| 1. |
- Barlow, Rebecca L., et al.
(författare)
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Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphe Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning
- 2015
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 40:7, s. 1619-1630
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Tidskriftsartikel (refereegranskat)abstract
- 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-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A 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 raphe 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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| 2. |
- Pickering, Chris, et al.
(författare)
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Ethanol impairment of spontaneous alternation behaviour and associated changes in medial prefrontal glutamatergic gene expression precede putative markers of dependence
- 2015
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 132, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairments are observable in over half of cases with alcoholism, deficits in spatial working memory being particularly common. Previously we observed that rats make more alternation errors in a Y-maze test of spontaneous alternation behaviour/spatial working memory after 5-day intermittent ethanol. Here we used qPCR to quantify changes in gene expression accompanying this behavioural impairment. Male Wistar rats were treated with either saline or ethanol (1 or 2.5 g/kg) for 5 days followed by 2 drug-free days. Brains were dissected after Y-maze analysis and RNA was extracted from the medial prefrontal cortex, hippocampus and nucleus accumbens. Using the Qiagen GABA & Glutamate PCR array we measured changes in these two neurotransmitter systems. A dose of 1 g/kg ethanol did not affect spontaneous alternation behaviour or any other behavioural variable. 2.5 g/kg significantly decreased % correct alternations (p = 0.028) without affecting total distance (p = 0.54) and increased time in the choice area (p = 0.023) at the Y-maze centre, indicating a possible impairment in decision-making. In the medial prefrontal cortex, 2.5 g/kg ethanol decreased mRNA expression of brain-derived neurotrophic factor, NMDA NR2A subunit, mGluR8 receptor, Homer1, the glutamate transporters SLC1a1 and SLC1a6 and Srr. In the nucleus accumbens this dose did not affect mRNA expression of the dopamine D1 or D2 receptors but did upregulate the GABA transporter GAT-3. Even if only correlational, these data suggest that gene expression changes in the medial prefrontal cortex and associated cognitive impairment occur before adaptation of the dopaminergic system and, presumably, drug dependence.
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| 3. |
- Ruggeri, Barbara, et al.
(författare)
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Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis
- 2015
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 172:6, s. 543-552
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
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