| pA2 online © Copyright 2004 The British Pharmacological Society |
132P
GKT, University of London Winter Meeting December 2003 |
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The alpha-2-adrenoceptor
mediating inhibition of noradrenaline turnover but not that inhibiting
serotonin turnover is endogenously active in mouse brain |
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Print abstractIn a recent presentation to the society (MacDonald et al. 2003), we observed a residual effect on serotonin turnover of the alpha-2-agonist, dexmedetomidine in striatum of mice lacking the alpha-2A-adrenoceptor. We have extended these experiments by administering a non-subtype selective alpha-2-antagonist, atipamezole (ATI) to determine whether these receptors are functionally active. We compare the effects of ATI on serotonin (5-HT) turnover (assessed as the inverse ratio of 5-HT to its metabolite 5-hydroxyindoleacetic acid (5HIAA) with the effect of the drug at the alpha-2A-autoreceptor controlling release of noradrenaline (NA) (i.e. the ratio of the NA metabolite, 3-methoxy-4-hydroxy-phenyl-glycol, MHPG to NA) in four regions of mouse brain.
Male C57BL/6J alpha-2A knockout (KO) mice (Altman et al. 1999) were used with age and sex-matched mice as wild-type controls. One hour after ATI (1 mg/kg, s.c.), the mice were sacrificed and frontal cortex, hippocampus, thalamus/hypo-thalamus and striatum dissected. The samples were stored at -80°C until assayed for brain biogenic amines and metabolites by HPLC-EC. Comparison between the two groups was by ANOVA and Dunnett's t-test (P<0.05 considered significant).
In all regions, ATI caused a major (>100%) increase in NA turnover in the control mice but no significant change in the KO mice (table 1). In contrast, ATI did not evoke any significant change in the 5-HT turnover in either strain of mice. We noted strain dependent differences in turnover rates of 5-HT in thalamus/hypothalamus and striatum as well as the elevated NA turnover in KO mice (Lähdesmäki et al. 2003).
Table 1: Brain regional values for MHPG/NA and 5-HIAA/5-HT ratios 1h after atipamezole (ATI) 1 mg/kg in alpha-2A-KO mice and their wild type controls
| MHPG/NA | 5HIAA/5HT | |||
| Cortex | Wild-type | KO-mice | Wild-type | KO-mice |
| Saline (10) | 0.07±0.01 | 0.10±0.01# | 0.40±0.02 | 0.39±0.01 |
| ATI (8) | 0.16±0.01* | 0.12±0.01 | 0.45±0.02 | 0.39±0.03 |
| Hippocampus | ||||
| Saline (10) | 0.10±0.02 | 0.14±0.02 | 0.98±0.06 | 0.99±0.04 |
| ATI (8) | 0.21±0.05 | 0.16±0.04 | 0.90±0.07 | 1.18±0.07 |
| Thalamus/hypothalamus | ||||
| Saline (10) | 0.06±0.01 | 0.11±0.01# | 0.83±0.02 | 0.70±0.02# |
| ATI (8) | 0.13±0.02* | 0.17±0.03 | 0.88±0.04 | 0.71±0.04 |
| Striatum | ||||
| Saline (10) | ND | ND | 0.88±0.05 | 0.72±0.02# |
| ATI (8) | ND | ND | 0.91±0.04 | 0.80±0.05 |
ND = not detected. Results are in units (± s.e. mean) * P < 0.05 compared to saline mice from the same strain; # P<0.05 at least versus wild type control (Dunnett's t-test).
Drugs activating the alpha-2-adrenoceptors can inhibit 5-HT turnover; in striatum part of this effect is mediated by an alpha-2-adrenoceptor other than the alpha-2A-subtype. However, it seems that these receptors are not endogenously active, since blockade with a large dose of an adrenoceptor antagonist did not alter the turnover of 5-HT in any brain region in either controls or mice lacking alpha-2A-receptors.
Altman J.D.et al.(1999)
Mol. Pharmacol.56, 154-161.
Lähdesmäki J. et al.(2003) Neuropharmacol. 44,
882-892.
MacDonald, E. et al. (2003) Br. J. Pharmacol. 139, 174P.