Publications by authors named "Michael J Watt"

44 Publications

Rosiglitazone restores nitric oxide synthase-dependent reactivity of cerebral arterioles in rats exposed to prenatal alcohol.

Alcohol Clin Exp Res 2021 Jul 12;45(7):1359-1369. Epub 2021 Jun 12.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Background: Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero.

Methods: We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero.

Results: We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero.

Conclusions: PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.
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http://dx.doi.org/10.1111/acer.14634DOI Listing
July 2021

The stalk-eyed fly as a model for aggression - is there a conserved role for 5-HT between vertebrates and invertebrates?

J Exp Biol 2020 01 2;223(Pt 1). Epub 2020 Jan 2.

Department of Integrative Biology, University of Colorado-Denver, Denver, CO 80217, USA

Serotonin (5-HT) has largely been accepted to be inhibitory to vertebrate aggression, whereas an opposing stimulatory role has been proposed for invertebrates. Herein, we argue that critical gaps in our understanding of the nuanced role of 5-HT in invertebrate systems drove this conclusion prematurely, and that emerging data suggest a previously unrecognized level of phylogenetic conservation with respect to neurochemical mechanisms regulating the expression of aggressive behaviors. This is especially apparent when considering the interplay among factors governing 5-HT activity, many of which share functional homology across taxa. We discuss recent findings using insect models, with an emphasis on the stalk-eyed fly, to demonstrate how particular 5-HT receptor subtypes mediate the intensity of aggression with respect to discrete stages of the interaction (initiation, escalation and termination), which mirrors the complex behavioral regulation currently recognized in vertebrates. Further similarities emerge when considering the contribution of neuropeptides, which interact with 5-HT to ultimately determine contest progression and outcome. Relative to knowledge in vertebrates, much less is known about the function of 5-HT receptors and neuropeptides in invertebrate aggression, particularly with respect to sex, species and context, prompting the need for further studies. Our Commentary highlights the need to consider multiple factors when determining potential taxonomic differences, and raises the possibility of more similarities than differences between vertebrates and invertebrates with regard to the modulatory effect of 5-HT on aggression.
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http://dx.doi.org/10.1242/jeb.132159DOI Listing
January 2020

Sex differences in anxiety-like behaviors in rats.

Physiol Behav 2019 11 2;211:112670. Epub 2019 Sep 2.

Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 East Clark St, Vermillion, SD 57069, United States; Department of Anatomy and Brain Health Research Center, University of Otago, PO Box 56, Dunedin 9054, New Zealand. Electronic address:

The use of animal models for behavioral and pharmaceutical testing is employed in many different fields of research but often relies solely on male animals. When females are included, the existing literature frequently offers inconsistent results regarding the effects of sex and/or estrous cycle on anxiety-like behaviors. Our current study sought to establish baseline or normative behaviors in three commonly employed tests of anxiety-like behavior, and determine any sex or cycle differences. Anxiety-like behaviors in male and naturally-cycling female Sprague-Dawley rats were assessed using elevated plus maze, open field, and a social interaction/avoidance paradigm. Female rats were examined once daily to determine their stage of estrous. Results from the elevated plus maze but not the open field showed that female rats spent significantly more time in open areas than did male rats; however, there was no effect of estrous cycle stage. The social avoidance test revealed that female rats spent significantly more time in the interaction zone with an empty wire mesh cage (novel object), but there was no sex difference in time spent with an age- and sex- matched target rat. Females often exhibited greater locomotion as compared to males in social and non-social tests, but this was not related to primary anxiety measures in these tests. Overall, our findings indicate that outcomes differ in tests of anxiety-like behaviors, highlighting sex differences in the expression of anxiety-like behaviors that depend on the test employed. Importantly, the lack of estrous cycle effects suggest that for these anxiety-based tests, female Sprague-Dawley rats could be collapsed across the cycle phases to facilitate the inclusion of females in future behavioral experiments.
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http://dx.doi.org/10.1016/j.physbeh.2019.112670DOI Listing
November 2019

Sex differences in aggression: Differential roles of 5-HT2, neuropeptide F and tachykinin.

PLoS One 2019 29;14(1):e0203980. Epub 2019 Jan 29.

Department of Integrative Biology, University of Colorado-Denver, Denver, United States of America.

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin's (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2's involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350964PMC
September 2019

Negative consequences of early-life adversity on substance use as mediated by corticotropin-releasing factor modulation of serotonin activity.

Neurobiol Stress 2018 Nov 7;9:29-39. Epub 2018 Aug 7.

Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Early-life adversity is associated with increased risk for substance abuse in later life, with women more likely to report past and current stress as a mediating factor in their substance use and relapse as compared to men. Preclinical models of neonatal and peri-adolescent (early through late adolescence) stress all support a direct relationship between experiences of early-life adversity and adult substance-related behaviors, and provide valuable information regarding the underlying neurobiology. This review will provide an overview of these animal models and how these paradigms alter drug and alcohol consumption and/or seeking in male and female adults. An introduction to the corticotropin-releasing factor (CRF) and serotonin systems, their development and their interactions at the level of the dorsal raphe will be provided, illustrating how this particular stress system is sexually dimorphic, and is well positioned to be affected by stressors early in development and throughout maturation. A model for CRF-serotonin interactions in the dorsal raphe and how these influence dopaminergic activity within the nucleus accumbens and subsequent reward-associated behaviors will be provided, and alterations to the activity of this system following early-life adversity will be identified. Overall, converging findings suggest that early-life adversity has long-term effects on the functioning of the CRF-serotonin system, highlighting a potentially important and targetable mediator linking stress to addiction. Future work should focus on identifying the exact mechanisms that promote long-term changes to the expression and activity of CRF receptors in the dorsal raphe. Moreover, it is important to clarify whether similar neurobiological mechanisms exist for males and females, given the sexual dimorphism both in CRF receptors and serotonin indices in the dorsal raphe and in the behavioral outcomes of early-life adversity.
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http://dx.doi.org/10.1016/j.ynstr.2018.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108067PMC
November 2018

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

Eur J Neurosci 2018 07 10;48(2):1833-1850. Epub 2018 Jul 10.

Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota.

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100 mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress.
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http://dx.doi.org/10.1111/ejn.14019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105450PMC
July 2018

Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus.

Transl Psychiatry 2018 06 8;8(1):113. Epub 2018 Jun 8.

Division of basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA.

Cognitive deficits are widespread in psychiatric disorders and frequently as debilitating as the affective component. Widely prescribed antidepressants for treating depressive disorders have limited efficacy in normalizing cognitive function. Erythropoietin (Epo) has been shown to improve cognitive function in schizophrenia and treatment resistant depressed patients. However, the potent elevation of red blood cell counts by Epo can cause hematological complications in non-anemic patients. We investigated a chemically engineered, posttranslational modification of Epo, carbamoylation, which renders it non-erythropoietic. We conducted mass-spectrometry-based peptide mapping of carbamoylated Epo (Cepo) and tested its ability to improve cognitive function after social defeat stress. Gene expression analysis in discrete brain regions was performed to obtain mechanistic insight of Cepo action. Cepo reversed stress-induced spatial working memory deficits while affecting long-term (24 h) novel object recognition in these rats. Contextual fear conditioning following defeat was enhanced by Cepo, but attenuated in controls. However, Cepo improved fear extinction in all rats compared to vehicle treatment. Cepo induced differential gene expression of BDNF, VGF, Arc, TH. and neuritin in the mPFC and discrete hippocampal subfields, with strongest induction in the dorsal hippocampus. Analysis of gene-brain region-behavior interactions showed that Cepo-induced neurotrophic mechanisms influence cognitive function. Carbamoylated erythropoietin can be developed as a therapeutic neurotrophic agent to treat cognitive dysfunction in neuropsychiatric diseases. Due to its distinct mechanism of action, it is unlikely to cross react with the activity of currently prescribed small molecule drugs and can be used as an add-on biologic drug.
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http://dx.doi.org/10.1038/s41398-018-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993867PMC
June 2018

Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction.

Prog Neuropsychopharmacol Biol Psychiatry 2017 10 19;79(Pt B):136-154. Epub 2017 Jun 19.

Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA. Electronic address:

Repeated exposure to stress during childhood is associated with increased risk for neuropsychiatric illness, substance use disorders and other behavioral problems in adulthood. However, it is not clear how chronic childhood stress can lead to emergence of such a wide range of symptoms and disorders in later life. One possible explanation lies in stress-induced disruption to the development of specific brain regions associated with executive function and reward processing, deficits in which are common to the disorders promoted by childhood stress. Evidence of aberrations in prefrontal cortex and nucleus accumbens function following repeated exposure of juvenile (pre- and adolescent) organisms to a variety of different stressors would account not only for the similarity in symptoms across the wide range of childhood stress-associated mental illnesses, but also their persistence into adulthood in the absence of further stress. Therefore, the goal of this review is to evaluate the current knowledge regarding disruption to executive function and reward processing in adult animals or humans exposed to chronic stress over the juvenile period, and the underlying neurobiology, with particular emphasis on the prefrontal cortex and nucleus accumbens. First, the role of these brain regions in mediating executive function and reward processing is highlighted. Second, the neurobehavioral development of these systems is discussed to illustrate how juvenile stress may exert long-lasting effects on prefrontal cortex-accumbal activity and related behavioral functions. Finally, a critical review of current animal and human findings is presented, which strongly supports the supposition that exposure to chronic stress (particularly social aggression and isolation in animal studies) in the juvenile period produces impairments in executive function in adulthood, especially in working memory and inhibitory control. Chronic juvenile stress also results in aberrations to reward processing and seeking, with increased sensitivity to drugs of abuse particularly noted in animal models, which is in line with greater incidence of substance use disorders seen in clinical studies. These consequences are potentially mediated by monoamine and glutamatergic dysfunction in the prefrontal cortex and nucleus accumbens, providing translatable therapeutic targets. However, the predominant use of male subjects and social-based stressors in preclinical studies points to a clear need for determining how both sex differences and stressor heterogeneity may differentially contribute to stress-induced changes to substrates mediating executive function and reward processing, before the impact of chronic juvenile stress in promoting adult psychopathology can be fully understood.
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http://dx.doi.org/10.1016/j.pnpbp.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610933PMC
October 2017

Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice.

