Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives...

Methamphetamine (MA) is a potent psychostimulant capable of exerting both rewarding and aversive effects, the balance of which likely drives variation in voluntary MA intake. Understanding the genetic factors underlying sensitivity to these effects of MA is critical for developing effective treatments. The activity of dorsal raphe serotonin neurons is linked to reward processing. Here, we performed whole-cell patch-clamp electrophysiology in dorsal raphe serotonin neurons from mice with high or low MA intake corresponding with high or low MA reward sensitivity. The MA drinking (MADR) mice consist of the MA reward sensitive MA high drinking (MAHDR) and the MA reward insensitive MA low drinking (MALDR) lines. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and MAHDR mice are homozygous for a mutation in the Taar1 gene, Taar1^m1J, that encodes non-functional TAAR1, whereas MALDR mice possess at least one copy of the reference Taar1⁺ allele that encodes functional TAAR1. Our previous research using CRISPR-Cas9-generated MAHDR-Taar1^+/+ knock-in mice in which Taar1^m1J was replaced with Taar1⁺, and non-edited MAHDR-Taar1^m1J/m1J controls demonstrated that lack of TAAR1 function is critical for heightened MA consumption and MA reward sensitivity. Here, electrophysiological recordings in the MADR lines demonstrate a MA-induced decrease in dorsal raphe serotonin neuron activity from MALDR, but not MAHDR mice. However, in the presence of serotonin autoreceptor antagonists, MA potentiates dorsal raphe serotonin neuron activity of MAHDR, but not MALDR mice. Importantly, potentiation in the presence of the antagonists is abolished in knock-in mice expressing functional TAAR1. The knock-in mice did not display binge-level MA intake, consistent with the loss of MA-reward sensitivity previously reported in mice with functional TAAR1. Finally, because MA is a substrate of the serotonin transporter, we evaluated whether the serotonin transporter is necessary for MA-induced potentiation of dorsal raphe serotonin neuron activity in mice with non-functional TAAR1. The serotonin transporter antagonist fluoxetine blocks MA-induced potentiation for both MAHDR and MAHDR-Taar1^m1J/m1J mice. Thus, TAAR1 function directly impacts MA reward sensitivity and MA intake and serves as a critical regulator of MA-induced activity of dorsal raphe serotonin neurons through its interaction with the serotonin transporter.