Functional interactions between 5-HT2A and presynaptic 5-HT1A 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.