Parallel regulation by olanzapine of the patterns of expression of 5-HT2A and D3 receptors in rat central nervous system and blood cells.
Patterns of protein expression can be used to identify biomarkers of disease, prognosis or treatment response. Peripheral 5-HT2A and D3 receptors have been proposed as protein markers in schizophrenia. We investigated the possible parallel regulation of these candidate biomarkers in central nervous system (CNS) and peripheral blood cells by a comparative study of the effects of antipsychotic treatment on the expression of the receptors in both systems in rats. Acute (24 and 48 h) and subchronic (16 days) treatment of rats with olanzapine induced a significant decrease in 5-HT2A receptor density both in frontal cortex (Bmax=76.2%, 83.0% and 46.0% of control after 24 h, 48 h and 16 days of treatment, respectively; P<0.01) and blood platelets (Bmax approximately 55% of control at all times measured; P<0.01), without any changes in receptor affinity. Furthermore, olanzapine induced redistribution in 5-HT2A-like immunoreactivity and time-dependent remodelling of synaptic circuits involved in the activity of pyramidal and GABAergic neurons in frontoparietal motor cortex of treated rats, as assessed by immunohistochemical studies. D3 receptor mRNA levels increased significantly by 52.5% (P<0.01) and 21.1% (P<0.05) in nucleus accumbens, and by 53.4% (P<0.05) and 91.7% (P<0.01) in lymphocytes, after acute (24 h and 48 h) treatment with olanzapine, returning to levels similar to control after subchronic treatment (16 days). In conclusion, we observed in rats after olanzapine treatment: (1) parallelism in the regulation of 5-HT2A receptors in frontal cortex and in blood platelets; (2) parallelism in the regulation of D3 mRNA levels in nucleus accumbens and lymphocytes. These results endorse the interest in future studies aimed at validating these receptors as candidate biomarkers in schizophrenia.
Padín
J Fernando
JF
Membrane Biology and Applied Pharmacology Research Group, Drug Research and Development Group, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Galicia, Spain.
Rodríguez
Miguel A
MA
Domínguez
Eduardo
E
Dopeso-Reyes
Iria G
IG
Buceta
Montserrat
M
Cano
Ernesto
E
Sotelo
Eddy
E
Brea
José
J
Caruncho
Hector J
HJ
Isabel Cadavid
M
M
Castro
Marián
M
Isabel Loza
M
M
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001773:Blood Cells / Q000187:drug effects*; D015152:Blotting, Northern / Q000379:methods; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000493:pharmacokinetics; D007650:Ketanserin / Q000493:pharmacokinetics; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077152:Olanzapine; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014316:Tritium / Q000493:pharmacokinetics
D001569:Benzodiazepines; D018492:Dopamine Antagonists; D006220:Haloperidol; D007650:Ketanserin; D000077152:Olanzapine; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D050637:Receptors, Dopamine D3; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium