Multivariate analysis of subjective responses to d-amphetamine in healthy volunteers finds novel genetic pathway associations

Abstract

Rationale Researchers studying behavioral and physiologic effects of d-amphetamine have explored individual response differences to the drug. Concurrently, genome wide analyses have identified several single nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components. Objectives To identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis. Methods Individuals (N=375) without substance abuse histories completed surveys and detailed cardiovascular monitoring during randomized, blinded sessions: d-amphetamine (10mg, 20mg), placebo. We applied parallel-independent component analysis (Para-ICA) to data previously analyzed with univariate approaches, revealing new associations between genes and behavioral responses to d-amphetamine. Results Three significantly associated (p<.001) phenotype-genotype pairs emerged. The first component included physiologic measures of systolic and diastolic blood pressure (BP) and mean arterial pressure (MAP) along with SNPs in calcium and glutamatergic signaling pathways. The second associated components included the ‘Anger’ items from the Profile of Mood States (POMS) questionnaire and the Marijuana effects from the Addiction Research Center Inventory (Cuyas, Verdejo-Garcia et al.), with enriched genetic pathways involved in Cardiomyopathy and MAPK signaling. The final pair included ‘Anxious’, ‘Fatigue’, and ‘Confusion’ items from the POMS questionnaire, plus functional pathways related to cardiac muscle contraction and cardiomyopathy. Conclusions Multifactorial genetic networks related to calcium signaling, glutamatergic and dopaminergic synapse function and amphetamine addiction appear to mediate common behavioral and cardiovascular responses to d-amphetamine.

Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial

“…Dexamphetamine did not differ significantly from placebo for the stop signal task. After repetition of the dexamphetamine challenge on day 7 or 10 in the placebo arm, dexamphetamine effects were similar to those on day -5, but were not statistically compared because the effect of the amphetamine challenge has been well established in literature (Laruelle, 2000;Van Der Aart et al, 2016;Yarosh et al, 2015).…”

“…However, since the challenge only provides information on peripherally obtained human blood samples, an additional challenge is required in order to evaluate PD effects in the CNS. In psychopharmacological research, dexamphetamine has been extensively used as a challenge agent for its subjective and psychomotor effects (Laruelle, 2000; Yarosh et al, 2015) as assessed by various methods, including the Neurocart (Van Der Aart et al, 2016), a drug-sensitive CNS test battery (Groeneveld et al, 2016). Considering the efficacy of JNJ-54175446 in attenuating the pharmacological effects of dexamphetamine in preclinical studies (Bhattacharya et al, 2013; Gubert et al, 2016; Lord et al, 2014), this acute dexamphetamine challenge could be used as a translational model to evaluate JNJ-54175446’s effects in the CNS.…”

Interplay Between Amphetamine and Activity Level in Gene Networks of the Mouse Striatum

“… 96 Rora was over-expressed in the A relative to the S treatment [log2(fold change A/S) = 0.32, FDR-adjusted P -value < .034] confirming the effects that amphetamine elicits on Rora expression. Rora participates in the amphetamine metabolism, 97 angiogenesis, learning, and positive regulation of circadian rhythm. 98 Mutations in Rora have been associated with impaired in motor functions and motor coordination.…”

Dysmorphic contribution of neurotransmitter and neuroendocrine system polymorphisms to subtherapeutic mood states

“…Similar studies (Takeuchi et al, ) relate the polymorphism of DRD2 with the POMS test and find differences between sexes in a similar population. Yarosh, Meda, Wit, Hart, & Pearlson, (), performed a multivariate analysis of polymorphisms of a whole genome association study with the POMS test in healthy subjects treated with amphetamine, finding association with SNPs related to genes of the glutamatergic signal pathways, which seem to mediate behavior and in cardiovascular responses to amphetamine.…”