Dataset Information

Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.

ABSTRACT: Clinical descriptions of cocaine addiction include compulsive drug seeking and maladaptive decision-making despite substantial aversive consequences. Research suggests that this may result from altered orbitofrontal cortex (OFC) function and its participation in outcome-based behavior. Clinical and animal studies also implicate serotonin in the regulation of OFC function in addiction and other neuropsychiatric disorders. Here we test the hypothesis that exposure to cocaine, through self-administration (CSA) or yoked-administration (CYA), alters the regulation of OFC function by 5-HT. Using whole-cell electrophysiology in brain slices from naïve rats we find that 5-HT1A receptors generate hyperpolarizing outward currents in layer-V OFC pyramidal neurons, and that 5-HT2A receptors increase glutamate release onto these cells. Following extended withdrawal from CSA or CYA, this 5-HT regulation of OFC activity is largely lost. In-situ hybridization of 5-HT receptor transcripts reveals that 5-HT1A receptor mRNA is unaffected and 5-HT2A receptor mRNA is significantly elevated after CSA or CYA. These results demonstrate that 5-HT control of OFC neurons is disrupted for extended periods following cocaine exposure. We hypothesize that this dysregulation of 5-HT signaling leads to enduring disruptions of OFC network activity that this is involved in impaired decision-making associated with cocaine addiction.

SUBMITTER: Wright AM

PROVIDER: S-EPMC6075564 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.

Wright Andrew M AM Zapata Agustin A Baumann Michael H MH Elmore Joshua S JS Hoffman Alexander F AF Lupica Carl R CR

Cerebral cortex (New York, N.Y. : 1991) 20171201 12

Clinical descriptions of cocaine addiction include compulsive drug seeking and maladaptive decision-making despite substantial aversive consequences. Research suggests that this may result from altered orbitofrontal cortex (OFC) function and its participation in outcome-based behavior. Clinical and animal studies also implicate serotonin in the regulation of OFC function in addiction and other neuropsychiatric disorders. Here we test the hypothesis that exposure to cocaine, through self-administ ...[more]

PMID: 27733540

Similar Datasets

Project description:Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 ?M) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that early sensorineural hearing loss affects the ability of 5-HT receptor activation to modulate A1 pyramidal cell excitability.

Project description:Prenatal cocaine exposure (PCE) can cause persistent neuropsychological and motor abnormalities in affected children, but the physiological consequences of PCE remain unclear. Conclusions drawn from clinical studies can sometimes be confounded by polysubstance abuse and nutritional deprivation. However, existing observations suggest that cocaine exposure in utero, as in adults, increases synaptic dopamine and promotes enduring dopamine-dependent plasticity at striatal synapses, altering behaviors and basal ganglia function.We used a combination of behavioral measures, electrophysiology, optical imaging, and biochemical and electrochemical recordings to examine corticostriatal activity in adolescent mice exposed to cocaine in utero.We show that PCE caused abnormal dopamine-dependent behaviors, including heightened excitation following stress and blunted locomotor augmentation after repeated treatment with amphetamine. These abnormal behaviors were consistent with abnormal ?-aminobutyric acid (GABA) interneuron function, which promoted a reversible depression in corticostriatal activity. PCE hyperpolarized and reduced tonic GABA currents in both fast-spiking and persistent low-threshold spiking type GABA interneurons to increase tonic inhibition at GABAB receptors on presynaptic corticostriatal terminals. Although D2 receptors paradoxically increased glutamate release following PCE, normal corticostriatal modulation by dopamine was reestablished with a GABAA receptor antagonist.The dynamic alterations at corticostriatal synapses that occur in response to PCE parallel the reported effects of repeated psychostimulants in mature animals, but differ in being specifically generated through GABAergic mechanisms. Our results indicate approaches that normalize GABA and D2 receptor-dependent synaptic plasticity may be useful for treating the behavioral effects of PCE and other developmental disorders that are generated through abnormal GABAergic signaling.

Project description:Alcohol use disorder (AUD) is a chronic mental illness in which patients often achieve protracted periods of abstinence prior to relapse. Epigenetic mechanisms may provide an explanation for the persisting gene expression changes that can be observed even after long periods of abstinence and may contribute to relapse. In this study we examined two stable histone modifications, histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3), in the prefrontal cortex of Withdrawal Seizure Resistant (WSR) mice 21 days after 72 hours of ethanol vapor exposure. These histone modifications were selected because they are associated with active promoters (H3K4me3) and repressed gene expression in a euchromatic environment (H3K27me3). We performed a genome-wide analysis to identify differences in H3K4me3 and H3K27me3 levels in post-ethanol exposure vs. control mice by ChIP-seq. We detected a global reduction in H3K4me3 peaks and increase in H3K27me3 peaks in post-ethanol exposure mice compared to controls, these changes are consistent with persistent reductions in gene expression and suggest differential epigenetic regulation of genes during this post-exposure period. We also examined the correspondence between genes that displayed changes in H3K4me3 and/or H3K27me3 and were differentially expressed. The expression of 52% of the genes with altered H3K4me3 binding and 40% of genes with H3K27me3 differences found here is altered by ethanol exposure based on analysis of prior studies. Finally, pathway analysis of genes displaying changes in H3K4me3 and H3K27me3 revealed enrichment for genes involved in proteoglycan and calcium signaling pathways, respectively. The chromatin changes associated with the 21-day post-exposure period suggest that this period is a unique state in the addiction cycle that differs from ethanol intoxication and acute withdrawal. These results provide insights into the enduring effects of ethanol on proteoglycan and calcium signaling genes in the brain.

Dataset Information

Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.

Publications

Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets