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Functional interactions between 5‐HT 2A and presynaptic 5‐HT 1A receptor‐based responses in mice genetically deficient in the serotonin 5‐HT transporter (SERT)
Author(s) -
Fox Meredith A,
Stein Alison R,
French Helen T,
Murphy Dennis L
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00578.x
Subject(s) - serotonin , agonist , 5 ht receptor , serotonin transporter , receptor , endocrinology , medicine , 5 ht1a receptor , receptor antagonist , reuptake inhibitor , chemistry , pharmacology , serotonin plasma membrane transport proteins , antagonist , biology
Background and purpose: Despite decreased presynaptic 5‐HT 1A and altered 5‐HT 2A receptor function in genetically‐deficient serotonin (5‐HT) transporter (SERT) mice, the 5‐HT 1A receptor antagonist N‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐2‐pyridinylcyclohexanecarboxamide maleate salt (WAY 100635) still induced head twitches in these mice, a well‐established 5‐HT 2A receptor‐mediated response. Experimental approach: Interactions between 5‐HT 1A and 5‐HT 2A receptors were assessed using the head‐twitch response following 5‐HT 1A and 5‐HT 2A receptor agonists and antagonists in SERT wild‐type (+/+), heterozygous (+/−), and knockout (−/−) mice. The role of brain 5‐HT availability in WAY 100635 induced head twitches was also examined. Key results: WAY 100635 induced head twitches in a SERT gene‐dose dependent manner, inducing 5‐fold more head twitches in SERT −/− versus SERT +/+ mice. In SERT −/− mice, inhibition of 5‐HT synthesis with p‐chlorophenylalanine (PCPA) markedly depleted tissue 5‐HT in all five brain areas examined and abolished WAY 100635 induced head twitches. Further, the selective 5‐HT reuptake inhibitor fluvoxamine increased WAY 100635 induced head twitches in SERT +/+ and +/− mice. Head twitches following the 5‐HT 2A receptor agonist (+/−)‐2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane (DOI) were robust in SERT +/+ and +/− mice but much reduced in SERT −/− mice. DOI‐induced head twitches were decreased by the 5‐HT 1A agonist 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (8‐OH‐DPAT) in SERT +/+ and +/− mice. All drug‐induced head twitches were blocked by the 5‐HT 2A receptor antagonist a‐Phenyl‐1‐(2‐phenylethyl)‐4‐piperidinemethanol (MDL 11,939). Conclusions and implications: These data show that indirect activation of 5‐HT 2A receptors via blockade of presynaptic 5‐HT 1A receptors potentiated head‐twitch responses, suggesting functional interactions between these receptors, interactions affected by altered 5‐HT availability. Our findings strongly support the correlation of WAY 100635 induced head twitches with increased 5‐HT availability, induced genetically or pharmacologically.