GABA neurocircuits controlling the Hypothalamic-Pituitary-Adrenal Axis

Andreas Søderman

Studenteropgave: Speciale

Abstrakt

#Previous studies have demonstrated that classical benzodiazepines decrease hypothalamic–pituitary–adrenocortical cortex (HPA) axis activity. Paradoxically, high doses of enzodiazepines also stimulate basal circulating corticosterone levels in some conditions. Because benzodiazepine agonists display little selectivity to any of the α subtypes of the γ-amino butyric acid GABAA receptor to which they bind, we propose that the unequivocal results are due to an a subtype-dependent modulation of the hypothalamic–pituitary–adrenocortical cortex axis output. To test this, basal hormonal output and induction of FOS in the hypothalamic paraventricular nucleus were measured after administration of various benzodiazepine ligands in mice. Zolpidem, a selective α1 subtype agonist, produced a very strong increase in plasma adrenocorticotropic hormone and corticosterone. The non-selective full agonist’s diazepam and zopiclone induced a lower increase in circulating corticosterone than after zolpidem. In contrast, the α2,3,5 selective benzodiazepine agonist and α1 antagonist L-838,417 had no effect on corticosterone levels. Strong induction of FOS in the paraventricular nucleus was found in response to zolpidem, diazepam, and zopiclone, but not L-838,417. Finally, pre-administration of L-838,417 prior to zolpidem strongly inhibited the effect of zolpidem on corticosterone. Likewise, the non-selective agonist’s diazepam and zopiclone at a dose that alone had no effect on corticosterone also inhibited the effect of zolpidem. Taken together, these results suggest that benzodiazepine ligands modulate the hypothalamic–pituitary–adrenocortical axis through partly opposite mechanisms; and that the net effect is dependent on the composition of the GABAA receptor subunits to which they bind. In order to further explain the biological mechanism by which the different benzodiazepins activate the hypothalamic–pituitary–adrenocortical axis, we performed in situ hybridization to clarify the GABAA subunit composition in the paraventricular nucleus and sub paraventricular area, we show in agreement with the available literature that the paraventricular nucleus is comprised of neurons with the α2 phenotype. We also find that the sub paraventricular nucleus is made up of neurons with the α1 phenotype this has not been shown elsewhere. In this study we also conclude that the neurons in the paraventricular nucleus that are activated after zolpidem administration do not co-express oxytocin to any significant degree. The study also makes an attempt to map afferent connection to the paraventricular nucleus, this is done using Cholera toxin subunit B as a retrograde tracer. We focuses the projections origination in the bed nucleus stria terminalis, and in agreement with the available literature find that the bed nucleus stria terminalis has numerous projections to the paraventricular nucleus, we also find that most of these projections originate in either the lateral division or in the medial division, anterior part of the bed nucleus stria terminalis.

UddannelserMiljøbiologi, (Bachelor/kandidatuddannelse) Kandidat
SprogEngelsk
Udgivelsesdato1 jun. 2006
VejledereHenning F. Bjerregaard & Jens D Mikkelsen

Emneord

  • Brain
  • stress
  • hpa axis
  • benzodiazepiner
  • Hjerne
  • PVN
  • Cortisol
  • Paraventricular nucleus
  • adrenal cortex
  • Stesolid
  • binyre
  • Benzodiazepins
  • GABA
  • Zolpidem
  • hpa aksen
  • corticosterone
  • stress aksen
  • Diazepam