The effect of paroxetine on 5-HT efflux in the rat dorsal raphe nucleus is potentiated by both 5-HT1A and 5-HT1B/D receptor antagonists.
Serotonin (5-HT) efflux in slices of rat dorsal raphe nucleus (DRN) was evoked by pseudo one pulse electrical stimulation (20 pulses at 100 Hz, 190 ms train duration) and measured, along with 5-HT uptake, by fast cyclic voltammetry (FCV). The selective serotonin re-uptake inhibitor (SSRI) paroxetine (10(-7) M) increased 5-HT efflux to 147 +/- 6% of pre-drug values at maximum (mean +/- SEM, n = 5) and the half-life of uptake to 443 +/- 38%. The non-selective 5-HT1 antagonist methiothepin (2 x 10(-7) M) increased 5-HT efflux to 147 +/- 9% at maximum but had no effect on uptake half-life. In contrast, (+)-WAY 100135 (10(-6) M) and GR 127935 (5 x 10(-8) M), selective antagonists at 5-HT1A and 5-HT1B/D receptors, respectively, affected neither 5-HT efflux nor uptake. When given in combination with paroxetine, the antagonists significantly increased the effect of paroxetine on efflux: methiothepin to 228 +/- 24% (P < 0.001), (+)-WAY 100135 to 212 +/- 31% (P < 0.05) and GR 127935 to 203 +/- 23% (P < 0.01). These data suggest that, under these experimental conditions, DRN 5-HT autoreceptors are tonically activated in the presence of the uptake blocker and that the antagonists act by blocking this counteracting autoinhibitory tone. The data also strongly indicate that 5-HT efflux in the rat DRN is under the control not only of 5-HT1A but also of 5-HT1B/D receptors.
Davidson
C
C
Anaesthetics Unit (Neurotransmission Laboratory), London Hospital Medical College, Royal London Hospital, Whitechapel, UK.
Stamford
J A
JA
D000818:Animals; D004558:Electric Stimulation; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors
D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C081293:WAY 100135; C090701:GR 127935; D012701:Serotonin; D017374:Paroxetine; D008719:Methiothepin