Clozapine inhibits isolated N-methyl-D-aspartate receptors expressed in xenopus oocytes in a subunit specific manner

Antipsychotic agents have typically been viewed as acting through dopaminergic targets, although mounting evidence suggests that drugs such as clozapine may act on glutamatergic systems. In order to explore the effects of clozapine on the NMDA class of glutamate receptors, oocytes expressing the NMDA receptor NR1 subunit, coupled with different NR2 subunits, were exposed to clozapine and NMDA induced current was measured with two electrode voltage-clamp techniques. Our results indicate that clozapine inhibits the NMDA receptor, but that this inhibition is subunit specific, being significantly greater for receptors containing NR2A and NR2B than for those containing NR2C. Interestingly, the inhibition required pretreatment with clozapine before activation of the receptor with NMDA. In addition to providing mechanistic insights, this finding may help to explain divergent results in the literature regarding the effects of antipsychotic agents on glutamate receptors

Confounding effects of volatile anesthesia on CBV assessment in rodent forebrain following ethanol challenge

PURPOSE: To compare and contrast the pattern and characteristics of the cerebral blood volume (CBV) response to ethanol (EtOH) in rats under awake and anesthetized conditions. MATERIALS AND METHODS: Acute EtOH (0.75 g/kg) challenge-induced CBV changes were measured using a contrast-enhanced functional MRI CBV method in 15 male Sprague Dawley rats under three experimental conditions: 1.0% to 1.2% isoflurane (N = 5); 0.8% halothane (N = 5); and awake with no anesthetic (N = 5). Physiological parameters were collected from bench settings in nine rats from the above different conditions. Four parameters: 1) area under the curve (AUC%); 2) the maximum signal change (Max%); 3) EtOH absorption rate (alpha(2)); and 4) EtOH elimination rate (alpha(1)) were employed to compare EtOH-induced MRI signals between the awake and anesthetized groups. RESULTS: Both awake and anesthetized animals responded with an increase in CBV to EtOH challenge. However, the presence of anesthesia promoted a significant preferential flow to subcortical areas not seen in the awake condition. CONCLUSION: Unclear mechanisms of anesthesia add a layer of uncertainty to the already complex interpretation of EtOH\u27s influence on neuronal activity, cellular metabolism, and hemodynamic coupling

Rat supraoptic magnocellular neurones show distinct large conductance, Ca2+-activated K+ channel subtypes in cell bodies versus nerve endings

Large conductance, Ca2+-activated K+ (BK) channels were identified in freshly dissociated rat supraoptic neurones using patch clamp techniques.The single channel conductance of cell body BK channels, recorded from inside-out patches in symmetric 145 mM K+, was 246.1 pS, compared with 213 pS in nerve ending BK channels (P < 0.01).At low open probability (Po), the reciprocal of the slope in the ln(NPo)-voltage relationship (N, number of available channels in the patch) for cell body and nerve ending channels were similar: 11 vs. 14 mVper e-fold change in NPo, respectively.At 40 mV, the [Ca2+]i producing half-maximal activation was 273 nM, as opposed to > 1.53 μM for the neurohypophysial channel, indicating the higher Ca2+ sensitivity of the cell body isochannel.Cell body BK channels showed fast kinetics (open time constant, 8.5 ms; fast closed time constant, 1.6 and slow closed time constant, 12.7 ms), identifying them as ‘type I’ isochannels, as opposed to the slow gating (type II) of neurohypophysial BK channels.Cell body BK activity was reduced by 10 nM charybdotoxin (NPo, 37 % of control), or 10 nM iberiotoxin (NPo, 5 % of control), whereas neurohypophysial BK channels are insensitive to charybdotoxin at concentrations as high as 360 nM.Whilst blockade of nerve ending BK channels markedly slowed the repolarization of evoked single spikes, blockade of cell body channels was without effect on repolarization of evoked single spikes.Ethanol reversibly increased neurohypophysial BK channel activity (EC50, 22 mM; maximal effect, 100 mM). In contrast, ethanol (up to 100 mM) failed to increase cell body BK channel activity.In conclusion, we have characterized BK channels in supraoptic neuronal cell bodies, and demonstrated that they display different electrophysiological and pharmacological properties from their counterparts in the nerve endings

Percutaneous transcatheter device closure of an isolated congenital LV diverticulum: first case report

A congenital left ventricular diverticulum is a rare cardiac malformation. It is a developmental anomaly that occurs during embryogenesis. Presentations vary from asymptomatic patients to sudden death. To date, the treatment described has been surgical correction. The authors report the first transcatheter closure of an isolated congenital left ventricular diverticulum in a 12-year-old symptomatic girl.Siddhant Jain, Rajiv Mahajan and Manoj Kumar Rohi