Publications by authors named "Jesse R Schank"

29 Publications

  • Page 1 of 1

An Adolescent Porcine Model of Voluntary Alcohol Consumption Exhibits Binge Drinking and Motor Deficits in a Two Bottle Choice Test.

Alcohol Alcohol 2021 Apr;56(3):266-274

Regenerative Bioscience Center, University of Georgia, 425 River Road, Athens, GA, 30602, USA.

Aims: Alcohol is the most commonly abused substance leading to significant economic and medical burdens. Pigs are an attractive model for studying alcohol abuse disorder due to the comparable alcohol metabolism and consumption behavior, which are in stark contrast to rodent models. This study investigates the usage of a porcine model for voluntary binge drinking (BD) and a detailed analysis of gait changes due to motor function deficits during alcohol intoxication.

Methods: Adolescent pigs were trained to drink increasing concentration (0-8%) of alcohol mixed in a 0.2% saccharin solution for 1 h in a two bottle choice test for 2 weeks. The training period was followed by a 3-week alcohol testing period, where animals were given free access to 8% alcohol in 0.2% saccharin solution and 0.2% saccharin water solution. Blood alcohol levels were tested and gait analysis was performed pre-alcohol consumption, last day of training, and Day 5 of each testing period.

Results: Pigs voluntarily consumed alcohol to intoxication at all timepoints with blood alcohol concentration (BAL) ≥80 mg/dl. Spatiotemporal gait parameters including velocity, cadence, cycle time, swing time, stance time, step time, and stride length were perturbed as a result of intoxication. The stratification of the gait data based on BAL revealed that the gait parameters were affected in a dose-dependent manner.

Conclusion: This novel adolescent BD porcine model with inherent anatomical and physiological similarities to humans display similar consumption and intoxication behavior that is likely to yield results that are translatable to human patients.
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http://dx.doi.org/10.1093/alcalc/agaa105DOI Listing
April 2021

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1.

Sci Rep 2020 07 3;10(1):11017. Epub 2020 Jul 3.

Department of Physiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.

The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the Na/HCO transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed lower pH in neurons than wildtype controls, determined by intracellular pH in hippocampal neuronal cultures. Neurons from knockout mice had a higher action potential threshold and a more depolarized membrane potential, thus reducing membrane excitability. In a two-bottle free choice procedure, knockout mice consumed more alcohol than controls and consistently increased alcohol consumption after repeated alcohol deprivation periods. Quinine and sucrose preference was similar between genotypes. Knockout mice showed increased propensity for alcohol-induced conditioned place preference. In loss of righting reflex assessment, knockout mice revealed increased sensitivity to alcohol-induced sedation and developed tolerance to the sedation after repeated alcohol administrations. Furthermore, chronic alcohol consumption caused NBCn1 downregulation in the hippocampus and striatum of mice and humans. These results demonstrate an important role of NBCn1 in regulation of alcohol consumption and sensitivity to alcohol-induced sedation.
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http://dx.doi.org/10.1038/s41598-020-67291-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335059PMC
July 2020

Neurokinin receptors in drug and alcohol addiction.

Authors:
Jesse R Schank

Brain Res 2020 05 15;1734:146729. Epub 2020 Feb 15.

University of Georgia, Department of Physiology and Pharmacology, 501 DW Brooks Drive, Athens, GA 30602, USA. Electronic address:

The neurokinins are a class of peptide signaling molecules that mediate a range of central and peripheral functions including pain processing, gastrointestinal function, stress responses, and anxiety. Recent data have linked these neuropeptides with drug-related behaviors. Specifically, substance P (SP) and neurokinin B (NKB), have been shown to influence responses to alcohol, cocaine, and/or opiate drugs. SP and NKB preferentially bind to the neurokinin-1 receptor (NK1R) and neurokinin-3 receptor (NK3R), respectively, but do have some affinity for all classes of neurokinin receptor at high concentrations. NK1R activity has been shown to influence reward and reinforcement for opiate drugs, stimulatory and neurochemical responses to cocaine, and escalated and stress-induced alcohol seeking. In reinstatement models of relapse-like behavior, NK1R antagonism attenuates stress-induced reinstatement for all classes of drugs tested to date. The NK3R also influences alcohol intake and behavioral/neurochemical responses to cocaine, but less research has been performed in regard to this particular receptor in preclinical models of addiction. Clinically, agents targeting these receptors have shown some promise, but have produced mixed results. Here, the preclinical findings for the NK1R and NK3R are reviewed, and discussion is provided to interpret clinical findings. Additionally, important factors to consider in regards to future clinical work are suggested.
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http://dx.doi.org/10.1016/j.brainres.2020.146729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138066PMC
May 2020

Translational Research in the Neurobiological Mechanisms of Alcohol and Substance Use Disorders.

Neurotherapeutics 2020 01;17(1):1-3

Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia.

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http://dx.doi.org/10.1007/s13311-020-00833-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007449PMC
January 2020

Intermittent Ethanol Access Increases Sensitivity to Social Defeat Stress.

Alcohol Clin Exp Res 2020 03 3;44(3):600-610. Epub 2020 Feb 3.

From the, Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia.

Background: Comorbidity between alcoholism and depression is extremely common. Recent evidence supports a relationship between alcohol exposure and stress sensitivity, an underlying factor in the development of depression. Our laboratory has recently shown that chronic alcohol gavage increases sensitivity to social defeat stress (SDS). However, the effects of voluntary alcohol consumption, resulting from protocols such as intermittent ethanol access (IEA), on defeat stress sensitivity have yet to be elucidated.

Methods: We first assessed the effects of 4 weeks of IEA to 20% alcohol on sensitivity to subthreshold SDS exposure. Next, to examine neuroinflammatory mechanisms, we analyzed gene expression of inhibitor of NFkB (IkB) following IEA or chronic alcohol exposure (10 days of 3.0 g/kg alcohol via intragastric gavage). Then, we quantified NFkB activation via β-galactosidase immunohistochemistry following IEA or chronic alcohol gavage in NFkB-LacZ mice.

Results: IEA-exposed mice displayed an increase in sensitivity to subthreshold SDS compared to water-drinking controls. We also found that IkB gene expression was decreased in the nucleus accumbens (NAC) and amygdala (AMY) following IEA but was not altered following chronic alcohol gavage. Finally, we observed increased NFkB activity in the central amygdala (CEA), basolateral amygdala (BLA), and medial amygdala (MEA) after IEA, and increased NFkB activity solely in the CEA following chronic alcohol gavage.

Conclusions: These findings further corroborate that prior alcohol exposure, in this case intermittent voluntary consumption, can impact development of depressive-like behavior by altering stress sensitivity. Furthermore, our results suggest the CEA as a potential mediator of alcohol's effects on stress sensitivity, as NFkB was activated in this region following both IEA and chronic alcohol gavage. Thus, this study provides novel insight on alterations in the NFkB pathway and identifies specific regions to target in future experiments assessing the functional role of NFkB in these processes.
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http://dx.doi.org/10.1111/acer.14278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069801PMC
March 2020

Sex differences in oral oxycodone self-administration and stress-primed reinstatement in rats.

Addict Biol 2020 11 12;25(6):e12822. Epub 2019 Dec 12.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.

The opioid epidemic has become a severe public health problem, with approximately 130 opioid-induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone-seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self-administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self-administration model in adult male and female rats, as well as to examine a potential mechanism of stress-primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self-administration sessions. We also found that active oxycodone self-administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress-primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin-1 receptor, consistent with our prior work examining stress-induced reinstatement of alcohol- and cocaine-seeking.
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http://dx.doi.org/10.1111/adb.12822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289656PMC
November 2020

Escalated Alcohol Self-Administration and Sensitivity to Yohimbine-Induced Reinstatement in Alcohol Preferring Rats: Potential Role of Neurokinin-1 Receptors in the Amygdala.

Neuroscience 2019 08 23;413:77-85. Epub 2019 Jun 23.

Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia. Electronic address:

Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666424PMC
August 2019

Sex Differences in Aversion-Resistant Ethanol Intake in Mice.

Alcohol Alcohol 2019 Jul;54(4):345-352

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.

Aims: Compulsive ethanol intake, characterized by persistent consumption despite negative consequences, is an addictive behavior identified by the DSM-5 as a central criterion in diagnosing alcohol use disorders (AUD). Epidemiological data suggest that females transition from recreational alcohol use to AUD more rapidly than males. Because of this potential sex difference in the etiology of AUD, it is critical to assess addictive behaviors such as compulsive intake in both males and females in preclinical studies.

Methods: We used the model of aversion-resistant ethanol consumption to assess compulsive-like ethanol intake. In these experiments, C57BL6/J mice were first provided with continuous access two-bottle choice between water and ethanol to establish baseline intake. Ethanol solution was then adulterated with increasing concentrations of the bitter tastant quinine hydrochloride. Animals that consume ethanol solution despite its pairing with this negative stimulus are thought to be exhibiting compulsive-like behavior.

