Premium
The effect of chronic treatment with diazepam on stress and hypertension in Schlager BPH/2J hypertensive mice
Author(s) -
Davern Pamela,
Chowdhury Sara,
Jackson Kristy,
Nguyen-Huu Thu-Phuc,
Head Geoffrey
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1091.48
Subject(s) - diazepam , gabaergic , amygdala , hypothalamus , endocrinology , gabaa receptor , medicine , spontaneously hypertensive rat , chemistry , chronic stress , receptor , pharmacology , blood pressure
Schlager hypertensive mice (BPH/2J) are a neurogenic model of hypertension that show a greater BP increase with the onset of the dark when they become active. This induces greater neuronal activation (as detected by Fos) in the medial amygdala (MeAm), central amygdala, paraventricular hypothalamus and dorsomedial hypothalamus of BPH/2J compared with normotensive BPN/3J mice. Aversive stress (dirty‐cage switch) increased MAP in BPH/2J more than in BPN/3J and also produced greater Fos expression in the hypothalamus and amygdala. MeAm neurons are tonically inhibited by GABAergic interneurons and lesions of the MeAm reduce hypertension in BPH/2J mice. Diazepam acts via GABAA receptors to induce anxiolytic effects via fibres innervating GABAergic neurons. Together this suggests that BPH/2J hypertension could be due to a lack of GABA activation of the MeAm. Therefore, we investigated whether stress activated neurons in the MeAm receive less GABA inhibition and if this can be restored by chronic GABA A activation with treatment of diazepam. We used male BPN/3J and BPH/2J mice that were implanted with telemetry probes and recordings of cardiovascular and activity parameters were made before and after diazepam (2.5mg/kg/day) or vehicle administration for 7 days. The results show that chronic diazepam treatment in BPN/3J mice (n=7) decreased MAP (−4.8 mmHg; P <0.01), while BPH/2J mice (n=7) had no significant change in MAP (+2.1mmHg). Restraint stress in diazepam treated mice reduced BP and was associated with fewer activated neurons (Fos) in the MeAm in BPN/3J mice (18±1.2) compared with BPH/2J mice (25±1.2; P <0.01). In the MeAm of BPH/2J mice, 68% of activated neurons (Fos) also expressed GABAA receptors, with no colocalisation observed in BPN/3J mice. Together our data suggests a fundamental irregularity of GABA inhibitory regulation in the MeAm of BPH/2J hypertensive mice.