• Energy Research
• Closed Access close
• DE close
• Neuroscience close

Abstract : Some serotonin 5‐HT3 receptor ligands of tropeine structure have been recently shown to modulate ionophore function and binding of glycine receptors. This led us to study the effects of the tropeines tropisetron and atropine on recombinant human glycine receptors transiently expressed in Xenopus oocytes by using whole‐cell voltage‐clamp electrophysiology. Glycine currents were inhibited by atropine in an apparently competitive manner and with considerable selectivity of the tropeines for α2 versus α1 subunits. Coexpression of β with α subunits and replacement of the N‐terminal region of the α1 subunits by the corresponding β segment resulted in similar increases in the inhibitory potencies. Our data suggest common sites of the tropeines for inhibition on the N‐terminal region of glycine receptors. The point mutations R271K and R271L of the α1 subunit decreased, whereas a T112A substitution increased, the inhibition constants (Ki) of the tropeines. These changes in the Ki values of the tropeines were associated with opposite changes in the EC50 of glycine. Selectivities for the tropeines versus glycine (EC50/Ki) varied within three orders of magnitude. These results, when expressed in terms of free energy changes, can be interpreted according to a two‐state receptor model.

Ethanol intoxication (EI) is a frequent comorbidity of traumatic brain injury (TBI), but the impact of EI on TBI pathogenic cascades and prognosis is unclear. Although clinical evidence suggests that EI may have neuroprotective effects, experimental support is, to date, inconclusive. We aimed at elucidating the impact of EI on TBI-associated neurological deficits, signaling pathways, and pathogenic cascades in order to identify new modifiers of TBI pathophysiology. We have shown that ethanol administration (5 g/kg) before trauma enhances behavioral recovery in a weight-drop TBI model. Neuronal survival in the injured somatosensory cortex was also enhanced by EI. We have used phospho-receptor tyrosine kinase (RTK) arrays to screen the impact of ethanol on TBI-induced activation of RTK in somatosensory cortex, identifying ErbB2/ErbB3 among the RTKs activated by TBI and suppressed by ethanol. Phosphorylation of ErbB2/3/4 RTKs were upregulated in vGlut2+ excitatory synapses in the injured cortex, including excitatory synapses located on parvalbumin (PV)-positive interneurons. Administration of selective ErbB inhibitors was able to recapitulate, to a significant extent, the neuroprotective effects of ethanol both in sensorimotor performance and structural integrity. Further, suppression of PV interneurons in somatosensory cortex before TBI, by engineered receptors with orthogonal pharmacology, could mimic the beneficial effects of ErbB inhibitors. Thus, we have shown that EI interferes with TBI-induced pathogenic cascades at multiple levels, with one prominent pathway, involving ErbB-dependent modulation of PV interneurons.

Our presently somewhat limited knowledge of the modulation of the content, release and turnover of endorphins in brain and pituitary by acute and chronic drug treatment is reviewed and discussed particularly in relation to the problem of addiction. In vitro studies in striatal slices and isolated anterior and intermediate/posterior lobes of the pituitary point to the existence of specific interactions between endorphins and neurotransmitters. In vivo studies have revealed acute GABA-mediated effects of benzodiazepines upon striatal levels of met-enkephalin activity. Morphine exerts no acute effects upon endorphin levels, but decreases the levels of particular endorphins in specific areas of brain and pituitary after long-term treatment; somewhat similar effects are observed after prolonged intake of ethanol, whereas chronic haloperidol treatment results in an increase in levels of endorphins in brain and pituitary. Incorporation studies employing the intermediate/posterior lobe of the pituitary have revealed that the changes in beta-endorphin levels produced by prolonged treatment with morphine or haloperidol reflect a respective depressed or enhanced synthesis of the beta-endorphin precursor pro-opiocortin, whilst the enzymatic processing of this precursor remains unmodified. Studies in cell-free preparations demonstrated that m-RNA extracted from the intermediate/posterior lobes of chronically morphinized rats possesses a decreased "activity".

A measurement protocol providing a correct adjustment of the irradiation frequencies for well separated fat and water images of the lumbar spine is presented. To determine accurately the Larmor frequencies of water and fat protons within the vertebral bodies, a volume selective spectrum of a volume element (13 mm)3 located in a lumbar vertebral body was acquired with the 90 degrees-180 degrees-180 degrees double spin-echo method. These Larmor frequencies are used to adjust the frequency-selective pulse of the SENEX chemical-shift imaging sequence. This procedure provides well separated fat and water images for a large field of view even in the inhomogeneous region of the vertebral column. Their clinical importance is demonstrated by localized Larmor frequency-guided (LLFG) SENEX 1H images of the lumbar spine in healthy persons of different age and in a patient with acute myeloid leukemia.

