| pA2 online © Copyright 2004 The British Pharmacological Society |
010P
University of Newcastle Winter Meeting December 2004 |
Mice overexpressing the 5-HT transporter gene show evidence of decreased 5-HT1A autoreceptor function K.A. Jennings, W.J. Sheward1, A.J. Harmar1& T. Sharp. University Dept. of Pharmacology, Mansfield Road, Oxford OX1 3QT and 1University Dept. of Neuroscience, George Square, Edinburgh EH8 9JZ . |
|
Print abstractA polymorphic allele of the 5-HT transporter (5-HTT) gene leading to enhanced 5-HTT expression (Heils et al 1996), has been linked to a faster onset of antidepressant action (Smeraldi et al 1998). Desensitization of 5-HT1A autoreceptor function is thought to be pivotal in effective antidepressant action. Here we assessed 5-HT1A autoreceptor function in mice engineered to overexpress 5-HTT by measuring hypothermia, and decreased cortical 5-HT release, in response to administration of the 5-HT1A/7 agonist, 8-OH-DPAT. Initial studies validated the hypothermia model given recent evidence of 5-HT7 receptor involvement (Hedlund et al 2004).
For validation of the hypothermia model, mice (C57 male, 8-12 weeks, 5/group) were injected i.p. with saline, WAY100365 (5-HT1A antagonist; 1 mg/kg) or SB269970 (5-HT7 antagonist; 10 mg/kg) followed 20 min later by saline or 8-OH-DPAT (0.5 mg/kg). Rectal temperature was measured immediately before and 20 min after 8-OH-DPAT. The same protocol was used in 5-HTT overexpressing and wild-type mice (CBAxC57Bl6J, 3-6 months, 6/group). Microdialysis measurements of 5-HT efflux (1µM citalopram in perfusion medium) were made in the medial prefrontal cortex of chloral hydrate anaesthetised wild type and 5-HT overexpressing mice (Jennings et al 2003). Once basal 5-HT levels had stabilised (3-4 h), 8‑OH-DPAT (0.5 mg/kg i.p.) was injected and measurements were continued for 1 h. Data were analysed by 2-way ANOVA with appropriate post hoc test. Mean ± SEM values are given.
8-OH-DPAT-induced hypothermia was not affected by SB269970 but was abolished by WAY100635 (P=0.001). 8-OH-DPAT evoked hypothermia in wild-type but not in 5-HTT over-expressing mice (-3.6 ± 0.3 versus 1.2 ± 0.5 ºC; effect of genotype F(1,20)=8.3; P=0.009). Baseline core temperatures did not differ between genotypes. In microdialysis experiments 8-OH-DPAT decreased extracellular 5-HT in wild-type controls but this effect was significantly less in 5-HTT overexpressing mice 20 min post drug (60.4 ± 3.8 vs. 76.3 ± 4.0 % of pre-drug values respectively; P=0.019).
In summary the present data show that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A receptors and that this response is absent in 5-HTT overexpressing mice. These mice also show an attenuated initial decrease in cortical 5‑HT efflux in response to 8-OH-DPAT. Collectively these data suggest that increased 5-HTT expression is associated with decreased 5-HT1A autoreceptor function. These findings are relevant to reported associations between genetic variation in 5-HTT expression and onset of antidepressant action.
Hedlund et al 2004 Eur J Pharmacol 487; 125-132.
Heils et al 1996 J Neurochem 66; 2621-2624.
Jennings et al 2003 Proceedings of the 10th International Conference of in vivo Methods, Stockholm; 389-391.
Smeraldi et al 1998 Mol Psychiatry 3; 508-511.