Results: We found that higher concentrations of quinine were required to suppress ethanol consumption in female mice relative to males. We found no effect of estrous cycle phase on baseline ethanol intake or on quinine-adulterated ethanol intake in females.

Conclusions: Collectively, these data suggest that females exhibit a higher degree of aversion-resistance than male mice. Because we observed no effect of estrous cycle phase, it is likely that the presence of threshold levels of estradiol or progesterone, as opposed to their natural fluctuation across the estrous cycle, mediates increased aversion-resistance in females. Alternatively, or in combination, developmental effects of sex hormones could contribute to aversion-resistant ethanol intake.
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http://dx.doi.org/10.1093/alcalc/agz022DOI Listing
July 2019

The neurokinin-1 receptor mediates escalated alcohol intake induced by multiple drinking models.

Neuropharmacology 2018 07 3;137:194-201. Epub 2018 May 3.

Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA. Electronic address:

We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.
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http://dx.doi.org/10.1016/j.neuropharm.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701855PMC
July 2018

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation.

J Neuroinflammation 2018 Feb 27;15(1):60. Epub 2018 Feb 27.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA.

Background: Several psychiatric conditions are affected by neuroinflammation and neuroimmune activation. The transcription factor nuclear factor kappa light-chain-enhancer of activated B cells (NFkB) plays a major role in inflammation and innate immunity. The neurokinin-1 receptor (NK1R) is the primary endogenous target of the neuroactive peptide substance P, and some data suggests that NK1R stimulation may influence NFkB activity. Both NK1R and NFkB have been shown to play a functional role in complex behaviors including stress responsivity, depression, and addiction. In this study, we test whether NFkB activity in the brain (stimulated by lipopolysaccharide administration) is dependent upon the NK1R.

Methods: Adult male Wistar rats were treated systemically with the NK1R antagonist L822429 followed by administration of systemic lipopolysaccharide (LPS, a strong activator of NFkB). Hippocampal extracts were used to assess expression of proinflammatory cytokines and NFkB-DNA-binding potential. For behavioral studies, rats were trained to consume 1% (w/v) sucrose solution in a continuous access two-bottle choice model. After establishment of baseline, animals were treated with L822429 and LPS and sucrose preference was measured 12 h post-treatment.

Results: Systemic LPS treatment causes a significant increase in proinflammatory cytokine expression and NFkB-DNA-binding activity within the hippocampus. These increases are attenuated by systemic pretreatment with the NK1R antagonist L822429. Systemic LPS treatment also led to the development of anhedonic-like behavior, evidenced by decreased sucrose intake in the sucrose preference test. This behavior was significantly attenuated by systemic pretreatment with the NK1R antagonist L822429.

Conclusions: Systemic LPS treatment induced significant increases in NFkB activity, evidenced by increased NFkB-DNA binding and by increased proinflammatory cytokine expression in the hippocampus. LPS also induced anhedonic-like behavior. Both the molecular and behavioral effects of LPS treatment were significantly attenuated by systemic NK1R antagonism, suggesting that NK1R stimulation lies upstream of NFkB activation following systemic LPS administration and is at least in part responsible for NFkB activation.
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http://dx.doi.org/10.1186/s12974-018-1098-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389133PMC
February 2018

Substance P and the Neurokinin-1 Receptor: The New CRF.

Int Rev Neurobiol 2017 18;136:151-175. Epub 2017 Aug 18.

Center for Social and Affective Neuroscience, Linkoping University, Linkoping, Sweden.

Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). First isolated 85 years ago and sequenced 40 years later, SP has been extensively studied. Early studies identified a role for SP and the NK1R in contraction of intestinal smooth muscle, central pain processing, and neurogenic inflammation. An FDA-approved NK1R antagonist, aprepitant, is used clinically for the treatment of chemotherapy-induced nausea, as the NK1R influences the activity of the brain stem emesis centers. More recently, SP and the NK1R have gained attention for their role in complex psychiatric processes including stress, anxiety, and depression. However, clinical development of NK1R antagonists for these indications has so far been unsuccessful. Several preclinical studies have also demonstrated a role of the NK1R in drug taking and drug seeking, especially as it relates to escalated consumption and stress-elicited seeking. This line of research developed in parallel with findings supporting a role of corticotropin-releasing factor (CRF) in stress-induced drug seeking. Over this time, CRF arguably gained more attention as a target for development of addiction pharmacotherapies. However, this effort has not resulted in a viable drug for use in human populations. Given promising clinical findings for the efficacy of NK1R antagonists on craving in alcoholics, along with recent data suggesting that a number of negative results from NK1R trials were likely due to insufficient receptor occupancy, the NK1R merits being revisited as a target for the development of novel pharmacotherapeutics for addiction.
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http://dx.doi.org/10.1016/bs.irn.2017.06.008DOI Listing
June 2018

Bidirectional relationship between alcohol intake and sensitivity to social defeat: association with Tacr1 and Avp expression.

