GABA regulates the rat hypothalamic-pituitary-adrenocortical axis via different GABA-A receptor alpha-subtypes.
The control of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) is balanced by excitatory and inhibitory inputs. The GABA-A receptor, which is a major target for the inhibitory control, is composed of five subunits. The presence of an alpha(1)-, alpha(2)-, alpha(3)-, or alpha(5)-subunit in the GABA-A receptor protein complex is necessary for benzodiazepines to exert their potentiating effect on the receptor. We postulate that the effect of nonselective benzodiazepines on the hypothalamo-pituitary adrenocortical (HPA) axis is critically dependent on the composition of the GABA-A receptor subunits through which they act. We show here that positive modulators of alpha(1)-subtype containing GABA-A receptors with zolpidem (10 mg/kg) increase HPA activity in terms of increase in plasma corticosterone and induction of Fos in the PVN, whereas activation of non-alpha(1)-subtype GABA-A receptors using L-818,417 (10 mg/kg) likely inhibits the activity. We also show that the alpha(2)-subunit gene is highly expressed in the PVN, but its expression is not affected by chronic mild stress. These results show that the stimulatory effect on HPA activity after positive modulation of GABA-A receptors composed of alpha(1)-subunit(s) affects a selective afferent system than the PVN, which is distinct from another afferent system(s) activated by non alpha(1)-containing GABA-A receptors.
Mikkelsen
Jens D
JD
Department of Translational Neurobiology, NeuroSearch A/S, Ballerup, Denmark. JDM@Neurosearch.dk
Bundzikova
Jana
J
Larsen
Marianne H
MH
Hansen
Henrik H
HH
Kiss
Alexander
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009434:Neural Pathways / Q000033:anatomy & histology / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005464:Fluorobenzenes; D018755:GABA Agonists; D018757:GABA Modulators; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D011963:Receptors, GABA-A; D014230:Triazoles; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; C409903:L 838,417; D003346:Corticotropin-Releasing Hormone; D003975:Diazepam