High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress

Molander, Anna; Mar, Adam; Norbury, Agnes; Steventon, Sarah; Moreno, Margarita; Caprioli, Daniele; Theobald, David E. H.; Belin, David; Everitt, Barry J.; Robbins, Trevor W.; Dalley, Jeffrey W.

doi:10.1007/s00213-011-2167-x

Cited by 100 publications

(76 citation statements)

References 55 publications

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“…Considering higher plasma corticosterone concentrations induced by CFC stress than OF stress (Hirata et al, 2008;Hirata et al, 2009), the different neuronal responses between the two tests might be related to different types and intensities of stressors. While exposing animals to an OF arena drives the motivation of novelty-seeking behavior on one hand, it also increases the anxiety on the other hand, because of the novelty of unfamiliar environments (Gray and McNaughton, 2003;Padilla et al, 2010;Molander et al, 2011). Our observation that administration of diazepam suppressed both anxiety-related behavior and c-Fos expression in the DRL without affecting the total moving distance supports this notion.…”

Section: Discussionsupporting

confidence: 72%

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Shikanai

Yoshida²,

Konno

et al. 2012

J. Neurosci.

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The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor.

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Section: Discussionsupporting

confidence: 72%

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Shikanai

Yoshida²,

Konno

et al. 2012

J. Neurosci.

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“…It is important to reiterate, however, that the bred lines exhibit differences in other traits that have been associated with addiction liability, including impulsivity (19), and these differences are not necessarily apparent in outbred LR/HR rats (22,23; see also ref. 18).…”

Section: Discussionmentioning

confidence: 99%

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Flagel

Chaudhury

Waselus

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with "temperament," including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/ bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor. addiction | dopamine | fibroblast growth factor | nucleus accumbens | reinstatement A pproximately 16% of adults in the United States report drug use within the past year (1). However, not everyone who experiments with drugs becomes an addict, as an estimated 8.5% of the population, or 25 million Americans, meet Diagnostic and Statistical Manual of Mental Disorders IV (2) criteria for substance abuse and dependence (1). Environmental and societal factors play a role in addiction liability (e.g., refs. 3-5), and there is ample evidence demonstrating a role for genetic factors (e.g., refs. 6-10). However, studying the interplay among these factors is difficult in human studies because of the inability to control for environmental factors and the challenge of parsing causes from consequences. Preclinical animal models are therefore essential for defining the complex interactions between genes and environment, and uncovering the neural mechanisms that might render an individual more susceptible to drug addiction. The first animal model characterizing individual differences in the propensity to take drugs of abuse was introduced over two decades ago by Piazza et al. (11), who showed that, like humans, only some rats readily self-administer such drugs. Furthermore...

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“…Rats identified as having extremely high impulsivity on the 5CSRTT (upper 25% of population) do not show high novelty reactivity, which is considered another measure of impulsivity or risk taking (Belin et al, 2008;Molander et al, 2011). In humans, children with ADHD who are considered to be more impulsive showed either an increase in impulsive action or impulsive choice, but behavior on the two types of tasks was not correlated (Sonuga-Barke, 2002).…”

Section: Discussionmentioning

confidence: 99%

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

Torregrossa

Xie

Taylor

2012

Neuropsychopharmacol

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Chronic stress during adolescence is associated with an increased risk for alcoholism and addictive disorders. Addiction is also associated with increased impulsivity, and stress during adolescence could alter cortical circuits responsible for response inhibition. Therefore, the present study determined the effect of chronic exposure to the stress hormone corticosterone (CORT) during adolescence on tests of impulsivity in adulthood and examined possible biochemical mechanisms. Male Sprague-Dawley rats were exposed to CORT by their drinking water during adolescence (post-natal day 30-50). The rats were then tested in adulthood to assess behavior on the 5-choice serial reaction time task (5CSRTT), stop-signal reaction time task (SSRTT), and the delay-discounting task, which differentially assess attention, impulsive action, and impulsive choice. Yohimbine-induced impulsivity on the 5CSRTT and biochemical analysis of the lateral orbital frontal cortex (lOFC) was also assessed owing to the ability of yohimbine to activate the hypothalamic-pituitary-adrenal axis and influence impulsivity. Adolescent CORT-treated rats were found to behave largely like controls on the 5CSRTT, but did show reduced premature responses when the intertrial interval was increased. Nevertheless, the CORT-treated rats tended to have more yohimbineinduced impulsive responses at low doses on this task, which was not found to be due to increased pCREB in the lOFC, but could be related to a higher expression/activity of the AMPA receptor subunit GluR1. Adolescent CORT-treated rats performed more accurately on the SSRTT, but showed greater impulsivity on the delay-discounting task, as indicated by steeper discounting functions. Therefore, adolescent CORT exposure reduced impulsive action but increased impulsive choice, indicating that chronic stress hormone exposure in adolescence can have long-term consequences on behavior.

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High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress

Abstract: This investigation indicates that behavioural impulsivity in rats on the 5-CSRTT, which predicts vulnerability for cocaine addiction, is distinct from anxiety, novelty reactivity and novelty-induced stress responses, and thus has relevance for the aetiology of drug addiction.

Cited by 100 publications

References 55 publications

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

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