The effects of central delivery of a positive allosteric modulator of GABA A receptors upon stress and hypertension in Schlager hypertensive mice

Hypertensive Schlager mice (BPH/2J) have neurogenic hypertension associated with abnormal reactivity of neurons in the forebrain integrating the response to aversive stress. We found that they also have functional and molecular differences in GABA A receptors compared to their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced by chronic stress and when administered, decreases anxiety by positive allosteric modulation of GABA A receptors. We therefore compared the effect of chronic intracerebroventricular allopregnanolone and its vehicle on blood pressure and stress reactivity in BPH/2J and BPH/3J mice. Implantation of telemetric probes enabled continuous recordings of blood pressure (BP) at rest and during aversive stressors (restraint and dirty cage switch stress). Two weeks of allopregnanolone reduced MAP (‐9.8±4.3mmHg) and the depressor response to ganglionic blockade (‐10.5mmHg) in BPH/2J but had little effect in BPN/3J. Furthermore, allopregnanolone selectively reduced the pressor response to restraint stress by 27.4% in BPH/2J mice. The selective antihypertensive and stress inhibitory effects of allopregnanolone in BPH/2J mice suggests that allosteric modulation of GABA A receptors has therapeutic potential to treat stress related hypertension.