Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.
The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.
Neuroscience Training Program, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Keith B
KB
Hengen
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Nathan R
NR
Nelson
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Kyle M
KM
Stang
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Stephen M
SM
Johnson
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Stephanie M
SM
Smith
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Jyoti J
JJ
Watters
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Gordon S
GS
Mitchell
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Madison, Wisconsin, United States of America.
Mary
M
Behan
D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D012125:Respiratory Center / Q000378:metabolism*; D012727:Sex Characteristics
D001463:Barbiturates; D011963:Receptors, GABA-A; D007530:Isoflurane; C032232:barbituric acid