The Effects of Early Rearing Environment on the Development of GABAA and Central Benzodiazepine Receptor Levels and Novelty-Induced Fearfulness in the Rat

Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABAA receptors in mice heterozygous for the gamma2 subunit was reduced, mainly in hippocampus and cerebral cortex. The gamma2 +/- mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus gamma2 +/- mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders.

Decreased GABA A -receptor clustering results in enhanced anxiety and a bias for threat cues

Stressful experiences in early life are known risk factors for anxiety and depressive illnesses, and they inhibit hippocampal neurogenesis and the expression of GABA(A) receptors in adulthood. Conversely, deficits in GABAergic neurotransmission and reduced neurogenesis are implicated in the etiology of pathological anxiety and diverse mood disorders. Mice that are heterozygous for the gamma2 subunit of GABA(A) receptors exhibit a modest functional deficit in mainly postsynaptic GABA(A) receptors that is associated with a behavioral, cognitive, and pharmacological phenotype indicative of heightened trait anxiety. Here we used cell type-specific and developmentally controlled inactivation of the gamma2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the gamma2 subunit induced selectively in immature neurons of the embryonic and adult forebrain resulted in reduced adult hippocampal neurogenesis associated with heightened behavioral inhibition to naturally aversive situations, including stressful situations known to be sensitive to antidepressant drug treatment. Reduced adult hippocampal neurogenesis was associated with normal cell proliferation, indicating a selective vulnerability of postmitotic immature neurons to modest functional deficits in gamma2 subunit-containing GABA(A) receptors. In contrast, a comparable forebrain-specific GABA(A) receptor deficit induced selectively in mature neurons during adolescence lacked neurogenic and behavioral consequences. These results suggest that modestly reduced GABA(A) receptor function in immature neurons of the developing and adult brain can serve as a common molecular substrate for deficits in adult neurogenesis and behavior indicative of anxious and depressive-like mood states.

https://www.jneurosci.org/content/jneuro/27/14/3845.full.pdf

GABAergic Control of Adult Hippocampal Neurogenesis in Relation to Behavior Indicative of Trait Anxiety and Depression States

Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study.

BACKGROUND:Melatonin has sedative, analgesic, antiinflammatory, antioxidative, and chronobiotic effects. We determined the impact of oral melatonin premedication on anxiolysis, analgesia, and the potency of the rest/activity circadian rhythm.METHODS:This randomized, double-blind, placebo-controlled

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The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy.

In a randomised, double-blind, parallel groups study, 40 patients referred for surgical removal of impacted third molars received either (a) temazepam 40 mg orally followed at 35 min by IV saline or (b) oral placebo followed by IV diazepam 10 mg (Diazemuls). Patients were divided into High-Anxious and Low-Anxious groups by median split of their anxiety scores on the Speilberger State Anxiety Scale at the time of oral medication. Compared with placebo, temazepam significantly attenuated anticipatory anxiety in the High-Anxious group while in the Low-Anxious group no difference was found between the treatments. Preoperative but not intraoperative heart-rate distinguished between the High-Anxious and Low-Anxious groups and neither oral temazepam nor IV diazepam abolished the heart-rate response to the traumatic stages of the surgical procedure. The results are interpreted as providing support in a “real life” human stress setting for Gray's neuropsychological model of anxiety.

Hugh Barry

Papers

Differential effect of benzodiazepine sedation in high and low anxious patients in a real life stress setting