Pharmacogenetics of stimulant abuse liability: association of CDH13 variant with amphetamine response in a racially-heterogeneous sample of healthy young adults

Leventhal, Adam M.; Kirkpatrick, Matthew G.; Pester, Mollie S.; McGeary, John E.; Swift, Robert M.; Sussman, Steve; Kahler, Christopher W.

doi:10.1007/s00213-016-4462-z

Cited by 5 publications

(7 citation statements)

References 43 publications

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“…GWASs have also identified associations between several single nucleotide polymorphisms (SNPs) in CDH13 and multiple behavioral disorders as well, including ADHD (Lesch et al , 2008, Mavroconstanti et al , 2013, Neale et al , 2010, Salatino-Oliveira et al , 2015), bipolar disorder symptoms (Cho et al , 2015), schizophrenia (Borglum et al , 2014) violent behavior (Tiihonen et al , 2015) and alterations in working memory performance (Arias-Vásquez & Altink, 2011). CDH13 is also associated with subjective response to amphetamine in non-addicted subjects (Hart et al , 2012b, Leventhal et al , 2016); which may be an intermediate phenotype of drug abuse. Thus, multiple lines of evidence suggest that various alleles of CDH13 pleiotropically affect a wide array of behaviors; however, the neural and psychological mechanisms through which these behaviors are modified remain open questions.…”

Section: Introductionmentioning

confidence: 99%

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

King

Militello

Hart

et al. 2017

Genes Brain and Behavior

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Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knock-out rats and AdipoQ knock-out mice using intravenous cocaine self-administration and conditioned place preference paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/−) and knock-out (−/−) rats showed increased cue-induced reinstatement compared to wild-type rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 −/− rats showed higher responding for a saccharin reinforcer and learned the choice reaction time task more slowly than wild-types. However, we found no differences between Cdh13 −/− and +/+ rats in responding for sensory reinforcement, number of premature responses in the reaction time task, tendency to approach a Pavlovian food cue, conditioned place preference and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ −/− mice there was a significant increase in conditioned place preference to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.

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Section: Introductionmentioning

confidence: 99%

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

King

Militello

Hart

et al. 2017

Genes Brain and Behavior

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“…(1) Raw data were scored using standard methods of each instrument, yielding scored measures at each time point. (2) Area under the curve (AUC) values were calculated using the trapezoidal method across the eight TP of assessment on each session (AUC AMP , AUC MA , AUC PBO ) . (3) Within-subject drug effects were calculated as ΔAUC AMP = AUC AMP minus AUC PBO , and ΔAUC MA = AUC MA minus AUC PBO .…”

Section: Materials and Methodsmentioning

confidence: 99%

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy

White,

Gonsalves,

Harris

et al. 2024

ACS Chem. Neurosci.

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Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with Damphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140−150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMPand MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGlu MA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGlu MA r = +0.52, p < 0.05; ΔGlu AMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = −0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA (r = 0.95 AMP, p = 5 × 10 −10 ; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGlu AMP r = +0.59 to +0.65, p's < 0.05; ΔGlu MA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

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“…The study used a within-subjects design, in which participants attended a baseline session, followed by two four-hour experimental sessions at which a 20 mg dose of oral d-amphetamine or placebo was administered under double-blind conditions (session order was counterbalanced). The present findings are a secondary analysis of a larger study examining individual difference factors that predict response to the acute effects of d-amphetamine (Kirkpatrick et al, 2016;Leventhal et al, 2017;Pang et al, 2016).…”

Section: Designmentioning

confidence: 99%

“…The 20 mg d-amphetamine dose was selected based on previous studies indicating differences in acute d-amphetamine response as a function of trait personality measures (Kirkpatrick et al, 2013;White et al, 2006). This dose produces reliable subjective effects in naïve participants (see time course graphs in Leventhal et al, 2017 andPang et al, 2016), without increasing adverse effects associated with larger doses.…”

Section: Drugmentioning

confidence: 99%

Rewarding effects of physical activity predict sensitivity to the acute subjective effects of d-amphetamine in healthy volunteers

et al. 2018

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While individual differences in reward sensitivity are believed to generalize across drugs and alternative rewards, this notion has received little empirical attention in human research. Here, we tested whether individual differences in the subjective rewarding effects of physical activity were associated with the subjective response to d-amphetamine administration. Healthy volunteers ( n=95; age 18-35 years) completed questionnaires measuring the self-reported pleasurable effects of physical activity and other covariates, and this was followed by two double-blind counterbalanced sessions during which they received either 20 mg oral d-amphetamine or placebo. Subjective drug effects measures were collected before and repeatedly after drug administration. Subjective d-amphetamine-related effects were then reduced via principal components analysis into latent factors of "positive mood," "arousal," and "drug high." Multiple regression models controlling for placebo-related scores, session order, demographics, body mass index, level of physical activity, and use of other drugs showed that degree of self-reported physical activity reward was positively associated with d-amphetamine-induced positive mood and arousal ( βs≥0.25, ps≤0.04), but was not associated with d-amphetamine-induced changes in drug high ( β=0.13, p=0.24). These results provide novel evidence suggesting that individual differences in reward sensitivity cross over between d-amphetamine reward and physical activity reward in humans.

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Pharmacogenetics of stimulant abuse liability: association of CDH13 variant with amphetamine response in a racially-heterogeneous sample of healthy young adults

Cited by 5 publications

References 43 publications

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy

Rewarding effects of physical activity predict sensitivity to the acute subjective effects of d-amphetamine in healthy volunteers

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