Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Havranek, Michael M; Vonmoos, Matthias; Müller, Christian P.; Büetiger, Jessica R.; Tasiudi, Eve; Hulka, Lea M.; Preller, Katrin H.; Mößner, Rainald; Grünblatt, Edna; Seifritz, Erich; Quednow, Boris B.

doi:10.1038/npp.2015.146

Cited by 18 publications

(10 citation statements)

References 55 publications

(81 reference statements)

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“…PCR efficiency was determined with the program LinRegPCR (http://www.hartfaalcentru.nl), gene expression and normalization analysis was conducted using the QBase plus software (Biogazelle), for further details, see Havranek et al . and Havranek et al . .…”

Section: Methodsmentioning

confidence: 91%

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Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

et al. 2018

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Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.

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Section: Methodsmentioning

confidence: 91%

“…The inclusion and exclusion criteria have been previously described in detail (Havranek et al . ). Briefly, CU were included if cocaine was their primary drug of choice, they used more than 0.5 g per month and were not abstinent for more than 6 months.…”

Section: Methodsmentioning

confidence: 97%

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

et al. 2018

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“…Taken together, accumulating evidence supports the view that several psychoactive drugs are instrumentalized specifically to enhance cognitive performance. Long term regular use of these drugs can induce tolerance for the cognitive effects and even lead to cognitive deficits (Vonmoos et al, 2013;Wolff et al, 2014;Havranek et al, 2015;Müller, 2017).…”

Section: Improved Cognitive Performance and Counteracting Fatiguementioning

confidence: 99%

Non-pharmacological factors that determine drug use and addiction

Ahmed

Badiani

Miczek

et al. 2020

Neuroscience & Biobehavioral Reviews

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Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood. Here we review the emerging neurobiological mechanisms beyond pharmacological reinforcement which determine drug effects and use frequency. Important progress was made on the understanding of how the character of an environment and social stress determine drug self-administration. This is expanded by new evidence on how behavioral alternatives and opportunities for drug instrumentalization generate different patterns of drug choice. Emerging evidence suggests that the neurobiology of non-pharmacological factors strongly determines pharmacological and behavioral drug action and may, thus, give rise for an expanded system's approach of psychoactive drug use and addiction.

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“…In line with a recent publication demonstrating that increased delay discounting in cocaine users might be explained by an interaction between a genetic variation of an alpha-adrenergic receptor and cocaine use (Havranek et al, 2016), this finding suggests that adaptations in the norepinephrine system might also account for some cognitive changes found in cocaine users. Another recent study indicates that genetic variation in serotonin transporters also plays an important role in the development of working memory deficits in chronic cocaine users (Havranek et al, 2015); thus, changes in the serotonin system might be involved in cocaine-related cognitive impairments. Gaining greater insight into the various changes in the monoamine neurotransmitter systems may help explain the broad cognitive impairments of cocaine users, which are somewhat different from the more distinct cognitive deficit profiles in chronic users of other substances such as ecstasy, amphetamine and opiates (van Holst & Schilt, 2011).…”

Section: Neurobiological Linkage Between Cocaine Use and Cognitive Fumentioning

confidence: 99%

Cognitive Dysfunctions in Chronic Cocaine Users

Vonmoos

Quednow

2017

The Neuroscience of Cocaine

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After nearly three decades of research, there is still no clarity on the causal relationship between chronic cocaine use and cognitive functioning. However, the current literature consistently suggests that broad cognitive impairments occur in not only dependent cocaine users but also recreational cocaine users, with impairments involving attention, working memory declarative memory and executive functions. Moreover, it was recently shown that chronic cocaine users exhibit specific deficits in sociocognitive abilities, which very likely contribute to the social dysfunctions that occur in their daily lives. Correlation analyses and initial longitudinal studies indicate that most cognitive deficits are at least partially cocaine-induced. Accordingly, there is also some evidence regarding the recovery of cognitive functions in decreasing and long-term abstinent users.

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Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Cited by 18 publications

References 55 publications

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use

Non-pharmacological factors that determine drug use and addiction

Cognitive Dysfunctions in Chronic Cocaine Users

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