Differential autoreceptor control of extracellular 5-HT in guinea pig and rat: species and regional differences.
BACKGROUND
Central 5-hydroxytryptamine (5-HT) release is regulated by inhibitory 5-HT autoreceptors, including 5-HT(1A) and 5-HT(1B) receptors.


OBJECTIVE
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.
Neuropharmacology Research, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, CM19 5AW, Essex, UK. Zoe.A.Hughes@gsk.com
Zoë A
ZA
Hughes
Lee A
LA
Dawson
D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism* / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology; D005625:Frontal Lobe / Q000378:metabolism / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009928:Organ Specificity; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D013045:Species Specificity; D013141:Spiro Compounds / Q000494:pharmacology
D017660:Autoreceptors; D010879:Piperazines; D010881:Piperidones; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; C108518:SB 22489G; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide