Effect of local inhibition of gamma-aminobutyric acid uptake in the dorsomedial hypothalamus on extracellular levels of gamma-aminobutyric acid and on stress-induced tachycardia: a study using microdialysis.
Previous studies involving local microinjection of drugs that interfere with gamma-aminobutyric acid (GABA)A receptor-mediated synaptic inhibition have led to the suggestion that endogenous GABA suppresses the activity of a sympatho-excitatory mechanism in the dorsomedial hypothalamus in rats. In this study, microdialysis was used to assess and to alter pharmacologically extracellular-levels of GABA within this region while simultaneously monitoring heart rate and blood pressure. In anesthetized rats, local microdialysis for 15 min with 2.5, 10 and 40 mM nipecotic acid, an inhibitor of GABA uptake, caused concentration-related increases in GABA and taurine in the extracellular space, but no significant change in heart rate or arterial pressure. Similar perfusion with 37.5, 75 and 150 mM KCl caused concentration-related increases in GABA as well as aspartate, glutamate, taurine, glycine and alanine. Only modest, variable increases in heart rate and no effect on arterial pressure were observed during the perfusions with high potassium. In conscious rats, unilateral microdialysis of the dorsomedial hypothalamus with 0.5 mM nipecotic acid for 2 to 2.5 hr before stress coupled with contralateral microinjection of muscimol (88 pmol/250 nl) 5 min before stress significantly reduced air stress-induced tachycardia; this reduction in tachycardia was associated with markedly elevated levels of GABA in dialysates collected from the dorsomedial hypothalamus. Neither treatment alone significantly influenced stress-induced increases in heart rate, although perfusion with nipecotic acid alone evoked similar elevations in extracellular GABA. These results suggest that extracellular levels of endogenous GABA in the dorsomedial hypothalamus may regulate the cardiovascular response to stress.
Anderson
J J
JJ
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis.
DiMicco
J A
JA
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003956:Dialysis / Q000379:methods; D005110:Extracellular Space / Q000378:metabolism*; D006339:Heart Rate / Q000502:physiology; D007033:Hypothalamus, Middle / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D013312:Stress, Physiological / Q000150:complications* / Q000503:physiopathology; D013610:Tachycardia / Q000209:etiology / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000493:pharmacokinetics
D000596:Amino Acids; D009557:Nipecotic Acids; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline; D011188:Potassium