Differential autoreceptor control of extracellular 5-HT in guinea pig and rat: species and regional differences.

RATIONALE: Central 5-hydroxytryptamine (5-HT) release is regulated by inhibitory 5-HT autoreceptors, including 5-HT(1A) and 5-HT(1B) receptors.
OBJECTIVES: The purpose of this study was to use combinations of selective autoreceptor antagonists to elucidate the role of these receptors in controlling extracellular 5-HT in terminal areas. METHODS. Microdialysis was carried out in awake rats and guinea pigs to measure extracellular 5-HT in the frontal cortex and dentate gyrus. Using the selective 5-HT(1A) receptor antagonist, WAY-100635, and the selective 5-HT(1B) receptor antagonist, SB-224289, we have compared the roles of 5-HT(1A) and 5-HT(1B) autoreceptors in controlling extracellular 5-HT.
RESULTS: SB-224289 (4 mg/kg i.p.) alone produced a significant 50% increase in extracellular 5-HT in the dentate gyrus of guinea pigs, but not in the frontal cortex of the same animals. Co-administration of WAY-100635 (0.3 mg/kg s.c.), did not change the SB-224289-induced increase in dentate gyrus 5-HT but did produce a significant augmentation (60% increase) of guinea pig frontal cortex 5-HT. In contrast, neither autoreceptor antagonist, alone or in combination, affected extracellular 5-HT in the frontal cortex or dentate gyrus of rats.
CONCLUSIONS: These data indicate that there is a species difference in the autoreceptor control of 5-HT release. Furthermore, in the guinea pig there is a divergence between dorsal and median raphe innervated brain regions. On the basis that antagonism of 5-HT(1A) and 5-HT(1B) receptors produced an immediate increase in extracellular 5-HT in multiple brain regions in the guinea pig, it is suggested that this might be a novel mechanism for achieving antidepressant efficacy.