Stress 2017 03 8;20(2):197-204. Epub 2017 Mar 8.

a Division of Basic Biomedical Sciences , Sanford School of Medicine, University of South Dakota , Vermillion , SD , USA.

The inbred mouse strains, C57BL/6 and BALB/c have been used widely in preclinical psychiatric research. The differences in stress susceptibility of available strains has provided a useful platform to test pharmacological agents and behavioral responses. Previous brain gene profiling efforts have indicated that the inflammation and immune response gene pathway is the predominant gene network in the differential stress response of BALB/c and C57BL/6 mice. The implication is that a composite stress paradigm that includes a sequence of extended, varied and unpredictable stressors induces inflammation-related genes in the hippocampus. We hypothesized that the regulation of inflammation genes in the brain could constitute a primary stress response and tested this by employing a simple stress protocol, repeated exposure to the same stressor for 10 days, 2 h of restraint per day. We examined stress-induced regulation of 13 proinflammatory cytokine genes in male BALB/c and C57BL/6 mice using quantitative PCR. Elevated cytokine genes included tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), interleukin 10 (IL10), tumor necrosis factor (TNF) super family members and interleukin 1 receptor 1 (IL1R1). In addition, we examined restraint stress-induced regulation of 12 glutamate receptor genes in both strains. Our results show that restraint stress is sufficient to elevate the expression of inflammation-related genes in the hippocampus of both BABLB/c and C57BL/6 mice, but they differ in the genes that are induced and the magnitude of change. Cell types that are involved in this response include endothelial cells and astrocytes. Lay summary Repeated exposure to a simple restraint stress altered the activities of genes involved in inflammation and the functions of the excitatory neurotransmitter, glutamate. These changes in the hippocampus of the mouse brain showed differences that were dependent on the strain of mice and the length of the stress exposure. The effects of stress on activity of these genes may lead to alterations in behavior.
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http://dx.doi.org/10.1080/10253890.2017.1298587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724770PMC
March 2017

Amphetamine Withdrawal Differentially Increases the Expression of Organic Cation Transporter 3 and Serotonin Transporter in Limbic Brain Regions.

J Exp Neurosci 2016 21;10:93-100. Epub 2016 Jul 21.

Division of Basic Biomedical Sciences, Sanford School of Medicine, Center for Brain and Behavior Research, University of South Dakota, Vermillion, SD, USA.

Amphetamine withdrawal increases anxiety and stress sensitivity related to blunted ventral hippocampus (vHipp) and enhances the central nucleus of the amygdala (CeA) serotonin responses. Extracellular serotonin levels are regulated by the serotonin transporter (SERT) and organic cation transporter 3 (OCT3), and vHipp OCT3 expression is enhanced during 24 hours of amphetamine withdrawal, while SERT expression is unaltered. Here, we tested whether OCT3 and SERT expression in the CeA is also affected during acute withdrawal to explain opposing regional alterations in limbic serotonergic neurotransmission and if respective changes continued with two weeks of withdrawal. We also determined whether changes in transporter expression were confined to these regions. Male rats received amphetamine or saline for two weeks followed by 24 hours or two weeks of withdrawal, with transporter expression measured using Western immunoblot. OCT3 and SERT expression increased in the CeA at both withdrawal timepoints. In the vHipp, OCT3 expression increased only at 24 hours of withdrawal, with an equivalent pattern seen in the dorsomedial hypothalamus. No changes were evident in any other regions sampled. These regionally specific changes in limbic OCT3 and SERT expression may partially contribute to the serotonergic imbalance and negative affect during amphetamine withdrawal.
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http://dx.doi.org/10.4137/JEN.S40231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957605PMC
August 2016

Differential effects of glucocorticoid and mineralocorticoid antagonism on anxiety behavior in mild traumatic brain injury.

Behav Brain Res 2016 10 27;312:362-5. Epub 2016 Jun 27.

Center for Brain and Behavior Research, University of South Dakota, Sanford School of Medicine, Division of Basic Biomedical Sciences, 414 East Clark St, Vermillion, SD, United States. Electronic address:

Mild traumatic brain injuries (TBIs) comprise three-quarters of all TBIs occurring in the United States annually, and psychological symptoms arising from them can last years after injury. One commonly observed symptom following mild TBI is generalized anxiety. Most mild TBIs happen in stressful situations (sports, war, domestic violence, etc.) when glucocorticoids are elevated in the brain at the time of impact, and glucocorticoids have negative effects on neuronal health following TBI. Therefore, blocking glucocorticoid receptors might prevent emergence of anxiety symptoms post-injury. Adult male rats received mifepristone (20mg/kg) or spironolactone (50mg/kg) to block glucocorticoid and mineralocorticoid receptors, respectively, 40min prior to being exposed to acute social defeat stress followed immediately by mild TBI. In defeated rats with concomitant mild TBI, mifepristone restored time spent in the open arms of an elevated plus maze to control levels, demonstrating for the first time that glucocorticoid receptors play a critical role in the development of anxiety after mild TBI. Future treatments could target these receptors, alleviating anxiety as a major side effect in victims of mild TBI sustained in stressful situations.
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http://dx.doi.org/10.1016/j.bbr.2016.06.048DOI Listing
October 2016

Assessment strategies and fighting patterns in animal contests: a role for serotonin?

