Acute and repeated treatment with the 5-HT7 receptor antagonist SB 269970 induces functional desensitization of 5-HT7 receptors in rat hippocampus.
BACKGROUND
SB 269970, a 5-HT(7) receptor antagonist may produce a faster antidepressant-like effect in animal models, than do antidepressant drugs, e.g., imipramine. The present work was aimed at examining the effect of single and repeated (14 days) administration of SB 269970 on the 5-HT(7) receptor in the hippocampus.


METHODS
The reactivity of 5-HT(7) receptors was determined using 5-carboxamidotryptamine (5-CT), which increased the bursting frequency of spontaneous epileptiform activity in hippocampal slices. Additionally, the effects of SB 269970 administration on the affinity and density of 5-HT(7) receptors were investigated using [(3)H]-SB 269970 and the influence of SB 269970 and imipramine on mRNA expression levels of Gα(s) and Gα(12) mRNA were studied using RT-qPCR.


RESULTS
Acute and repeated treatment with SB 269970 led to attenuation of the excitatory effects of activation of 5-HT(7) receptors. Neither single nor repeated administration of SB 269970 changed the mean affinity of 5-HT(7) receptors for [(3)H]-SB 269970. Repeated, but not single, administration of SB 269970 decreased the maximum density of [(3)H]-SB 269970 binding sites. While administration of imipramine did not change the expression of mRNAs for Gα(s) and Gα(12) proteins after both single and repeated administration of SB 269970, a reduction in Gα(s) and Gα(12) mRNA expression levels was evident.


CONCLUSIONS
These findings indicate that even single administration of SB269970 induces functional desensitization of the 5-HT(7) receptor system, which precedes changes in the receptor density. This mechanism may be responsible for the rapid antidepressant-like effect of the 5-HT(7) antagonist in animal models.
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. ktok@if-pan.krakow.pl
Krzysztof
K
Tokarski
Agnieszka
A
Zelek-Molik
Beata
B
Duszyńska
Grzegorz
G
Satała
Bartosz
B
Bobula
Magdalena
M
Kusek
Piotr
P
Chmielarz
Irena
I
Nalepa
Grzegorz
G
Hess
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D055724:Electrophysiological Phenomena; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000096:biosynthesis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D000929:Antidepressive Agents, Tricyclic; D010636:Phenols; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D012701:Serotonin; C047087:5-carboxamidotryptamine; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019205:GTP-Binding Protein alpha Subunits, Gs; D007099:Imipramine