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.(ABSTRACT TRUNCATED AT 250 WORDS)
Bouthillier
A
A
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Blier
P
P
de Montigny
C
C
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology*; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000187:drug effects; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000502:physiology*; D013134:Spiperone / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D012701:Serotonin; D013134:Spiperone; D008238:Lysergic Acid Diethylamide