Curr Zool 2016 Jun 25;62(3):257-263. Epub 2016 Mar 25.

Integrative Biology, University of Colorado-Denver, Denver, CO 80217-3364, USA.

Accurate assessment of the probability of success in an aggressive confrontation with a conspecific is critical to the survival and fitness of the individuals. Various game theory models have examined these assessment strategies under the assumption that contests should favor the animal with the greater resource-holding potential (RHP), body size typically being the proxy. Mutual assessment asserts that an individual can assess their own RHP relative to their opponent, allowing the inferior animal the chance to flee before incurring unnecessary costs. The model of self-determined persistence, however, assumes that an individual will fight to a set personal threshold, independent of their opponent's RHP. Both models have been repeatedly tested using size as a proxy for RHP, with neither receiving unambiguous support. Here we present both morphological and neurophysiological data from size-matched and mismatched stalk-eyed fly fights. We discovered differing fighting strategies between winners and losers. Winners readily escalated encounters to higher intensity and physical contact and engaged in less low-intensity, posturing behaviors compared with losers. Although these fighting strategies were largely independent of size, they were associated with elevated levels of 5-HT. Understanding the neurophysiological factors responsible for mediating the motivational state of opponents could help resolve the inconsistencies seen in current game theory models. Therefore, we contend that current studies using only size as a proxy for RHP may be inadequate in determining the intricacies of fighting ability and that future studies investigating assessment strategies and contest outcome should include neurophysiological data.
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http://dx.doi.org/10.1093/cz/zow040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804268PMC
June 2016

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

Brain Res 2016 08 18;1644:278-87. Epub 2016 May 18.

Division of Basic Biomedical Sciences, Center for Brain and Behavior Research, University of South Dakota, 414 East Clark St, Vermillion, SD, United States. Electronic address:

Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal.
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http://dx.doi.org/10.1016/j.brainres.2016.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920069PMC
August 2016

Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats.

Front Behav Neurosci 2016 19;10:71. Epub 2016 Apr 19.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota Vermillion, SD, USA.

Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.
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http://dx.doi.org/10.3389/fnbeh.2016.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835499PMC
May 2016

Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

Behav Brain Res 2016 May 10;304:51-9. Epub 2016 Feb 10.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.
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http://dx.doi.org/10.1016/j.bbr.2016.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795455PMC
May 2016

David vs. Goliath: Serotonin modulates opponent perception between smaller and larger rivals.

Behav Brain Res 2015 Oct 15;292:521-7. Epub 2015 Jul 15.

University of Colorado-Denver, Denver, CO, United States.

During agonistic encounters, the perception of a larger opponent through morphological signaling typically suppresses aggression in the smaller individual, preventing contest intensity escalation. However, non-morphological factors such as central serotonin (5-HT) activity can influence individual aggression, potentially altering contest intensity despite initial size discrepancies. When male stalk-eyed flies (Teleopsis dalmanni) fight, contest escalation is directly proportional to similarity in body size, with escalation being lower in size-mismatched contests. We have shown that both high-intensity aggression and the probability of winning are increased in males with pharmacologically elevated 5-HT relative to size-matched non-treated opponents. Here, we hypothesized that, in size-mismatched contests, increasing brain 5-HT in the smaller opponent could similarly increase aggression and counteract the low contest intensity normally driven by size discrepancy. Size-mismatched male pairs (greater than 5% difference in eyestalk length) engaged in a forced fight paradigm, with the smaller fly either untreated or with pharmacologically elevated 5-HT levels. The expression of high-intensity aggressive behaviors was significantly increased in smaller treated opponents, but the probability of winning was not altered. This suggests that while elevated serotonergic activity can increase aggression and intensity despite perception of a larger opponent, this is not sufficient to overcome size biases with respect to contest outcome. However, the fact that larger opponents continued to win against smaller treated flies was not simply a function of size. Instead, untreated larger males adjusted their fighting strategy to match the increased aggression of their smaller treated opponent, suggesting contextual flexibility in behavior based on individual opponent assessment.
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http://dx.doi.org/10.1016/j.bbr.2015.07.028DOI Listing
October 2015

Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress.

Neuropharmacology 2015 Oct 6;97:194-200. Epub 2015 Jun 6.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA. Electronic address:

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction.
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http://dx.doi.org/10.1016/j.neuropharm.2015.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537323PMC
October 2015

Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal.

Eur J Neurosci 2014 Dec 19;40(11):3684-92. Epub 2014 Sep 19.

