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Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats.

ABSTRACT: Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding the dopamine D2 receptor (DA D2R) and the 5-HT2c receptor (5-HT2cR), and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for HI and low impulsivity (LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following 10 or 50 days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats, decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localize to the OFC, infralimbic cortex, and striatum.

SUBMITTER: Besson M

PROVIDER: S-EPMC3746704 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats.

Besson Morgane M Pelloux Yann Y Dilleen Ruth R Theobald David Eh DE Lyon Alan A Belin-Rauscent Aude A Robbins Trevor W TW Dalley Jeffrey W JW Everitt Barry J BJ Belin David D

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20130501 10

Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the ...[more]

PMID: 23632436

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Project description:Though obesity is a global epidemic, the physiological mechanisms involved are little understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesized that maternal diet influences fetal 5-HT exposure, which then influences central appetite network development and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant low protein fed rat mothers exhibited elevated serum 5-HT, which was also evident in the placenta and fetal brains at E16.5. This increase was associated with reduced hypothalamic expression of 5-HT2CR - the primary 5-HT receptor influencing appetite. As expected, reduced 5-HT2CR expression was associated with impaired sensitivity to 5-HT-mediated appetite suppression. 5-HT primarily achieves effects on appetite via 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We reveal that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC and that 5-HT2AR mRNA is increased in the hypothalamus of in utero growth restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals are more sensitive to 5-HT2AR agonist-induced appetite suppression. These findings may not only reveal a 5-HT-mediated mechanism underlying programming of obesity susceptibility but also provide a promising means to correct it, via a 5-HT2AR agonist treatment. The study was carried out using male Wistar rats (Rattus norvegicus). On postnatal day 3, two experimental groups of offspring were established: controls (offspring of control dams) and recuperated (offspring of dams fed a low-protein diet (8% protein, w/v), but nursed by control dams. The animals were fed with standard chow until 3 months of age where the brains were collected for transcriptomic profiling

Dataset Information

Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats.

Publications

Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats.

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