title: Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide.
abstract: Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of overactivity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC overactivity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [(3)H]flunitrazepam to GABA(A) receptors at three anatomically defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA(A) receptor binding density was observed among all subjects. No significant differences in the amount of binding to GABA(A) receptors were observed between control subjects (n=21) and MDD subjects (n=9) or depressed suicide victims (n=17). These results demonstrate that GABA(A) receptor binding in the LC measured with [(3)H]flunitrazepam is not altered in subjects with depressive illnesses.
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: He
authors.initials: H
authors.lastname: Zhu
authors.forename: Beata
authors.initials: B
authors.lastname: Karolewicz
authors.forename: Emily
authors.initials: E
authors.lastname: Nail
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stockmeier
authors.forename: Katalin
authors.initials: K
authors.lastname: Szebeni
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Ordway
mesh_terms: D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001345:Autoradiography / Q000379:methods; D001667:Binding, Competitive / Q000187:drug effects; D003863:Depression / Q000473:pathology*; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D005445:Flunitrazepam / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013405:Suicide; D014316:Tritium / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam; D014446:Tyrosine 3-Monooxygenase; D003975:Diazepam