title: GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice.
abstract: OBJECTIVE
  Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice.
  
  
  METHODS
  Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry.
  
  
  RESULTS
  Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 ± 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 ± 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20% (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and ~50% of stress-activated neurons in these regions also expressed GABAA receptors and ~45% were neuropeptide Y-containing.
  
  
  CONCLUSIONS
  These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.
authors.affiliation: aNeuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne bDepartment of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Sara
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Jackson
authors.forename: Thu-Phuc
authors.initials: TP
authors.lastname: Nguyen-Huu
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D003975:Diazepam / Q000008:administration & dosage; D018757:GABA Modulators / Q000008:administration & dosage; D005730:Ganglionic Blockers / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009478:Neuropeptide Y / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010425:Pentolinium Tartrate / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011963:Receptors, GABA-A / Q000502:physiology*; D012149:Restraint, Physical; D013312:Stress, Physiological
chemical_list: D018757:GABA Modulators; D005730:Ganglionic Blockers; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D011963:Receptors, GABA-A; D010425:Pentolinium Tartrate; D003975:Diazepam