Addict Biol 2018 01 1;23(1):142-153. Epub 2017 Feb 1.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, GA, USA.

While epidemiological studies show that alcohol abuse is often co-morbid with affective disorders, the causal direction of this association is unclear. We examined this relationship using mouse models including social defeat stress (SDS), social interaction (SI) and voluntary alcohol consumption. C57BL6/J mice exposed to SDS segregate into two subpopulations, those that express depressive-like phenotypes ('susceptible') and those that do not ('resilient'). First, we stratified SDS-exposed mice and measured their voluntary alcohol consumption. Next, we determined whether SI behavior in alcohol-naïve mice could predict alcohol intake. Finally, we assessed the effect of binge-like alcohol exposure on sensitivity to SDS. We quantified Tacr1 (neurokinin-1 receptor gene) and Avp (vasopressin peptide gene) mRNA in brain regions involved in depression, addiction and social behavior. We found that susceptible mice consumed more alcohol compared with resilient mice, suggesting that depression-like phenotypes associate with increased alcohol intake. Interestingly, we observed a negative correlation between SI and alcohol intake in stress- and alcohol-naïve mice, suggesting that individual differences in SI associate with alcohol preference. Finally, alcohol pre-treatment increased sensitivity to SDS, indicating that alcohol exposure alters sensitivity to social stress. Quantification of mRNA revealed that increased expression of Tacr1 and Avp generally associated with decreased SI and increased alcohol intake. C57BL6/J mice are an inbred strain; thus, it is likely that individual differences in behavior and gene expression are driven by epigenetic factors. Collectively, these results support a bidirectional relationship between alcohol exposure and susceptibility to stress that is associated with variations in neuropeptide expression.
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http://dx.doi.org/10.1111/adb.12494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538906PMC
January 2018

Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice.

Addict Biol 2017 Sep 7;22(5):1279-1288. Epub 2016 Jun 7.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-α signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.
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http://dx.doi.org/10.1111/adb.12416DOI Listing
September 2017

The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation.

Psychopharmacology (Berl) 2016 06 5;233(12):2355-63. Epub 2016 Apr 5.

Department of Clinical and Experimental Medicine, Linkopings University, Linkoping, Sweden.

Rationale: Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh.

Methods: In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol.

Results: We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice.

Conclusion: Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.
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http://dx.doi.org/10.1007/s00213-016-4285-yDOI Listing
June 2016

DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

J Neurosci 2015 Apr;35(15):6153-64

Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.

Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.
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http://dx.doi.org/10.1523/JNEUROSCI.4571-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397609PMC
April 2015

The neurokinin-1 receptor in addictive processes.

Authors:
Jesse R Schank

J Pharmacol Exp Ther 2014 Oct 18;351(1):2-8. Epub 2014 Jul 18.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia

Stress can trigger drug-seeking behavior, increase self-administration rates, and enhance drug reward. A number of stress-related neuropeptides have been shown to mediate these behavioral processes. The most studied peptide in this category is corticotropin-releasing hormone (CRH), which has been shown to mediate stress-induced reinstatement of drug seeking, escalated self-administration, and drug withdrawal, but it does not seem to be involved in baseline drug self-administration or cue-induced reinstatement. This pattern of effects holds for many classes of drugs, including alcohol, opiates, and psychostimulants. The neurokinin-1 receptor (NK1R) is the preferred receptor for the endogenous stress-related neuropeptide substance P (SP). The SP/NK1R system is a major mediator of stress and anxiety, and over the last several years, it has been demonstrated that the SP/NK1R system can have effects similar to those of CRH on drug taking and drug seeking. Specifically, NK1R inhibition attenuates escalated self-administration of alcohol as well as stress-induced reinstatement of alcohol and cocaine seeking; however, in contrast to other stress systems, the NK1R also appears to have a role in primary reward and reinforcement for opiates. This review outlines the role of NK1R in drug-seeking behaviors and highlights recent results from clinical studies that suggest that the NK1R may be a promising drug target going forward.
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http://dx.doi.org/10.1124/jpet.113.210799DOI Listing
October 2014

Kappa-opioid receptor antagonism: a mechanism for treatment of relief drinking?

