Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A.
Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT(1A), 5-HT(2A), and 5-HT(2C)) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). Samples were obtained from postmortem brain tissue (Brodmann area 10) from 20 persons with a history of MDD and 20 matched controls as determined by a retrospective diagnostic evaluation obtained from family members. Levels of 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor were quantitated via Western blot analyses. Basal and stimulated PKA and PKC activity were also determined. The depressed samples showed significantly increased 5-HT(2A) receptor abundance relative to controls, but no differences in 5-HT(1A) or 5-HT(2C) receptors. Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT(2A) receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT(2A) receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT(2A) receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT(2A) receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.
Shelton
R C
RC
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. richard.shelton@vanderbilt.edu
Sanders-Bush
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E
Manier
D H
DH
Lewis
D A
DA
D000328:Adult; D000367:Age Factors; D000368:Aged; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012737:Sex Factors; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
D044402:Receptor, Serotonin, 5-HT2A; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate