1 Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABA A receptors, the mechanism of modulation is not well understood. 2 The applicability of an allosteric model with two binding sites for g-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated. 3 This model predicts that BZDs should enhance the efficacy of partial agonists. 4 Consistent with this prediction, diazepam increased the efficacy of the GABA A receptor partial agonist kojic amine in chick spinal cord neurons. 5 To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant a1(L263S)b3g2 GABA A receptors expressed in HEK-293 cells. 6 In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors. 7 The results indicate that BZD-like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond.

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Background:Compounds targeting the benzodiazepine binding site of the GABA A -R are widely prescribed for the treatment of anxiety disorders, epilepsy, and insomnia as well as for preanesthetic sedation and muscle relaxation. It has been hypothesized that these various pharmacological effects are mediated by different GABA A -R subtypes. If this hypothesis is correct, then it may be possible to develop compounds targeting particular GABA A -R subtypes as, for example, selective anxiolytics with a diminished side effect profile. The pyrazolo[1,5-a]-pyrimidine ocinaplon is anxioselective in both preclinical studies and in patients with generalized anxiety disorder, but does not exhibit the selectivity between α 1 /α 2 -containing receptors for an anxioselective that is predicted by studies using transgenic mice. Results:We hypothesized that the pharmacological properties of ocinaplon in vivo might be influenced by an active biotransformation product with greater selectivity for the α 2 subunit relative to α 1 . One hour after administration of ocinaplon, the plasma concentration of its primary biotransformation product, DOV 315,090, is 38% of the parent compound. The pharmacological properties of DOV 315,090 were assessed using radioligand binding studies and two-electrode voltage clamp electrophysiology. We report that DOV 315,090 possesses modulatory activity at GABA A -Rs, but that its selectivity profile is similar to that of ocinaplon. Conclusion:These findings imply that DOV 315,090 could contribute to the action of ocinaplon in vivo, but that the anxioselective properties of ocinaplon cannot be readily explained by a subtype selective effect/action of DOV 315,090. Further inquiry is required to identify the extent to which different subtypes are involved in the anxiolytic and other pharmacological effects of GABA A -R modulators.

Glutamate receptors play a major role in relapse of cocaine addiction. Effective treatments for prevention of relapse are still lacking. Previously, our laboratory has shown that pregnanolone hemisuccinate (3α5βHS or PAHS), the synthetic analogue of pregnanolone sulfate, inhibits reinstatement of cocaine seeking behavior in rats. In order to determine the mechanism of action of 3α5βHS, recombinant NMDA, AMPA and GABAA receptors were expressed in Xenopus laevis oocytes and two electrode voltage‐clamp recordings were performed. We observed that 3α5βHS inhibits all four subtypes of the NMDA receptor with similar efficacies (about −20%). However, the potency at the NR1A/2A subunit combination is 10 to 30 fold higher as compared with the NR1A/2B, 2C, and 2D subtypes. The EC50 for NR1A/2A is 0.32μM, whereas the EC50's for the NR1A/2B, 2C, and 2D subtypes are 4.3μM, 12.3μM and 9.8μM, respectively. Four subtypes of the GABA‐A receptor (α1β2γ2s, α2β2γ2s, α3β2γ2s, and α5β2γ2s) are inhibited by 3α5βHS with potencies ranging from 6–9μM and maximum efficacy of −18%. The AMPA receptor subtype GluR1 is slightly inhibited by 3α5βHS, however, 3α5βHS has no effect on GluR3 and the heteromeric GluR1/R2 receptor. The use of a multifunction compound acting on multiple receptor subtypes such as 3α5βHS may be effective in the treatment of cocaine seeking.

Objective: 3.5% of Magnetic Resonance (MR) Imaging studiesat St. James's UniversityHospital. Leeds. UK. are terminated before completiondue to patient distress during the procedure.The study aimed to quantify the anxiety associated with a terminated procedure and compare this with patients who tolerated the full MR scan. Methods: Twenty patients who requested early termination of an MR scan were assessed immediately with the SpielbergerState Trait Anxiety Inventory to give a measure of state and trait anxiety. They were compared with a group of twenty patients who completed an MR scan. We attempted to match the comparison group by age, sex and imagingprocedure. Results:The mean state anxietyscores were significantly higher in the patients requesting an early terminationof scans (almost double the mean score of the comparison group). There was no significant difference between the groups on trait anxiety even though this was measuredat the same time as state anxiety. Conclusion: Severe anxiety is associated with early termination of MR scans. The level of anxiety in this situation is very high. The anxiety may not be predictable from measures of trait anxiety. This was confirmed in part by comments from some patients expressing surprise at the severity of their anxiety. Doctors referring patients for MR scans shouldbe awareof the potentialfor severeanxietyreactions and counsel patientsaccordingly. RETROSPECTIVE STUDY OF MUNCHAUSEN SYNDROME