Biol Psychiatry 2014 May;75(10):750-1

Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia.

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http://dx.doi.org/10.1016/j.biopsych.2014.03.004DOI Listing
May 2014

microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking.

J Neurosci 2014 Mar;34(13):4581-8

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3'-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3'-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3'-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action.
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http://dx.doi.org/10.1523/JNEUROSCI.0445-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965783PMC
March 2014

The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking.

Neuropsychopharmacology 2014 Apr 31;39(5):1093-101. Epub 2013 Oct 31.

Department of Human Genetics, Emory University, Atlanta, GA, USA.

Neurokinin-1 receptors (NK1Rs) have been shown to mediate alcohol and opiate, but not cocaine reward in rodents. We recently reported that NK1R antagonism also blocks stress-induced reinstatement of alcohol seeking in rats, but it is presently unknown whether these antirelapse properties extend to other drug classes. Although some work has suggested that intracranial substance P (SP) infusion reinstates cocaine seeking following extinction, no studies have indicated a direct role for the NK1R in reinstatement of cocaine seeking. Here, we explored the effect of the NK1R antagonist L822429 on yohimbine-induced reinstatement of alcohol or cocaine seeking in Long-Evans rats. Consistent with our previous findings with footshock-induced reinstatement of alcohol seeking in Wistar rats, we found that L822429 attenuates yohimbine-induced reinstatement of alcohol seeking, but does not affect baseline alcohol self-administration. We observed a similar suppression of yohimbine-induced reinstatement of cocaine seeking by L822429, and found that Long-Evans rats exhibit greater sensitivity to NK1R antagonism than Wistar rats. Accordingly, Long-Evans rats exhibit differences in the expression of NK1Rs in some subcortical brain regions. Combined, our findings suggest that while NK1R antagonism differentially influences alcohol- and cocaine-related behavior, this receptor mediates stress-induced seeking of both drugs.
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http://dx.doi.org/10.1038/npp.2013.309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957103PMC
April 2014

Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats.

Biol Psychiatry 2013 Apr 16;73(8):774-81. Epub 2013 Feb 16.

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892-1108, USA.

Background: Genetic deletion or antagonism of the neurokinin 1 receptor (NK1R) decreases alcohol intake, alcohol reward, and stress-induced alcohol relapse in rodents, while TACR1 variation is associated with alcoholism in humans.

Methods: We used L822429, a specific antagonist with high affinity for the rat NK1R, and examined whether sensitivity to NK1R blockade is altered in alcohol-preferring (P) rats. Operant alcohol self-administration and progressive ratio responding were analyzed in P-rats and their founder Wistar line. We also analyzed Tacr1 expression and binding and sequenced the Tacr1 promoter from both lines.

Results: Systemic L822429 decreased alcohol self-administration in P-rats but did not affect the lower rates of alcohol self-administration in Wistar rats. Tacr1 expression was elevated in the prefrontal cortex and the amygdala of P-rats. In central amygdala, elevated Tacr1 expression was accompanied by elevated NK1R binding. Central amygdala (but not prefrontal cortex) infusion of L822429 replicated the systemic antagonist effects on alcohol self-administration in P-rats. All P-rats, but only 18% of their founder Wistar population, were CC homozygous for a-1372G/C single nucleotide polymorphism. In silico analysis indicated that the Tacr1-1372 genotype could modulate binding of the transcription factors GATA-2 and E2F-1. Electromobility shift and luciferase reporter assays suggested that the-1372C allele confers increased transcription factor binding and transcription.

Conclusions: Genetic variation at the Tacr1 locus may contribute to elevated rates of alcohol self-administration, while at the same time increasing sensitivity to NK1R antagonist treatment.
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http://dx.doi.org/10.1016/j.biopsych.2012.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773538PMC
April 2013

Stress-related neuropeptides and addictive behaviors: beyond the usual suspects.

