Effects of short-term serotonin depletion on the efficacy of serotonin neurotransmission: electrophysiological studies in the rat central nervous system.
The effects of short-term serotonin (5-HT) depletion by p-chlorophenylalanine (PCPA) on the firing activity of dorsal raphe nucleus 5-HT neurons, on the responsiveness of dorsal hippocampus pyramidal neurons to microiontophoretically applied 5-HT and on the efficacy of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of CA3 dorsal hippocampus pyramidal neurons were assessed in chloral hydrate-anesthetized rats. PCPA (250 mg/kg/day i.p. for 2 days) reduced the 5-HT content of the dorsal hippocampus by 90%. However, the number of spontaneously active 5-HT neurons per microelectrode trajectory through the dorsal raphe or their average rate of firing was unaltered. The effect of afferent 5-HT pathway stimulation was reduced in only 40% of treated rats, whereas the sensitivity of CA3 pyramidal neurons to microiontophoretic 5-HT was not modified. The function of the terminal 5-HT autoreceptor was assessed using methiothepin, an autoreceptor antagonist. Methiothepin (1 mg/kg, i.v.) significantly enhanced the efficacy of the stimulation in PCPA-treated rats, although the degree of enhancement was much less than in controls. A greater reduction of the effectiveness of the stimulation was obtained by increasing the dose of PCPA (350 mg/kg/day i.p. for 2 days). This regimen reduced the 5-HT content of the dorsal hippocampus by 95%. In these rats, the sensitivity of the terminal 5-HT autoreceptor was assessed by increasing the frequency of the stimulation from 1 to 5 Hz. This procedure reduced to a similar extent the efficacy of the stimulation in treated and control rats, suggesting that the reduced effectiveness of methiothepin in enhancing 5-HT synaptic transmission in PCPA-treated rats is due to a lower degree of activation of the terminal 5-HT autoreceptor. The present results showing that the 350 mg/kg/day regimen of PCPA, but not the 250 mg/kg/day regimen, reduced the efficacy of the stimulation of the ascending 5-HT pathway suggest that a greater than 90% depletion is required to affect 5-HT neurotransmission significantly. The reduced level of activation of terminal 5-HT autoreceptors in rats treated with the lower dose of PCPA may facilitate the release of the remaining 5-HT per stimulation-triggered action potential, ensuring a virtually unaltered synaptic efficacy.
Chaput
Y
Y
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Lesieur
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P
de Montigny
C
C
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D002490:Central Nervous System / Q000502:physiology*; D004594:Electrophysiology; D010134:Fenclonine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007478:Iontophoresis; D008297:Male; D008839:Microelectrodes; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D011985:Receptors, Serotonin; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D010134:Fenclonine