Synergism of 5-HT 1B/D antagonists with paroxetine on serotonin efflux in rat ventral lateral geniculate nucleus slices.
Serotonin (5-HT) efflux in rat ventral lateral geniculate nucleus (vLGN) slices was evoked by electrical stimulation (20 pulses at 100 Hz, 10 mA, 190 ms train) and measured, along with 5-HT uptake, by fast cyclic voltammetry at implanted carbon fibre microelectrodes. Paroxetine (100 nM), a selective serotonin reuptake inhibitor (SSRI), increased stimulated 5-HT efflux to 194 +/- 25% of pre-drug values at maximum (mean +/- SEM, n = 5) and the half-life of uptake to 684 +/- 135%. When given alone, neither the selective 5-HT 1B antagonist isamoltane (1 microM) nor the 5-HT 1D/B antagonist GR 127935 (50 nM), affected 5-HT efflux or uptake under this stimulation paradigm. When added in combination with paroxetine, both isamoltane and GR 127935 significantly potentiated the effect of paroxetine on stimulated 5-HT efflux: isamoltane to 302 +/- 48% at maximum (p < 0.05 vs. paroxetine alone), GR 127935 to 318 +/- 95% (p < 0.05 vs. paroxetine alone) of pre-drug values. Neither isamoltane nor GR 127935 had any effect on 5-HT uptake. The selective 5-HT 1A antagonist WAY 100635 (10 nM) had no effect on 5-HT efflux or uptake, alone or in combination with paroxetine. These data suggest that, under these experimental conditions, paroxetine gives rise to tonic activation of the vLGN terminal 5-HT autoreceptors. Furthermore, these data show that 5-HT 1B and possibly 5-HT 1D antagonists block this inhibitory autoreceptor tone and may thus be a useful addition to SSRI treatment in the clinic.
Davidson
C
C
Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, UK.
Stamford
J A
JA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005829:Geniculate Bodies / Q000187:drug effects*; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D010069:Oxadiazoles; D010879:Piperazines; D011412:Propanolamines; C090701:GR 127935; D012701:Serotonin; D017374:Paroxetine; C058392:isamoltane