The effects of BTS 54,505, a metabolite of sibutramine, on monoamine and excitatory amino acid-evoked responses in the rat dorsolateral geniculate nucleus in vivo.
1. The effects of BTS 54,505, the primary amine metabolite of the non-tricylic putative antidepressant sibutramine, on the responses evoked by visual stimulation and ionophoretic application of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and excitatory amino acids (EAAs) in the rat dorsolateral geniculate nucleus (dLGN) have been investigated. 2. Ionophoretic application of 5-HT to dLGN neurones attenuated visually-evoked (n = 46), NMDA-evoked (n = 21) and AMPA-evoked responses (n = 21), while ionophoretic application of NA potentiated visually-evoked activity in these cells (n = 27). 3. Simultaneous application of BTS 54,505 with 5-HT (over 120 s) resulted in a prolongation of the recovery time (i.e. the period required by a neurone to recover by 50%, RT50) from the 5-HT-mediated suppression of discharge activity (approximately 275% increase in RT50). BTS 54,505 also prolonged the recovery time from a NA-mediated potentiation of firing (approximately 450% increase in RT50). These effects on recovery time are attributed to the inhibition of uptake of both 5-HT and NA by BTS 54,505. The amplitude of the response to 5-HT or NA was unaffected by co-ejection of BTS 54,505. 4. Ionophoretic application of N-methyl-D-aspartate (NMDA) produced a current-dependent increase in neuronal firing, as did application of the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). A simultaneous 120 s application of BTS 54,505 inhibited the NMDA response in all cells studied (mean ED50 = 16 +/- 5 nA) but had no effect on AMPA-evoked activity in the majority of the same cells (n = 15/21).5. Short 10 s applications of BTS 54 505, at ejecting currents (>30 nA) that attenuated NMDA-evoked activity in all cells studied, had no effect on either response amplitude or recovery time from ionophoretic application of 5-HT, suggesting that inhibition of NMDA-evoked activity by BTS 54 505 was not mediated by 5-HT uptake blockade.6. These results suggest that BTS 54 505 inhibits NMDA-evoked activity, and the observation that this effect is unlikely to be due to raised levels of endogenous 5-HT following monoamine uptake blockade indicate that BTS 54 505 may interact directly with the NMDA receptor ionophore complex.
Scott
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Department of Physiology and Pharmacology, University of Nottingham Medical School, Queens Medical Centre.
Luscombe
G P
GP
Mason
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R
D000818:Animals; D003503:Cyclobutanes / Q000378:metabolism / Q000494:pharmacology*; D005074:Evoked Potentials, Visual / Q000187:drug effects*; D005829:Geniculate Bodies / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D007478:Iontophoresis; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
D003503:Cyclobutanes; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C087851:BTS 54 505; C058254:sibutramine; D009638:Norepinephrine