Effects of DAU 6215, a novel 5-hydroxytryptamine3 (5-HT3) antagonist on electrophysiological properties of the rat hippocampus.
1. The aim of the present study was to test the effects of DAU 6215 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]-octo-3-yl)-2,3-dihydro-2-ox o-1H- benzimidazole-1-carboxamide carboxamide hydrochloride), a newly synthesized, selective 5-hydroxytryptamine3 (5-HT3) antagonist, on the cell membrane properties and on characterized 5-HT-mediated responses of pyramidal neurones in the hippocampal CA1 region. 2. Administration of DAU 6215, even at concentrations several hundred fold its Ki, did not affect the cell membrane properties of pyramidal neurones, nor modify extracellularly recorded synaptic potentials, evoked by stimulating the Schaffer's collaterals. 3. Micromolar concentrations (15-30 microM) of 5-HT elicited several responses in pyramidal neurones that are mediated by distinct 5-HT receptor subtypes. DAU 6215 did not antagonize the 5-HT1A-induced membrane hyperpolarization and conductance increase, a response that was blocked by the selective 5-HT1A antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalamido)butyl- piperazine). Similarly, DAU 6215 did not affect the membrane depolarization and decrease in amplitude of the afterhyperpolarization, elicited by the activation of putative 5-HT4 receptors. 4. 5-HT increased the frequency of spontaneous postsynaptic potentials (s.p.s.ps) recorded in pyramidal neurones loaded with chloride. In agreement with previous observations, most of the s.p.s.ps were reversed GABAergic events, produced by the activation of 5-HT3 receptors on interneurones, because they persisted in the presence of the glutamate NMDA and non NMDA antagonists, D-aminophosphonovaleric acid (APV; 50 microM) and 6,7-dinitroquinoxaline-2,3-dione (DNQX; 25 microM), and were elicited by the selective 5-HT3 agonist, 2-methyl-5-HT (2-Me-5-HT, 50 microM). 5. The increase in frequency of s.p.s.ps induced by 5-HT was significantly antagonized by DAU 6215 in 70% of the cases, whereas the 5-HT3 antagonist always suppressed the effect of 2-Me-5-HT, at concentrations as low as 60 nM.6. The antagonistic effect of DAU 6215 was also tested on the 5-HT3-mediated block of induction of long-term potentiation (LTP), elicited by a primed burst (PB) stimulation. Extracellular recordings showed that low concentrations (60 nM) of DAU 6215 suppressed the inhibitory action of 5-HT onPB-induced LTP, without affecting the 5-HTlA-induced reduction in the amplitude of the population spike.7. These results provide evidence that DAU 6215 is an effective antagonist of the 5-HT3-mediated responses in the central nervous system and may offer a cellular correlate for the pharmacological effects of DAU 6215 as an anxiolytic and cognition enhancer.
Passani
M B
MB
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Italy.
Pugliese
A M
AM
Azzurrini
M
M
Corradetti
R
R
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C070191:itasetron; D012701:Serotonin; C045918:2-methyl-5-HT