Department of Biology & Center for Brain and Behavior Research, University of South Dakota, 414 E. Clark St, Vermillion, SD, 57069, USA.

Withdrawal from amphetamine increases anxiety and reduces the ability to cope with stress, which are factors that are believed to contribute to drug relapse. Stress-induced serotonergic transmission in the central nucleus of the amygdala is associated with anxiety states and fear. Conversely, stress-induced increases in ventral hippocampal serotonin (5-HT) levels have been linked to coping mechanisms. The goal of this study was to investigate the neurobiological changes induced by amphetamine that contribute to stress sensitivity during withdrawal. We tested the hypothesis that limbic serotonergic responses to restraint stress would be altered in male Sprague-Dawley rats chronically pretreated with amphetamine (2.5 mg/kg, intraperitoneal) and then subjected to 2 weeks of withdrawal. Amphetamine withdrawal resulted in increased stress-induced behavioral arousal relative to control treatment, suggesting that drug withdrawal induced greater sensitivity to the stressor. When microdialysis was used to determine the effects of restraint on extracellular 5-HT, stress-induced increases in 5-HT levels were abolished in the ventral hippocampus and augmented in the central amygdala during amphetamine withdrawal. Reverse dialysis of the glucocorticoid receptor antagonist mifepristone into the ventral hippocampus blocked the stress-induced increase in 5-HT levels in saline-pretreated rats, suggesting that glucocorticoid receptors mediate stress-induced increases in 5-HT levels in the ventral hippocampus. However, mifepristone had no effect on stress-induced increases in 5-HT levels in the central amygdala, indicating that stress increases 5-HT levels in this region independently of glucocorticoid receptors. During amphetamine withdrawal, the absence of stress-induced increases in ventral hippocampal 5-HT levels combined with enhanced stress-induced serotonergic responses in the central amygdala may contribute to drug relapse by decreasing stress-coping ability and heightening stress responsiveness.
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http://dx.doi.org/10.1111/ejn.12735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262691PMC
December 2014

Central CRF2 receptor antagonism reduces anxiety states during amphetamine withdrawal.

Neurosci Res 2014 Dec 6;89:37-43. Epub 2014 Sep 6.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA. Electronic address:

Increased depressive and anxiety-like behaviors are exhibited by rats and humans during withdrawal from psychostimulants. Anxiety-like behaviors observed during amphetamine withdrawal are mediated by increased expression and activity of corticotropin releasing factor type 2 (CRF2) receptors in the dorsal raphe nucleus (dRN). Anxiety-like behavior of rats during withdrawal can be reversed by CRF2 receptor antagonism in the dRN, but the efficacy of global central CRF2 receptor antagonism is unknown. Rats were treated with amphetamine (2.5mg/kg, ip.) or saline daily for 2 weeks, and were tested for anxiety-like behaviors during withdrawal. Rats undergoing withdrawal showed increased anxiety-like behavior, which was reduced by ventricular infusion of the CRF2 antagonist antisauvagine-30 (ASV 2 μg/2 μl). Surprisingly, ventricular ASV increased anxiety-like behavior in rats pre-treated with saline, but had an anxiolytic effect in un-treated rats. Western blots were performed to determine whether differences in CRF receptor densities could explain ASV-induced behavioral results. Saline pre-treated rats showed reduced CRF1 receptor expression in the lateral septum compared to amphetamine pre-treated and un-treated rats. Overall, these results suggest that central CRF2 antagonism reduces anxiety states during amphetamine withdrawal, and that behavioral effects may be dependent upon the balance of CRF1 and CRF2 receptor activity in anxiety-related regions.
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http://dx.doi.org/10.1016/j.neures.2014.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259847PMC
December 2014

A bench-scale assessment of ozone pre-treatments for landfill leachates.

Environ Technol 2014 Jan-Feb;35(1-4):145-53

Department of Civil and Environmental Engineering, Florida State University, Tallahassee, FL, USA.

Leachate from stabilized landfill can pose unique challenges to conventional biological wastewater treatment. Ozone-based advanced oxidation processes have garnered recent consideration as an option to reduce the organic strength and recalcitrance of aged landfill leachate. With a bench-scale investigation, the reported work examines the potential for leachate conditioning for further biological treatment by treatment with low-mg/L doses of ozone (0-7.5 mg/L 03). While not sufficient for significant organics mineralization, the tested ozone doses could potentially produce both selective and non-selective oxidation of recalcitrant leachate organic compounds leaving bio-available products in the pre-treated leachate. Leachate conditioning by 03 or 03/H202 was assessed via monitoring of three anthropogenic organic leachate contaminants(tris-(2-chloroethyl) phosphate, tris-(butoxyethyl)-phosphate and 17beta-estradiol (E2)) with ozonation, and ozonation followed by anaerobic incubation. In addition, chemical oxygen demand (COD) and BOD5 analysis of the ozonated leachate, and methane and total gas formation during the anaerobic incubation were used to assess the degree of leachate conditioning. When treated with O3 alone, 58% removal of E2 was observed with an ozone dose of 4.5-5.4mg/L. Direct oxidation of the three leachate contaminants was limited with O3/H202 pre-treatment. However, this pre-treatment was observed to have significantly improved degradation of E2 during anaerobic incubation of ozonated leachates (removal rate of E2 was 53.7% with 15 days of incubation), indicating the potential for ozone synthesized co-metabolism. However, overall anaerobic microbial activity was not significantly impacted by the applied ozone pre-treatments, as measured by methane formation, total gas formation, and COD removal during incubation.
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http://dx.doi.org/10.1080/09593330.2013.821141DOI Listing
April 2014

Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors.

