000041311 001__ 41311
000041311 005__ 20240415155114.0
000041311 0247_ $$2doi$$a10.6083/bpxhc41311
000041311 037__ $$aIR
000041311 041__ $$aeng
000041311 245__ $$aRole of the lateral habenula-dorsal raphe circuit in methamphetamine-induced aversion
000041311 260__ $$bOregon Health and Science University
000041311 269__ $$a2023-07-20
000041311 336__ $$aAbstract
000041311 520__ $$aStrong initial sensitivity to aversive drug effects likely results in drug avoidance and reduces the probability of addiction. The activation of glutamatergic lateral habenula (LHb) afferents projecting to dorsal raphe (DR) serotonin (5-HT) and GABA interneurons is implicated in the perception of aversion induced by several stimuli. Specifically, inhibition of DR 5-HT neurons is associated with the perception of aversion, whereas activation of these neurons is associated with reward. Our research was designed to test the role of this circuit in methamphetamine (MA)-induced aversion using mice selectively bred for differential genetic risk for voluntary MA consumption. Mice bred for low MA intake (MALDR) exhibit high sensitivity to the aversive effects of MA and low sensitivity to MA reward, whereas mice bred for high MA intake (MAHDR) have opposite MA aversion and reward phenotypes. MA is a full trace amine-associated receptor 1 (TAAR1) agonist and studies from our lab have found TAAR1 functionality is critical for sensitivity to the aversive effects of MA. MALDR mice possess functional TAAR1, whereas MAHDR mice possess a mutation, resulting in the loss of TAAR1 function. We performed research to determine whether MA-induced activation of the LHb and the effect of MA on DR 5-HT neuron firing differs between the MALDR and MAHDR lines. Acute MA induced significantly greater neural activation, measured by cFos expression, in the LHb of MALDR mice, compared to MAHDR mice. Using ex-vivo electrophysiology, we found that MA affects firing frequency in DR 5-HT neurons of MAHDR mice but not of MALDR mice. Greater MA-induced neural activation in the LHb of MALDR mice may be related to their high sensitivity to MA-induced aversion, whereas effects of MA in the DR of MAHDR mice may be related to their sensitivity to the rewarding effects of MA, which are not found in MALDR mice. 
000041311 540__ $$fCC BY
000041311 542__ $$fIn copyright - joint owners
000041311 650__ $$aGenetics$$019472
000041311 650__ $$aNeurosciences$$022870
000041311 650__ $$aElectrophysiology$$018311
000041311 650__ $$aReward$$025422
000041311 650__ $$aSerotonin$$025891
000041311 650__ $$aMethamphetamine$$022135
000041311 650__ $$aSubstance-Related Disorders$$032029
000041311 650__ $$aRodentia$$025590
000041311 650__ $$aModels, Animal$$033025
000041311 6531_ $$aaversion
000041311 6531_ $$adrug effects
000041311 6531_ $$aaddiction
000041311 6531_ $$adrug avoidance
000041311 691__ $$aSchool of Medicine$$041369
000041311 692__ $$aDepartment of Behavioral Neuroscience$$041394
000041311 7001_ $$aRios, Samantha$$uOregon Health and Science University$$041354
000041311 7001_ $$aIngram, Susan$$uUniversity of Colorado
000041311 7001_ $$aRichards-Phillips, Tamara$$uOHSU & VA Portland Health Care System$$041347
000041311 711__ $$aResearch Week$$uOregon Health and Science University$$d2023
000041311 7201_ $$7Personal
000041311 8564_ $$9a092dd3b-8ba3-42ef-825c-63a008331f79$$s270072$$uhttps://digitalcollections.ohsu.edu/record/41311/files/ResearchWeek.2023.Rios.Samantha.pdf
000041311 980__ $$aResearch Week
000041311 981__ $$aPublished$$b2023-07-20