, Volume 345, Issue 4, pp 410-416

Presynaptic α2-adrenoceptors mediating inhibition of noradrenalh and 5-hydroxytryptamine release in rat cerebral cortex: further characterization as different α2-adrenoceptor subtynes

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In a previous investigation it was suggested that the α2-adrenoceptors regulating 3H-noradrenaline (3H-NA) release and the α2-heteroreceptors regulating the release of 3H-5-hydroxytryptamine (3H-5-HT) from rat cerebrocortex synaptosomes represent different subtypes of the α2-adrenoceptor in that (−)-mianserin potently blocked the receptors sited on 5-HT terminals but was ineffective at the autoreceptors (Raiteri et al. 1983).

In this work a number of α2-adrenoceptor antagonists were tested against NA as an inhibitor of the K+ (15 mmol/l)-evoked release of 3H-NA or 3H-5-HT (in presence of 1 μmol/l desipramine or citalopram, respectively) from superfused rat neocortex synaptosomes. The order of apparent affinity of the antagonists was: idazoxan ≥ ORG 20769 (2-amino-4-(1-methyl-1,2,3, 6-tetrahydropyridin-4-yl)-thiazole-5-carbonitrile (Z)-2-butenedioate (1:1) salt) ≥ ORG 20350 (5-chloro-4-(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-amine (Z)-2-butenedioate (1:1) salt) ≥ ORG 20091 (5-chloro-4-(1-methyl -1,2,5,6-tetrahydropyridin -3- yl)-thiazole-2-amine (Z)-2-butenedioate (2:1) salt) at the α2-autoreceptor and idazoxan ≥ ORG 20769 > ORG 20091 » ORG 20350 at the α2-heteroreceptor. Prazosin (1 gmol/l) or AR-C 239 (1 gmol/l) (2-[2-[4-(o-methoxyphenyl)piperazine-l-yl]ethyl]-4,4-dimethyl-1,3(2H,4H)isoquinolinedione) were ineffective in both systems.

Idazoxan and ORG 20769 had a comparable apparent affinity at the α2-autoreceptor (pKB values: 8.45 and 8.42, respectively) and at the heteroreceptor (pKB values: 8.16 and 8.15, respectively). In contrast, ORG 20350 was about 14-fold less. potent than the two previous compounds at the autoreceptor (pKB = 7.30) whereas it was ineffective at the heteroreceptor when tested up to 3 μmol/l (pKB < 5.5). Experiments with electrically-stimulated (2 Hz; 2 ms; 24 mA) rat cerebral cortex slices confirmed the data with synaptosomes. ORG 20350 shifted to the right in a parallel manner the concentration-response curve of clonidine at the α2-autoreceptors (pA2 = 7.25). The sulphydryl alkylating agent N-ethyl-maleimide (NEM; 3 μmol/l) which has been proposed to inactivate pertussis toxin sensitive G proteins, abolished the inhibition of both 3H-NA and 3H-5-HT release caused by the α2-adrenoceptor agonist clonidine (0.3 μmol/l) in hippocampus synaptosomes. The effect of exposure to NEM was not modified during “protection” experiments with idazoxan.

The results lend further support to the proposed existence of functional α2-adrenoceptor subtypes. It should be noted that the two pharmacologically distinct receptors here characterized are present in the same brain area and within the same animal species. They are sited on the axon terminals of different neurons. Their function appears that of inhibiting NA or 5-HT release, respectively. Both α2-auto- and heteroreceptors are likely to be coupled to G proteins. According to the current nomenclature, the receptors do not seem to belong to the α2B subtype. However only one of them might be classified as α2A.

Send offprint requests to M. Raiteri at the above address