FLEROBUTEROL, A BETA-ADRENOCEPTOR AGONIST, ENHANCES SEROTONERGIC NEUROTRANSMISSION - AN ELECTROPHYSIOLOGICAL STUDY IN THE RAT-BRAIN

The two beta-adrenoceptor agonists salbutamol and clenbuterol have been shown to be effective antidepressant drugs. Flerobuterol, a new beta-adrenoceptor agonist, exhibits antidepressant activity in animal models. Given the long-standing notion that the serotonergic (5-HT) system might be involved in the etiology and/or the therapeutics of affective disorders and that this class of adrenergic agents can alter factors regulating 5-HT transmission, the effects of acute and repeated administrations of flerobuterol on the 5-HT system were studied. Acute administration of flerobuterol (up to 2 mg/kg, IV) did not modify the firing rate of dorsal raphe 5-HT neurons. However, the sustained administration of flerobuterol for two days (0.5 mg/kg/day, SC, delivered by an osmotic minipump) produced a marked decrease of the firing rate of 5-HT neurons. The reversal of this effect of flerobuterol by the somatodendritic 5-HT autoreceptor antagonist spiperone suggests that this decrease in the firing activity of 5-HT neurons in rats treated for 2 days with flerobuterol resulted from an enhanced synaptic availability of 5-HT. This initial decrease in firing activity of 5-HT neurons was followed by a progressive recovery to normal after 14 days of treatment with flerobuterol. At this point in time, the effect of intravenous lysergic acid diethylamide on the firing of 5-HT neurons was attenuated, indicating that the somatodendritic 5-HT autoreceptors had desensitized. The effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of dorsal hippocampus pyramidal neurons was markedly enhanced in rats treated with flerobuterol for 14 days. This enhanced efficacy of the stimulation could not be ascribed to an increased sensitivity of the postsynaptic neurons to 5-HT, since their responsiveness to microiontophoretic applications of 5-HT was unaltered. Neither could this enhanced 5-HT signal transfer be attributed to a modification of the function of terminal 5-HT autoreceptors in controlling 5-HT release, since the decremental effect of increasing the frequency of stimulation (from 1-5 Hz) was similar in control and in flerobuterol-treated rats. In keeping with available data, it is most likely that the enhancement of 5-HT neurotransmission by long-term administration of flerobuterol is due to an increased availability of the neurotransmitter. It is concluded that the enhancement of 5-HT neurotransmission might underlie the therapeutic action of beta-adrenoceptor agonists in major depression.