enable routine TSE imaging at 7T within clinically acceptable acquisition times. In general, the combination of multiband imaging with PINS RF pulses represents a method to reduce total RF power deposition. Magn Reson Med 71:44–49, 2014. © 2013 Wiley Periodicals, Inc.

Although both alcohol intoxication and withdrawal have been demonstrated to produce significant endocrine alterations, no data exist on the effects of acute withdrawal on immune functions. Therefore, the current study investigated the effect of alcohol intoxication and acute withdrawal on plasma cortisol, prolactin and catecholamines, and blood leukocyte subset distribution in alcohol-dependent subjects. Nine male alcoholics admitted to the university clinic for alcohol dependence and 9 age-matched controls participated in the study. Blood was drawn from the alcohol-dependent subjects at 10:30 a.m. on day 0 (chronic alcohol intoxication), at the same time during acute alcohol withdrawal (day 1) and following the resolution of acute withdrawal (day 7). Blood was drawn from age- and gender-matched healthy control subjects at the corresponding time points. Plasma was then analyzed for hormone concentrations and blood examined for leukocyte subsets by flow cytometry. Alcohol-dependent patients displayed significantly elevated plasma cortisol during intoxication and withdrawal, which decreased to control levels following resolution of acute withdrawal. Small elevations of plasma prolactin and catecholamines were also observed during intoxication. Furthermore, alcohol-dependent subjects showed reduced absolute numbers of CD4⁺ and CD8⁺ T cells and natural killer cells compared with healthy controls across all time points. In contrast, although monocyte numbers were lower in alcohol-dependent patients during intoxication, acute alcohol withdrawal increased the number of monocytes in patients. Thus, alcohol dependence produces a general suppression of leukocyte subset populations in blood. However, resolution of acute alcohol withdrawal is associated with a return of plasma cortisol to control levels, and a concomitant increase in peripheral blood monocyte numbers.