5-HT1A receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission

Mutant mice that lack serotonin(1A) receptors exhibit enhanced anxiety-rela ted behaviors, a phenotype that is hypothesized to result from impaired aut oinhibitory control of midbrain serotonergic neuronal firing. Here we exami ned the impact of serotonin,, receptor deletion on forebrain serotonin neur otransmission using in vivo microdialysis in the frontal cortex and ventral hippocampus of serotonin(1A) receptor mutant and wild-type mice. Baseline dialysate serotonin levels were significantly elevated in mutant animals as compared with wild-types both in frontal cortex (mutant = 0.44 +/- 0.05 nM ; wild-type = 0.28 +/- 0.03 nM) and hippocampus (mutant = 0.46 +/- 0.07 nM; wild-type = 0.27 +/- 0.04 nM). A stressor known to elicit enhanced anxiety -like behaviors in serotonin(1A) receptor mutants increased dialysate 5-HT levels in the frontal cortex of mutant mice by 144% while producing no alte ration in cortical 5-HT in wild-type mice. There was no phenotypic differen ce in the effect of this stressor on serotonin levels in the hippocampus. F luoxetine produced significantly greater increases in dialysate 5-HT conten t in serotonin(1A) receptor mutants as compared with wild-types, with two- and three-fold greater responses being observed in the hippocampus and fron tal cortex, respectively. This phenotypic effect was mimicked in wild-types by pretreatment with the serotonin,, antagonist 4-iodo-N-[2-[4-(methoxyphe nyl)-1-piperazinyl]ethyl]N-2-pyridinyl-benzamide (p-MPPI). These results in dicate that deletion of central serotonin,A receptors results in a tonic di sinhibition of central serotonin neurotransmission, with a greater dysregul ation of serotonin release in the frontal cortex than ventral hippocampus u nder conditions of stress or increased interstitial serotonin levels.