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Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

ABSTRACT: The heterogeneity and distribution of GABA(A) receptor subunits mediates differential roles in behavior. It is thought that particular behavioral responses to benzodiazepine (BZ) ligands might be associated with an action at a regionally defined receptor subtype. However, the role of specific GABA(A) receptor subtypes in particular brain regions is less clear. Such detailed knowledge of regional alpha1-GABA(A) receptor function will advance our understanding of the neural circuitry underlying the role of GABA(A) receptors and the effects of GABA(A)-modulating drugs on behavior. By combining inducible, site-specific alpha1 subunit deletion, using a lentivirus expressing Cre-recombinase in mice with the alpha1 subunit gene flanked by loxP sites, we examine baseline and pharmacological effects of deletion of amygdala alpha1-GABA(A) receptors. We find that amygdala-specific reduction of alpha1 receptor subunits does not affect mRNA or protein levels of amygdala alpha2 or alpha3 subunit receptors. Nor does this inducible reduction affect baseline locomotion or measures of anxiety. However, we also find that this inducible, site-specific deletion does disrupt the normal sedative-locomotor inhibition as well as the anticonvulsive effects, of two distinct BZ-site ligands, diazepam and zolpidem, which is relatively alpha1-subunit selective. These data, using inducible, region and subunit-specific deletion, combined with pharmacogenetic approaches, demonstrate that amygdala expression of the alpha1-GABA(A) receptor subunit is required for normal BZ effects on sedation, locomotion, and seizure inhibition, but not for anxiolysis.

SUBMITTER: Heldt SA

PROVIDER: S-EPMC2905594 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

Heldt Scott A SA Ressler Kerry J KJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100501 21

The heterogeneity and distribution of GABA(A) receptor subunits mediates differential roles in behavior. It is thought that particular behavioral responses to benzodiazepine (BZ) ligands might be associated with an action at a regionally defined receptor subtype. However, the role of specific GABA(A) receptor subtypes in particular brain regions is less clear. Such detailed knowledge of regional alpha1-GABA(A) receptor function will advance our understanding of the neural circuitry underlying th ...[more]

PMID: 20505082

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Project description:BACKGROUND:Midazolam premedication is widely used before general anesthesia, but lacks clinical evidence of effectiveness. The present study aimed to evaluate the effectiveness of midazolam premedication following 4 aspects: anxiety reduction, sedation, hemodynamic stabilization, and analgesia. METHODS:In a randomized, single-blind, prospective study, a total of 128 women were allocated to the midazolam premedication group (Group P, n?=?64) or the control group (Group N, n?=?64). The patients were asked to complete the Beck anxiety inventory (BAI) 2 times: on the day before surgery (BS) and 30?minutes after midazolam premedication (T0). Depth of anesthesia using state entropy (SE), conventional hemodynamic data using heart rate (HR) and mean blood pressure (MBP), and analgesic profiles using surgical pleth index (SPI) were acquired at the following 4 points: T1-pre-induction, T2-prior to intubation, T3-intubation, and T4-20?minutes after intubation. RESULTS:No change in BAI score was observed between BS and T0 in both groups P and N (median and interquartile range [IQR], Group P: BS-4.5 [2.0-7.0], T0-4.0 [1.0-9.0], P?=?.603; Group N: BS-4.0 [1.0-8.5], T0-3.5 [1.0-6.0], P?=?.066). Midazolam premedication reduced SE at T2-4 (mean difference with 95% confidence interval [95% CI], T2-7.1 [1.6-12.6], P?=?.012; T3-10.4 [6.5-14.4], P?<?.001; T4-9.2 [5.0-13.4], P?<?.001). Midazolam premedication also reduced HR (mean differences [95% CI], T1-7.3 [2.5-12.1], P?=?.003; T3-6.6 [1.1-12.2], P?=?.020) and MBP at T1 and T3 (mean differences [95% CI], T1-7.3 [2.5-12.1], P?=?.003; T3-8.6 [1.3-15.9], P?=?.021), and lowered SPI at T1-3 (mean differences [95% CI]: T1-12.7 [6.1-19.4], P?<?.001; T2-6.0 [0.5-11.5], P?=?.033; T3-7.9 [1.7-14.1], P?=?.012). CONCLUSION:Midazolam premedication did not reduce the level of anxiety. However, midazolam premedication reduced the entropy values, stabilized hemodynamics, and provided analgesia during the induction of anesthesia. The purpose of midazolam premedication needs to be reconsidered.

Dataset Information

Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

Publications

Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

Similar Datasets

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