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

Abstract

1 The effects of BTS 54 505, the primary amine metabolite of the non-tricyclic 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), NMDAevoked (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 (,275% increase in RTm,). BTS 54 505 also prolonged the recovery time from a NA-mediated potentiation of firing (;450% increase in RTm). 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-N4DA receptor agonist a-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 EDm = 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.

Distinct Subsets of Hypothalamic Genes Are Modulated by Two Different Thermogenesis‐inducing Stimuli

“…This pathway is responsive, for example, to prostaglandin (31) and may depend on the disinhibition of neurons of the dorsomedial hypothalamus (30). In addition, at least two drugs currently used to treat obesity, sibutramine and rimonabant, are known to exert inhibitory actions on NMDA activity in the hypothalamus (32,33). It will be interesting to evaluate whether receptors composed by 2B subunits play an important role in this process and whether they are preferentially expressed in hypothalamic regions involved in the integrative control of thermogenesis.…”

Sibutramine: A Serotonin–Norepinephrine Reuptake-Inhibitor for the Treatment of Obesity

“…11 The possible binding of one of sibutramine's metabolites to the N-methyl-D-aspartate receptor requires further investigation. 20 Sibutramine does not cause or enhance neuronal release of NE or 5-HT, which differentiates it from fenfluramine and dexfenfluramine. 18,21, 22 Both of these agents are known to cause the release of presynaptic 5-HT as part of their mechanism of action.…”