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.

Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice.

Rationale: Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life.

Objectives: To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice.

Results: 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.