Paradoxical widespread c-Fos expression induced by a GABA agonist in the forebrain of transgenic mice with ectopic expression of the GABA(A) α6 subunit.

A GABA-site agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) at 3 mg/kg induces strong anxiolytic response in a transgenic Thy1α6 mouse line ectopically expressing the GABA(A) receptor α6 subunit gene under the Thy-1.2 promoter. Now, we compared brain activation patterns between Thy1α6 and wild-type mice to identify brain structures potentially mediating this anxiolytic response. Acutely efficient anxiolytics such as benzodiazepines typically depress most brain regions while activating specifically neurons within the central extended amygdala. Gaboxadol treatment (3 mg/kg, i.p., 2 h) induced a significant increase in c-Fos expression selectively in many Thy1α6 brain regions including the limbic cortex, anterior olfactory nucleus, septal area and central and basolateral nuclei of amygdala. It failed to activate the lateral part of mediodorsal thalamic nucleus (MDL) in the Thy1α6 mice that was activated in the wild-type mice. Detailed mapping of the α6 subunit mRNA by in situ hybridization revealed expression in the middle layers of the isocortex, olfactory areas, hippocampal formation and basolateral nucleus of amygdala (BLA) in the Thy1α6 forebrain. The ligand autoradiographies (t-butylbicyclophosphoro[(35)S]thionate ([(35)S]TBPS) and [(3)H]Ro 15-4513) revealed high levels of pharmacologically active extrasynaptic α6ß and α6ßγ2 GABA(A) receptors in these same areas. However, c-Fos induction by gaboxadol treatment in Thy1α6 brain was not restricted to areas highly expressing the α6-containing GABA(A) receptors suggesting that indirect pathways lead to the paradoxically widespread activation. Interestingly, the activation pattern by gaboxadol at the dose that is anxiolytic in Thy1α6 mice resembled closely that observed after various fear- and stress-provoking challenges. However, our results are consistent with a recent observation that optogenetic activation of specific neuronal pathways in the extended amygdala mediates anxiolytic responses. Our results suggest that the widespread neuronal inhibition as typically associated with benzodiazepines is not the exclusive mechanism of anxiolysis.

Conscious sedation by rectal administration of midazolam or midazolam plus ketamine as alternatives to general anesthesia for dental treatment of uncooperative children.

The trial included 24 children (aged 2-7 yr) referred for dental treatment under general anesthesia, since conventional behavioral management methods had failed to achieve treatment acceptance. As an alternative, they received, on two separate occasions with "identical" dental treatment, conscious sedation by rectal administration of either midazolam (0.3 mg/kg body weight (bwt)) or midazolam (0.3 mg/kg bwt) plus ketamine (1.0 mg/kg bwt). This allowed a double-blind, crossover design. The aims were to assess conscious sedation, combined with local anesthesia, as an alternative to general anesthesia, and further to evaluate the effects obtained by addition of a low dose of ketamine to rectally administered midazolam. The feasibility of dental treatment was rated as excellent or good for 16 of the 24 children when premedicated with midazolam, and for 18 of the 24 children when ketamine was added to midazolam. At least some treatment could be given to all children. Verbal contact was maintained with all children throughout both treatment sessions. The children were significantly less anxious when they arrived for the second session. Amnesia and drowsiness were significantly increased when ketamine was added to midazolam. The combination also tended to be more efficient in relief of anxiety and prevention of pain, but there were large variations in the children's responses to the drugs. Midazolam significantly reduced the blood oxygen level, but not with ketamine added. For most children, both regimens proved to be appropriate as alternatives to general anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)