Abstract Treatment of rats with ethanol for 3 weeks resulted in a significant increase in δ-opiate receptor binding whereas no change in μ-opiate receptor binding was observed. Scatchard analysis showed an increase in δ-receptor affinity without a change in the receptor density. Acute treatment with ethanol did not alter receptor characteristics. The data provide evidence that δ- and μ-opiate receptor sites can be differentially modulated in vivo.

Bei 200 Patienten mit den typischen Zeichen eines organischen Psychosyndroms wurden Hirndurchblutung, cerebraler Verbrauch von Sauerstoff und Glucose sowie der zur Oxydation gelangende Glucoseanteil bestimmt. In 170 Fallen (85%) war eine dieser Grosen fuhrend herabgesetzt, bei 28 Fallen (14%) lagen gesteigerte Werte vor, bei zwei Patienten (1%) waren die Befunde normal. Lediglich in 35 Fallen (17,5%) war eine Minderung der Hirndurchblutung der fuhrende Befund. Bei 68% der von uns untersuchten Patienten waren Storungen des Hirnstoffwechsels mit einem zum Teil erheblichen cerebralen Energiedefizit vorherrschend. Das bedeutet, das beim organischen Psychosyndrom viermal haufiger cerebrale Stoffwechselstorungen im Vordergrund stehen als cerebrale Durchblutungsstorungen. Damit werden auch die aus dem psychopathologischen Bild, dem EEG oder dem Pneumencephalogramm gestellten Diagnosen „cerebrale Durchblutungsstorungen“, „cerebrovasculare Insuffizienz“, „Cerebralsklerose“ oder „Hirnarteriosklerose“ in ihrem Aussagewert zweifelhaft.

NMDA receptors are ionotropic glutamate receptors assembled of subunits of the NR1 and of the NR2 family (NR2A-NR2D). The subunit diversity largely affects the pharmacological properties of NMDA receptors and, hence, gives rise to receptor heterogeneity. As an overall result of studies on recombinant and native NMDA receptors, ethanol inhibits the function of receptors containing the subunits NR2A and/or NR2B to a greater extent than those containing NR2C or NR2D. For example, in rat cultured mesencephalic neurons, NR2C expression was developmentally increased, whereas expression of NR2A and NR2B was decreased. These changes coincided with a developmental loss of sensitivity of NMDA responses to ethanol and ifenprodil, a non-competitive NMDA receptor antagonist that shows selectivity for NR2B-containing receptors. Also in rat locus coeruleus neurons, the low ethanol sensitivity of somatic NMDA receptors could be explained by a prominent expression of NR2C. The inhibitory site of action for ethanol on the NMDA receptor is not yet known. Patch-clamp studies suggest a target site exposed to or only accessible from the extracellular environment. Apparently, amino acid residue Phe(639), located in the TM3 domain of NR1, plays a crucial role in the inhibition of NMDA receptor function by ethanol. Since this phenylalanine site is common to all NMDA and non-NMDA receptor (AMPA/kainate receptor) subunits, this observation is consistent with accumulating evidence for a similar ethanol sensitivity of a variety of NMDA and non-NMDA receptors, but it cannot explain the differences in ethanol sensitivity observed with different NR2 subunits.

5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT(3)) receptors belong to the alcohol-sensitive superfamily of Cys-loop ligand-gated ion channels, and they are thought to play an important role in alcoholism. Alcohols with small molecular volumes increase the amplitude of currents evoked by low 5-HT concentrations and shift the 5-HT concentration-response curve for 5-HT(3) receptor activation leftward, indicative of increased receptor sensitivity to agonist. This action is significantly smaller when currents are mediated by heteromeric 5-HT(3AB) receptors compared with homomeric 5-HT(3A) receptors. In this study, we used the highly inefficacious 5-HT(3) receptor agonist dopamine to determine whether this difference between 5-HT(3A) and 5-HT(3AB) receptors reflects differential alcohol modulation of agonist binding affinity or channel gating efficacy. Human recombinant 5-HT(3A) and 5-HT(3AB) receptors were expressed in Xenopus oocytes, and currents were measured in the absence and presence of alcohols using the two-electrode voltage-clamp technique. Modulation by alcohols of peak currents elicited by maximally activating concentrations of dopamine was alcohol concentration-dependent. Potentiation by smaller alcohols was consistently significantly greater in 5-HT(3A) than in 5-HT(3AB) receptors, whereas inhibition by larger alcohols was not. A representative small (butanol) and large (octanol) alcohol failed to alter the EC(50) value for channel activation by dopamine. We conclude that the presence of the 5-HT(3B) subunit in 5-HT(3AB) receptors significantly reduces the enhancement of gating efficacy by small alcohols without altering the inhibitory actions of large alcohols.