Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia.
The occurrence of human cerebellar serotonin 5-HT(2A) receptors (5-HT(2A)R) is equivocal and their status in schizophrenia unknown. Using a range of techniques, we investigated cerebellar 5-HT(2A)R expression in 16 healthy subjects and 16 subjects with schizophrenia. Immunocytochemistry with a monoclonal antibody showed labelling of Purkinje cell bodies and dendrites, as well as putative astrocytes. Western blots showed a major band at approximately 45 kDa. Receptor autoradiography and homogenate binding with [(3)H]ketanserin revealed cerebellar 5-HT(2A)R binding sites present at levels approximately a third of that in prefrontal cortex. 5-HT(2A)R mRNA was detected by reverse transcriptase-polymerase chain reaction, with higher relative levels in men than women. Several aspects of 5-HT(2A)R expression were altered in schizophrenia. 5-HT(2A)R immunoreactivity in Purkinje cells was partially redistributed from soma to dendrites and was increased in white matter. 5-HT(2A)R mRNA was decreased in the male patients. 5-HT(2A)R measured by dot blots and [(3)H]ketanserin binding (B(max) and K(d)) were not significantly altered in schizophrenia. These data show that 5-HT(2A)R gene products (mRNA, protein, binding sites) are expressed in the human cerebellum at nonnegligible levels; this bears upon 5-HT(2A)R imaging studies which use the cerebellum as a reference region. 5-HT(2A)R expression is altered in schizophrenia; the shift of 5-HT(2A)R from soma to dendrites is noteworthy since atypical antipsychotics have the opposite effect. Finally, the results emphasise that expression of a receptor gene is a mutifaceted process. Measurement of multiple parameters is necessary to give a clear picture of the normal situation and to show the profile of alterations in a disease.
Eastwood
S L
SL
University Department of Psychiatry, Warneford Hospital, Oxford, UK.
Burnet
P W
PW
Gittins
R
R
Baker
K
K
Harrison
P J
PJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002451:Cell Compartmentation / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007650:Ketanserin / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; D012701:Serotonin; D007650:Ketanserin