Functional interactions between 5‐HT _1A receptor‐based responses in mice genetically deficient in the serotonin 5‐HT transporter (SERT)

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.