| pA2 online © Copyright 2004 The British Pharmacological Society |
078P
University of Newcastle Winter Meeting December 2004 |
Identification of transcriptional regulatory regions controlling CLTR1 expression in airway smooth muscle L. Ferrington, D.E. McBean*, H.J. Olverman, J.L. Leith & P.A.T. Kelly. Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, EH4 2XU, and *School of Health Sciences, Queen Margaret University College, Edinburgh, EH12 8TS, UK. |
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Print abstractSerotonergic terminal depletion and altered local cerebral glucose utilisation (LCMRglu) have been found in adult Dark Agouti (DA) rats 3 weeks after a single exposure to 3,4,-methylenedioxymethamphetamine (MDMA). While depletion is still evident at 6 weeks, LCMRglu is normalised (Quate et al, 2004). Here we examine the effects of the selective 5-HT1A agonist, 8-hydroxy-2-(di-N-propyl-amino)tetralin (8-OH-DPAT) upon LCMRglu in these MDMA-pretreated rats.
DA rats were injected (i.p.) with MDMA (15mg.kg-1) or saline (both n=10). 6 weeks later equal numbers from each group were injected (i.v) with 8-OH-DPAT (1mg.kg-1) or saline 1 minute prior to the measurement of LCMRglu using [14C]-2-deoxyglucose quantitative autoradiography (Kelly et al, 1995). Data (mean±sem) were analysed using t-test with Bonferroni correction (p<0.05).
Following acute saline there were no significant differences between pre-treatment groups in either physiological variables or LCMRglu. In both pre-treatment groups acute 8-OH-DPAT produced significant hypotension (from 137 ± 3 to 119 ± 4 mmHg in saline and 138 ± 2 to 121 ± 3 mmHg in MDMA ) and significant decreases in rectal temperature and heart rate. In saline pre-treated rats, 8-OH-DPAT produced widespread reductions in LCMRglu (range -16% to -60%), which were significantly different from control in 28 of the 62 brain areas analysed. Significant increases in LCMRglu were observed in 3 brain areas (19 to 36%). In MDMA pre-treated rats both increases and decreases in LCMRglu were also observed, however in comparison with saline control, decreases were both less marked and less widespread (-4% to -45%; 7 significant differences) and increases were potentiated (21 to 78%; 11 significant differences). In hippocampus similar significant reductions in LCMRglu were observed in both groups following 8-OH-DPAT.
These results suggest that MDMA-induced serotonergic depletion may alter the normal functional response to systemic manipulation of endogenous serotonergic systems by 8-OH-DPAT, and suggests that compensatory mechanisms that may act to normalise LCMRglu at 6 weeks post-MDMA might involve altered regulation of 5-HT1A receptors. However, it would appear that any alteration might not occur uniformly throughout the brain.
Kelly, P.A.T., Ritchie, I.M., McBean, D.E. et al. (1995) J.Cereb.Blood Flow Metabol.,15, 706-713.
Quate, L., McBean, D.E., Olverman, H.J. et al. (2004) FENS Abstr. 2, A219.9.
This study was funded by EC Grant No. QLG3-CT-2002-00809 .