Psychopharmacology (Berl) 2014 Apr 23;231(8):1627-36. Epub 2013 Nov 23.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E Clark St, Vermillion, SD, 57069, USA,

Rationale: Adverse social experience in adolescence causes reduced medial prefrontal cortex (mPFC) dopamine (DA) and associated behavioral deficits in early adulthood.

Objective: This study aims to determine whether mPFC DA hypofunction following social stress is specific to adolescent experience and if this results from stress-induced DA D2 receptor activation.

Materials And Methods: Male rats exposed to repeated social defeat during adolescence or adulthood had mPFC DA activity sampled 17 days later. Separate experiments used freely moving microdialysis to measure mPFC DA release in response to adolescent defeat exposure. At P40, 49 and 56 mPFC DA turnover was assessed to identify when DA activity decreased in relation to the adolescent defeat experience. Finally, nondefeated adolescent rats received repeated intra-mPFC infusions of the D2 receptor agonist quinpirole, while another adolescent group received intra-mPFC infusions of the D2 antagonist amisulpride before defeat exposure.

Results: Long-term decreases or increases in mPFC DA turnover were observed following adolescent or adult defeat, respectively. Adolescent defeat exposure elicits sustained increases in mPFC DA release, and DA turnover remains elevated beyond the stress experience before declining to levels below normal at P56. Activation of mPFC D2 receptors in nondefeated adolescents decreases DA activity in a similar manner to that caused by adolescent defeat, while defeat-induced reductions in mPFC DA activity are prevented by D2 receptor blockade.

Conclusions: Both the developing and mature PFC DA systems are vulnerable to social stress, but only adolescent defeat causes DA hypofunction. This appears to result in part from stress-induced activation of mPFC D2 autoreceptors.
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http://dx.doi.org/10.1007/s00213-013-3353-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969403PMC
April 2014

Adolescent social defeat decreases spatial working memory performance in adulthood.

Behav Brain Funct 2013 Oct 17;9:39. Epub 2013 Oct 17.

Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 East Clark Street, Vermillion, SD 57069-2390, USA.

Background: Adolescent social stress is associated with increased incidence of mental illnesses in adulthood that are characterized by deficits in cognitive focus and flexibility. Such enhanced vulnerability may be due to psychosocial stress-induced disruption of the developing mesocortical dopamine system, which plays a fundamental role in facilitating complex cognitive processes such as spatial working memory. Adolescent rats exposed to repeated social defeat as a model of social stress develop dopaminergic hypofunction in the medial prefrontal cortex as adults. To evaluate a direct link between adolescent social stress and later deficits in cognitive function, the present study tested the effects of adolescent social defeat on two separate tests of spatial working memory performance.

Methods: Adult rats exposed to adolescent social defeat and their controls were trained on either the delayed win-shift task or the delayed alternating T-Maze task and then challenged with various delay periods. To evaluate potential differences in motivation for the food reward used in memory tasks, consumption and conditioned place preference for sweetened condensed milk were tested in a separate cohort of previously defeated rats and controls.

Results: Compared to controls, adult rats defeated in adolescence showed a delay-dependent deficit in spatial working memory performance, committing more errors at a 90 s and 5 min delay period on the T-maze and win-shift tasks, respectively. Observed memory deficits were likely independent of differences in reward motivation, as conditioned place preference for the palatable food used on both tasks was similar between the adolescent social defeat group and control.

Conclusions: The results demonstrate that severe social stressors during adolescence can produce long term deficits in aspects of cognitive function. Given the dependence of spatial working memory on prefrontal dopamine, pharmacologically reversing dopaminergic deficiencies caused by adolescent social stress has the potential to treat such cognitive deficits.
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http://dx.doi.org/10.1186/1744-9081-9-39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853352PMC
October 2013

Effects of adolescent social defeat on adult amphetamine-induced locomotion and corticoaccumbal dopamine release in male rats.

Neuropharmacology 2013 Apr 6;67:359-69. Epub 2012 Dec 6.

Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 East Clark Street, Vermillion, SD 57069-2390, USA.

