Genetic Factors Modulating the Response to Stimulant Drugs in Humans

Hart, Amy; Wit, Harriet de; Palmer, Abraham A.

doi:10.1007/7854_2011_187

Cited by 33 publications

(26 citation statements)

References 174 publications

(189 reference statements)

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“…Time‐course analysis of gene expression revealed upregulation of 26 genes that persisted over late cocaine extinction, from the 3 rd until the 10 th day after self‐administration (Table ). Among these genes, Drd2 , Ghrl , Oprm1 , and Tet3 are particularly interesting; for example, Drd2 and Oprm1 influence the dopaminergic system underlying the rewarding properties of drugs of abuse (Hart, de Wit, & Palmer, ). However, we focused on the Tet3 gene because of its role in the DNA demethylation process, which may influence genomic transcription and probably extinction learning.…”

Section: Discussionmentioning

confidence: 99%

Increased 5‐hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self‐administration

et al. 2017

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Drug craving and relapse risk during abstinence from cocaine are thought to be caused by persistent changes in transcription and chromatin regulation. Although several brain regions are involved in these processes, the hippocampus seems to play an important role in context-evoked craving and drug-seeking behavior. Only a few studies have examined epigenetic alterations during a period of cocaine abstinence. To investigate the effects of cocaine abstinence on DNA methylation and gene expression, rats that self-administered the drug underwent cocaine abstinence in two time points with extinction training. During the cocaine extinction, we observed elevated global 5-hydroxymethylcytosine(5-hmC) levels with a concurrent increase in Tet3 transcript levels. Moreover, we did not find significant alterations in the levels of Tet3 mRNA and 5-hmC in rats subjected to cocaine abstinence without extinction training. Additionally, our findings demonstrated that the expression of Tet3 target genes was activated. Besides, altered DNA methylation was detected at promoter regions of miRNAs, such as miR-30d and miR-let7i. Further in silico analysis provided evidence that these two molecules targeted the 3' UTR region of the Tet3 gene and thus may contribute to its post-transcriptional regulation. This study has presented novel findings in the hippocampus of rats that underwent extinction training following cocaine self-administration. The alterations in the Tet3 gene expression and the level of 5-hmC may play an important role in extinction learning and the reduction of subsequent cocaine seeking.

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Section: Discussionmentioning

confidence: 99%

Increased 5‐hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self‐administration

et al. 2017

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“…Cocaine acts, in part, on the dopaminergic pathway by blocking the DA transporter (encoded by the DAT1/SLC6A3 gene) and allowing more DA to remain in the synapse to activate DA receptors (Nestler, 2001, Nestler, 2005, Volkow et al , 1996). There is inter-individual variation in how people experience the effects of cocaine and some of this variation may be due to genetic influences [reviewed in (Hart et al , 2012)]. There is evidence that the nature and intensity of these subjective effects may lead to increased or decreased use, and may lead to dependence or abuse particularly when the effects are positive (Fergusson et al , 2003, Haertzen et al , 1983).…”

Section: Introductionmentioning

confidence: 99%

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

Spellicy

Harding

Hamon

et al. 2014

Genes Brain and Behavior

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This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 gene (ANKK1) and/or the dopamine receptor D2 gene (DRD2) modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 minutes prior to cocaine administration, and at 5, 10,15, and 20 minutes following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (p = 0.00006), ‘any drug effect’ (p = 0.0003), and ‘like’ (p = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, LD analysis revealed this association was driven by the ANKK1 rs1800497 variant. A participant’s ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.

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“…The acute effects of d -amphetamine (AMPH) differ across individuals (de Wit et al, 1986; Hart et al, 2012; Nurnberger et al, 1982; Silberman et al, 1981; Veenstra-VanderWeele et al, 2006). People differ in the intensity of response to AMPH on various measures, including physiological (Stoops et al, 2007), choice to self-administer the drug (de Wit et al, 1986; Uhlenhuth et al, 1981), and subjective feelings of euphoria, friendliness, arousal, and elation (Crabbe et al, 1983; Silberman et al, 1981; White et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Personality and the acute subjective effects of d-amphetamine in humans

2013

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There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5,10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher-order factors (‘Euphoria’, ‘Arousal’, ‘Dysphoria’). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems.

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Genetic Factors Modulating the Response to Stimulant Drugs in Humans

Cited by 33 publications

References 174 publications

Increased 5‐hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self‐administration

Increased 5‐hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self‐administration

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

Personality and the acute subjective effects of d-amphetamine in humans

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