Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition

Nonkes, Lourens J.P.; Vondervoort, Ilse I.G.M. van de; Leeuw, Mark J.C. de; Wijlaars, Linda; Maes, J.H.R.; Homberg, Judith R.

doi:10.1101/lm.025908.112

Cited by 36 publications

(29 citation statements)

References 34 publications

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“…In addition, low levels of perseveration were also associated with increased 5-HT 2A receptor binding in the mOFC and lOFC. Whilst prior studies have demonstrated a role for 5-HTT (Holmes and Fam, 2013;Nonkes et al, 2012) and striatal DAergic mechanisms in reversal learning performance (Clarke et al, 2011;Collins et al, 2000;O'Neill and Brown, 2007), we found no evidence of abnormalities in binding at 5-HTT in highor low-perseverative rats nor any alterations in several key indices of DA transmission in the DMS. These findings indicate that natural variation in serotonergic tone and MAO-A and MAO-B gene expression in the OFC and DRN, together with reduced TPH2 mRNA expression in the DRN, may underlie poor spatial-discrimination reversal learning in rats.…”

Section: Discussioncontrasting

confidence: 99%

Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

Barlow

Alsiö

Jupp

et al. 2015

Neuropsychopharmacol

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Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid, in the OFC. Additionally, 5-HT 2A receptor binding in the OFC of mid-and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low-vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.

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Section: Discussioncontrasting

confidence: 99%

Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

Barlow

Alsiö

Jupp

et al. 2015

Neuropsychopharmacol

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“…The associative learning phenomena of latent inhibition – where previous exposure to a non-reinforced cue blunts future conditioning to that cue – has also been proposed to play a role in behavioral flexibility (Chess et al, 2012; Nonkes et al, 2012). Blunted latent inhibition may increase exploration of previously irrelevant rule sets during a strategy shift that could lead to an apparent facilitation of shifting.…”

Section: Resultsmentioning

confidence: 99%

“…A separate cohort of 32 rats were divided into 4 groups (n=8/group) to test the interaction between drug history (CTA vs air) and cue pre-exposure (pre exposed, “PE” vs non pre exposed, “NPE”) on classical conditioning using a procedure based on Nonkes et al (2012). CTA and air-treated rats were acclimatized to SCM one day before training began (see 2.3.1).…”

Section: Methodsmentioning

confidence: 99%

Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene

Braunscheidel

Gass

Mulholland

et al. 2017

Neurobiology of Learning and Memory

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While the psychoactive inhalant toluene causes behavioral effects similar to those produced by other drugs of abuse, the persistent behavioral and anatomical abnormalities induced by toluene exposure are not well known. To mimic human “binge-like” inhalant intoxication, adolescent, male Sprague-Dawley rats were exposed to toluene vapor (5700 ppm) twice daily for five consecutive days. These rats remained in their home cages until adulthood (P60), when they were trained in operant boxes to respond to a palatable food reward and then challenged with several different cognitive tasks. Rats that experienced chronic exposure to toluene plus abstinence (“CTA”) showed enhanced performance in a strategy set-shifting task using a between-session, but not a within-session test design. CTA also blunted operant and classical conditioning without affecting responding during a progressive ratio task. While CTA rats displayed normal latent inhibition, previous exposure to a non-reinforced cue enhanced extinction of classically conditioned approach behavior of these animals compared to air controls. To determine whether CTA alters the structural plasticity of brain areas involved in set-shifting and appetitive behaviors, we quantified basal dendritic spine morphology in DiI-labeled pyramidal neurons in layer 5 of the medial prefrontal cortex (mPFC) and medium spiny neurons in the nucleus accumbens (NAc). There were no changes in dendritic spine density or subtype in the mPFC of CTA rats while NAc spine density was significantly increased due to an enhanced prevalence of long-thin spines. Together, these findings suggest that the persistent effects of CTA on cognition are related to learning and memory consolidation/recall, but not mPFC-dependent behavioral flexibility.

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“…Extracellular 5-HT level is 5-10 fold increased in striatum, cortex and substantia nigra of 5-HTT-KO mice (Mathews et al, 2004) suggests importance of this model in studying 5-HT effects in different behavioral paradigms A reduced 5-HT level in 5-HTT-KO rodents resulted in improved performance in reversal learning (Brigman et al, 2010). A study by Nonkes et al, using Extra-dimensional Strategy Set-shifting (EDSS) task has reported HTT-/-rats showed improved strategy shifting and reduced latent inhibition, indicating that HTT has effects on attention and cognitive process (Nonkes et al, 2012).…”

Section: Serotonin Transporter Knock-out (5htt-ko) Rodentsmentioning

confidence: 94%

Does serotonin deficit mediate susceptibility to ADHD?

Banerjee

Nandagopal

2015

Neurochemistry International

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Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition

Cited by 36 publications

References 34 publications

Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphé Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning

Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene

Does serotonin deficit mediate susceptibility to ADHD?

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