The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity.
The dorsal raphe nucleus (DRN) is the origin of much of the 5-HT innervation of the forebrain. The activity of DRN 5-HT neurons is regulated by a number of receptors including GABA(A) and 5-HT(1A) inhibitory receptors and by excitatory alpha(1)-adrenoceptors. Using in vitro electrophysiological recording we investigated the action of progesterone and its metabolite, allopregnanolone on receptor-mediated responses of DRN 5-HT neurons. Neither allopregnanolone nor progesterone affected the alpha(1)-adrenoceptor agonist-induced firing. Allopregnanolone also had no effect on the inhibitory response to 5-HT. However, allopregnanolone significantly potentiated the inhibitory responses to GABA(A) receptor agonists. Progesterone did not enhance GABA(A) receptor-meditated inhibitory responses. Thus, the neuroactive metabolite of progesterone, allopregnanolone, has the ability to cause potentiation of GABA(A)-mediated inhibition of DRN 5-HT neurons. This effect on 5-HT neurotransmission may have relevance for mood disorders commonly associated with reproductive hormone events, such as premenstrual dysphoric disorder and postpartum depression.
Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, NE2 4HH, UK.
Vikas
V
Kaura
Colin D
CD
Ingram
Sarah E
SE
Gartside
Allan H
AH
Young
Sarah J
SJ
Judge
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011280:Pregnanolone / Q000097:blood / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*; D011903:Raphe Nuclei / Q000166:cytology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors
D000777:Anesthetics; D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D009118:Muscimol; D012701:Serotonin; D011374:Progesterone; D011280:Pregnanolone; C015542:gaboxadol