Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits.
Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.
1] Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA [2] Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
John H
0000000240440647
JH
Harkness
1] Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA [2] Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA.
Xiao
X
Shi
1] Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA [2] Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA [3] Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA [4] Veterans Affairs Portland Health Care System, Portland, OR, USA.
Aaron
A
Janowsky
1] Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA [2] Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA [3] Veterans Affairs Portland Health Care System, Portland, OR, USA.
Tamara J
TJ
Phillips
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D002755:Choice Behavior / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008694:Methamphetamine / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013649:Taste / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D000095383:Trace Amine-Associated Receptors
D000697:Central Nervous System Stimulants; D000242:Cyclic AMP; D008694:Methamphetamine; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors