THE 5-HT3 RECEPTOR AGONIST 1-(M-CHLOROPHENYL)-BIGUANIDE FACILITATES NORADRENALINE RELEASE BY BLOCKADE OF ALPHA(2)-ADRENOCEPTORS IN THE MOUSE-BRAIN CORTEX

We analyzed the facilitatory effect of the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (mCPBG) on the electrically evoked noradrenaline release in superfused mouse brain tissue. In addition, we determined the affinities of mCPBG and two other 5-HT receptor ligands, namely 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; also a 5-HT3 receptor agonist) and 5-carboxamidotryptamine (5-CT; a 5-HT1 receptor agonist) for alpha(2) binding sites. The latter two 5-HT receptor agonists were included because of the claimed involvement of alpha(2)-adrenoceptors in their effects on noradrenaline release. In superfusion experiments on mouse brain cortex slices preincubated with H-3-noradrenaline, tritium overflow evoked by 2-min periods of electrical field stimulation (3 Hz) was facilitated by mCPBG and, in addition, by rauwolscine (alpha(2)-adrenoceptor antagonist) and tetraethylammonium (K+ channel blocker) (which were examined for comparison). The effect of mCPBG was not affected by the 5-HT3 receptor antagonist tropisetron or by desipramine but was abolished by rauwolscine. In slices superfused with medium containing desipramine, the concentration-response curve of unlabelled noradrenaline for its inhibitory effect on the electrically (0.3 Hz) evoked overflow was shifted to the right by mCPBG and rauwolscine (apparent pA(2) 5.35 and 7.88, respectively). In another series of superfusion experiments, 4 electrical pulses, administered at 100 Hz, were used to evoke tritium overflow. Tritium overflow evoked by this stimulation procedure (under which an endogenous tone of noradrenaline does not develop) was not affected by mCPBG and rauwolscine but still increased by tetraethylammonium. The specific binding of H-3-rauwolscine to rat brain cortex homogenates was displaced monophasically by unlabelled rauwolscine, mCPBG, 2-methyl-5-HT and 5-CT (pK(i) 8.59, 5.84, 5.05 and 5.86, respectively). In conclusion the present results indicate that mCPBG acts as a low-affinity antagonist at alpha(2)-adrenoceptors. This property has to be considered in functional studies of 5-HT3 receptor-mediated effects in tissues containing alpha(2)-adrenoceptors as well.