Fig. 5: MA-induced potentiation of DR 5-HT neurons expressing non-functional TAAR1 is SERT dependent. | Neuropsychopharmacology

Fig. 5: MA-induced potentiation of DR 5-HT neurons expressing non-functional TAAR1 is SERT dependent.

From: Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake

Fig. 5: MA-induced potentiation of DR 5-HT neurons expressing non-functional TAAR1 is SERT dependent.The alternative text for this image may have been generated using AI.

All experiments were performed in the presence of antagonists for 5HT1A (WAY 100635, 100 nM) and 5HT1B (SB 216641, 200 nM) autoreceptors. A Mean firing frequency of MAHDR DR 5-HT neurons pre- and post-MA application in the presence of the AMPA receptor antagonist NBQX (10 µM) and GABAA receptor antagonist bicuculline (10 µM) [7 recordings (7 mice: Male = 4, Female = 3). Means ± SEM are presented collapsed on sex] B RMPs of MAHDR DR 5-HT neurons depolarized in response to MA in the presence of NBQX and bicuculline. Each set of symbols represents a recording in the absence and presence of MA. C The effect of MA is blocked in the presence of fluoxetine in recordings from MAHDR DR 5-HT neurons [7 recordings (6 mice: Male=3, Female = 4). Means ± SEM are presented collapsed on sex]. D RMPs of MAHDR DR 5-HT neurons were not significantly changed by MA in the presence of fluoxetine. Each set of symbols represents a recording in the absence and presence of MA. E Blockade of the MA effect by fluoxetine is confirmed in DR 5-HT neurons from MAHDR-Taar1m1J/m1J control mice [7 recordings (6 mice: Male = 3, Female = 3). Means ± SEM are presented collapsed on sex]. F RMPs of MAHDR-Taar1m1J/m1J DR 5-HT neurons were not significantly changed by MA in the presence of fluoxetine. Each set of symbols represents a recording in the absence and presence of MA. G Schematic of TAAR1 differences between lines. Left panel: MA enters DR 5-HT neurons of MAHDR and MAHDR-Taar1m1J/m1J control mice through SERT. Due to non-functional TAAR1, MA cannot activate TAAR1 signaling pathways, preventing the internalization of SERT from the membrane (denoted by the red Xs). In these mice, MA depolarizes DR 5-HT neurons resulting in increased activity in the presence of autoreceptor antagonists. The effect of MA can be blocked by the SERT antagonist fluoxetine. Right panel: MA enters DR 5-HT neurons of MALDR and MAHDR-Taar1+/+ KI mice through SERT. MA activates TAAR1 signaling pathways leading to internalization of SERT from the membrane. As a result, MA does not depolarize DR 5-HT neurons, and their activity remains unchanged in the presence of 5-HT autoreceptor antagonists. Created in BioRender. Rios, S. (2025) https://BioRender.com/t93y794.

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