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Background  Methamphetamine (MA) is a potent agonist at the trace amine-associated receptor 1 (TAAR1). This study evaluated a common variant (CV) in the human  TAAR1  gene, synonymous single nucleotide polymorphism (SNP) V288V, to determine the involvement of TAAR1 in MA dependence.    Methods  Participants (n = 106) with active MA dependence (MA-ACT), in remission from MA dependence (MA-REM), with active polysubstance dependence, in remission from polysubstance dependence, and with no history of substance dependence completed neuropsychiatric symptom questionnaires and provided blood samples.  In vitro  expression and function of CV and wild type TAAR1 receptors were also measured.    Results  The V288V polymorphism demonstrated a 40% increase in TAAR1 protein expression in cell culture, but message sequence and protein function were unchanged, suggesting an increase in translation efficiency. Principal components analysis resolved neuropsychiatric symptoms into four components, PC1 (depression, anxiety, memory, and fatigue), PC2 (pain), PC3 (drug and alcohol craving), and PC4 (sleep disturbances). Analyses of study group and  TAAR1  genotype revealed a significant interaction for PC3 (craving response) ( p  = 0.003). The control group showed no difference in PC3 associated with  TAAR1 , while adjusted mean craving for the MA-ACT and MA-REM groups, among those with at least one copy of V288V, was estimated to be, respectively, 1.55 ( p  = 0.036) and 1.77 ( p  = 0.071) times the adjusted mean craving for those without the  TAAR1  SNP.    Conclusions  Neuroadaptation to chronic MA use may be altered by  TAAR1  genotype and result in increased dopamine signaling and craving in individuals with the V288V genotype.

Trace amine-associated receptor gene polymorphism increases drug craving in individuals with methamphetamine dependence