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Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA(A) receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

Background There are three kinds of allosteric modulators acting through the benzodiazepine (BZ) binding site of the GABAA receptor: positive (agonist), neutral (antagonist), and negative (inverse agonist) modulators. Agonists and inverse agonists commonly exert bidirectional influences on observed behavioral parameters. In the present study we have investigated the modulation of behavioral responses to environmental novelty in two unconditioned paradigms: spontaneous locomotor activity (SLA) and forced swim test (FST), elicited by DMCM (methyl-6,7dimethoxy-4-ethyl-beta-carboline-3-carboxylate), a nonselective inverse agonist, in the dose range that previously did not produce anxiogenic effects and convulsions.

Supernumerary diaphragm is a rare congenital abnormality. This paper describes a neonate with respiratory distress caused by an overdistended left upper lobe and atelectasis of the left lower lobe entrapped below the accessory hemidiaphragm. Excision of the membrane dividing the hemithorax led to an uneventful recovery.