Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus.
The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT4 receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT4 receptor antagonist DAU 62805. Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT1A and excitatory 5-HT4 receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT1A receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT4 receptor activation.
Bijak
M
M
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Tokarski
K
K
Maj
J
J
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology
D000928:Antidepressive Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D012701:Serotonin; C055971:zacopride