Maturation of mesocorticolimbic dopamine systems occurs during adolescence, and exposure to social stress during this period results in behavioral dysfunction including substance abuse disorders. Adult male rats exposed to repeated social defeat in adolescence exhibit reduced basal dopamine tissue content in the medial prefrontal cortex, altered dopamine tissue content in corticoaccumbal dopamine regions following acute amphetamine, and increased amphetamine conditioned place preference following repeated amphetamine treatment. Such changes may reflect altered amphetamine-induced extracellular dopamine release in the corticoaccumbal regions. Therefore, we used in vivo microdialysis to measure extracellular dopamine simultaneously within the medial prefrontal cortex and nucleus accumbens core of previously defeated rats and controls, in response to either acute or repeated (7 daily injections) of amphetamine (1.0 mg/kg). Locomotion responses to acute/repeated amphetamine were also assessed the day prior to taking dopamine measurements. Adolescent defeat potentiated adult locomotion responses to acute amphetamine, which was negatively correlated with attenuated amphetamine-induced dopamine release in the medial prefrontal cortex, but there was no difference in amphetamine-induced accumbal dopamine release. However, both locomotion and corticoaccumbal dopamine responses to repeated amphetamine were equivalent between previously defeated rats and controls. These data suggest adolescent defeat enhances behavioral responses to initial amphetamine exposure as a function of diminished prefrontal cortex dopamine activity, which may be sufficient to promote subsequently enhanced seeking of drug-associated cues. Interestingly, repeated amphetamine treatment appears to normalize amphetamine-elicited locomotion and cortical dopamine responses observed in adult rats exposed to adolescent social defeat, providing implications for treating stress-induced dopamine dysfunction.
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http://dx.doi.org/10.1016/j.neuropharm.2012.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562400PMC
April 2013

Influence of chronic amphetamine treatment and acute withdrawal on serotonin synthesis and clearance mechanisms in the rat ventral hippocampus.

Eur J Neurosci 2013 Feb 14;37(3):479-90. Epub 2012 Nov 14.

Neuroscience Group, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.

Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis (in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal.
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http://dx.doi.org/10.1111/ejn.12050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563776PMC
February 2013

Adolescent social defeat alters markers of adult dopaminergic function.

Brain Res Bull 2011 Aug 30;86(1-2):123-8. Epub 2011 Jun 30.

Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, 57069-2390, USA.

Stressful experiences during adolescence can alter the trajectory of neural development and contribute to psychiatric disorders in adulthood. We previously demonstrated that adolescent male rats exposed to repeated social defeat stress show changes in mesocorticolimbic dopamine content both at baseline and in response to amphetamine when tested in adulthood. In the present study we examined whether markers of adult dopamine function are also compromised by adolescent experience of social defeat. Given that the dopamine transporter as well as dopamine D1 receptors act as regulators of psychostimulant action, are stress sensitive and undergo changes during adolescence, quantitative autoradiography was used to measure [(3)H]-GBR12935 binding to the dopamine transporter and [(3)H]-SCH23390 binding to dopamine D1 receptors, respectively. Our results indicate that social defeat during adolescence led to higher dopamine transporter binding in the infralimbic region of the medial prefrontal cortex and higher dopamine D1 receptor binding in the caudate putamen, while other brain regions analyzed were comparable to controls. Thus it appears that social defeat during adolescence causes specific changes to the adult dopamine system, which may contribute to behavioral alterations and increased drug seeking.
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http://dx.doi.org/10.1016/j.brainresbull.2011.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156656PMC
August 2011

Selection for intrinsic endurance modifies endocrine stress responsiveness.

Brain Res 2010 Oct 2;1357:53-61. Epub 2010 Aug 2.

Department of Neurosciences, The Medical University of South Carolina, Charleston, SC 29425, USA.

Physical exercise dampens an individual's stress response and decreases symptoms of anxiety and depression disorders. While the extrinsic relationship of exercise and psychological state is established, their intrinsic relationship is unresolved. We investigated the potential intrinsic relationship of exercise with stress responsiveness using NIH rats bidirectionally selected for intrinsic endurance capacity. Selection resulted in two populations, one with high intrinsic endurance (high capacity runners; HCR) and one with low intrinsic endurance (low capacity runners; LCR). Animals from these populations were subjected to the elevated plus maze (EPM) and novel environment to assess levels of anxiety-like behavior, and to restraint stress to determine stress responsiveness. Pre-test plasma corticosterone levels and the response of plasma corticosterone to exposure to the EPM and restraint were analyzed using ELISA. A dexamethasone suppression test was performed to assess negative feedback tone of corticosterone release. Pre-test plasma corticosterone levels were similar between LCR and HCR, and these populations had similar behavioral and corticosterone responses to the EPM. Following restraint, HCR animals exhibited more anxiotypic behavior than LCR animals on the EPM, and exhibited an increase in plasma corticosterone following EPM and restraint that was not observed in LCR animals. HCR animals also exhibited more anxiotypic behavior in the novel environment compared to LCR animals. Plasma corticosterone levels were equally reduced in both populations following dexamethasone administration. Overall, our data suggest a positive genetic relationship between exercise endurance and stress responsiveness, which is at odds with the established extrinsic relationship of these traits.
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http://dx.doi.org/10.1016/j.brainres.2010.07.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953393PMC
October 2010

Adolescent social defeat alters neural, endocrine and behavioral responses to amphetamine in adult male rats.

Brain Res 2010 Sep 23;1352:147-56. Epub 2010 Jul 23.

Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069-2390, USA.

The mesocorticolimbic dopamine system, which governs components of reward and goal-directed behaviors, undergoes final maturation during adolescence. Adolescent social stress contributes to adult behavioral dysfunction and is linked to adult psychiatric and addiction disorders. Here, behavioral, corticosterone and limbic dopamine responses to amphetamine were examined in adult male rats previously exposed to repeated social defeat stress during mid-adolescence. Amphetamine (2.5mg/kg, ip) was administered after a novel environment test, with behavior observed in the same context for 90min thereafter. Adult rats that had been defeated in adolescence showed increased locomotion in the novel environment but reduced amphetamine-induced locomotion relative to non-defeated age matched controls. Monoamine and corticosterone responses to amphetamine were examined following a second amphetamine injection 3 days later. In previously defeated rats, corticosterone and medial prefrontal cortex dopamine responses to amphetamine were blunted while dopamine responses in the nucleus accumbens core were elevated. Our results suggest that experience of social defeat stress during adolescent development can contribute to altered behavioral and endocrine responses to amphetamine in adulthood. Furthermore, these effects are paralleled by changes in amphetamine-induced dopamine responses in corticolimbic systems implicated in addiction disorders.
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http://dx.doi.org/10.1016/j.brainres.2010.06.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2926242PMC
September 2010

Opponent recognition and social status differentiate rapid neuroendocrine responses to social challenge.

Physiol Behav 2010 Apr 4;99(5):571-8. Epub 2010 Feb 4.

Department of Biology, University of South Dakota, 414 East Clark St, Vermillion, SD 57069, USA.

Individual social status discriminates rapid neuroendocrine responses to non-social stress in male Anolis carolinensis, but whether such status-influenced reactions are retained in response to subsequent social stress is unknown. Dominant and subordinate males modify their behavioral responses to social challenge according to familiarity of the opponent, suggesting that accompanying neuroendocrine responses may differ according to opponent recognition despite social rank. We examined endocrine and neurochemical correlates of prior social status and opponent recognition during the opening stages of social challenge. Male pairs interacted and established dominant/subordinate status, followed by 3 days separation. Subsequently, subjects were paired with either the same opponent or an unfamiliar male according to rank (dominant with subordinate). After 90 s of social exposure, subjects were caught and brains and plasma collected for measurement of circulating corticosterone and limbic monoamines. Controls included pairs experiencing just one 90 s encounter plus a group of non-interacting subjects. Opponent recognition differentiated status-influenced responses, such that dominant lizards paired with familiar subordinate opponents had increased hippocampal dopamine and epinephrine, but showed increased plasma corticosterone and ventral tegmental area (VTA) norepinephrine when challenged with an unfamiliar opponent. Subordinate lizards encountering familiar opponents also had increased corticosterone, along with decreased hippocampal dopamine and increased VTA epinephrine, but showed no changes in response to an unfamiliar opponent. Such plasticity in status-influenced rapid neuroendocrine responses according to opponent recognition may be necessary for facilitating production of behavioral responses adaptive for particular social contexts, such as encountering a novel versus familiar opponent.
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http://dx.doi.org/10.1016/j.physbeh.2010.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840053PMC
April 2010

Consequences of post-weaning social isolation on anxiety behavior and related neural circuits in rodents.

Front Behav Neurosci 2009 20;3:18. Epub 2009 Aug 20.

Department of Integrative Physiology, University of Colorado at Boulder Boulder, CO, USA.

Exposure to adverse experiences in early-life is implicated in the later vulnerability to development of psychiatric disorders, including anxiety and affective disorders in humans. Adverse early-life experiences likely impart their long-term consequences on mental health by disrupting the normal development of neural systems involved in stress responses, emotional behavior and emotional states. Neural systems utilizing the neurotransmitters serotonin, dopamine and the neuropeptide corticotropin-releasing factor (CRF) are implicated in mediating emotive behaviors, and dysfunction of these neurochemical systems is associated with mood/anxiety disorders. These neural systems continue maturing until early or mid-adolescence in humans, thus alterations to their development are likely to contribute to the long-term consequences of adverse early-life experiences. A large body of literature suggests that post-weaning isolation rearing of rodents models the behavioral consequences of adverse early-life experiences in humans. Overall, the majority findings suggest that post-weaning social isolation that encompasses pre-adolescence produces long-lasting alterations to anxiety behavior, while measures of monoaminergic activity in various limbic regions during social isolation suggest alterations to dopamine and serotonin systems. The goal of this review is to evaluate and integrate findings from post-weaning social isolation studies specifically related to altered fear and anxiety behaviors and associated changes in neuroendocrine function and the activity of monoaminergic systems.
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http://dx.doi.org/10.3389/neuro.08.018.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737489PMC
December 2009

Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults.

Behav Neurosci 2009 Jun;123(3):564-76

Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, the authors investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague-Dawley rats were exposed to repeated social defeat for 5 days while controls were placed in a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus-maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology.
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http://dx.doi.org/10.1037/a0015752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771678PMC
June 2009