Neuron 2012 Oct;76(1):192-208

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

Addictive disorders are chronic, relapsing conditions that cause extensive disease burden. Genetic factors partly account for susceptibility to addiction, but environmental factors such as stressful experiences and prolonged exposure of the brain to addictive drugs promote its development. Progression to addiction involves neuroadaptations within neurocircuitry that mediates stress responses and is influenced by several peptidergic neuromodulators. While corticotrophin releasing factor is the prototypic member of this class, recent work has identified several additional stress-related neuropeptides that play an important role in regulation of drug intake and relapse, including the urocortins, nociceptin, substance P, and neuropeptide S. Here, we review this emerging literature, discussing to what extent the properties of these neuromodulators are shared or distinct and considering their potential as drug targets.
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http://dx.doi.org/10.1016/j.neuron.2012.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495179PMC
October 2012

The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety.

Addict Biol 2012 May;17(3):634-47

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety ('hangover anxiety'). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism.
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http://dx.doi.org/10.1111/j.1369-1600.2012.00455.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334348PMC
May 2012

Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429.

Psychopharmacology (Berl) 2011 Nov 22;218(1):111-9. Epub 2011 Feb 22.

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive, Building 10-CRC, Room 1-5330, Bethesda, MD 20892-1108, USA.

Rationale: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.

Objective: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.

Methods: L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.

Results: At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.

Conclusions: To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.
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http://dx.doi.org/10.1007/s00213-011-2201-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192232PMC
November 2011

Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.

Neuropsychopharmacology 2010 Nov 25;35(12):2440-9. Epub 2010 Aug 25.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.

The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.
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http://dx.doi.org/10.1038/npp.2010.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956132PMC
November 2010

Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice.

Psychopharmacology (Berl) 2010 Mar 30;209(1):103-11. Epub 2010 Jan 30.

The Laboratory of Clinical and Translational Studies, National Institute On Alcohol Abuse and Alcoholism, 10 Center Drive, 10-CRC/1-5330, Bethesda, MD 20892-1108, USA.

Rationale: Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

Objective: The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

Methods: The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.

Results: L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.

Conclusions: Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.
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http://dx.doi.org/10.1007/s00213-010-1775-1DOI Listing
March 2010

Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

Biol Psychiatry 2008 Jun 20;63(11):1007-12. Epub 2008 Feb 20.

Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

Background: Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety.

Methods: In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety.

Results: We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect.

Conclusions: These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.
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http://dx.doi.org/10.1016/j.biopsych.2007.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405894PMC
June 2008

Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine.

Neuropsychopharmacology 2006 Oct 14;31(10):2221-30. Epub 2005 Dec 14.

Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA beta-hydroxylase (DBH) knockout (Dbh-/-) mice that lack norepinephrine (NE) to determine the consequences of chronic NE deficiency on midbrain DA neuron function in vivo. Basal extracellular DA levels were significantly attenuated in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC), of Dbh-/- mice, while amphetamine-induced DA release was absent in the NAc and attenuated in the CP and PFC. The decrease in dopaminergic tone was associated with a profound increase in the density of high-affinity state D1 and D2 DA receptors in the NAc and CP, while DA receptors in the PFC were relatively unaffected. As a behavioral consequence of these neurochemical changes, Dbh-/- mice were hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, as measured by locomotor activity and conditioned place preference. Antagonists of DA, but not 5-HT, receptors attenuated the locomotor hypersensitivity to cocaine in Dbh-/- mice. As DBH activity in humans is genetically controlled and the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence, these results have implications for the influence of genetic and pharmacological DBH inhibition on DA system function and drug addiction.
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http://dx.doi.org/10.1038/sj.npp.1301000DOI Listing
October 2006

Reduced anticonvulsant efficacy of valproic acid in dopamine beta-hydroxylase knockout mice.

Epilepsy Res 2005 Jun;65(1-2):23-31

Department of Human Genetics, Emory University School of Medicine, 301 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA.

Valproic acid (VPA) is a widely used treatment for both epilepsy and bipolar disorders, although its therapeutic mechanism of action is not fully understood. Because norepinephrine (NE) is implicated in seizure susceptibility and affective disorders, and given previous findings indicating that VPA can act on the NE system, it is possible that NE may mediate some of the therapeutic actions of VPA. To test this hypothesis, we measured flurothyl-induced seizure susceptibility and severity parameters after both acute and chronic VPA treatments in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. We found that the protective effects of acute VPA on seizure susceptibility, as measured by latency to first myoclonic jerk, were attenuated in Dbh -/- mice. Further, while acute VPA reduced the number of control mice that progressed to tonic extension, VPA did not reduce seizure severity in Dbh -/- mice. The carryover anticonvulsant effects following cessation of chronic VPA treatment were similar in both genotypes. Therefore, we conclude that NE is involved in some of the anticonvulsant effects of VPA, especially the effect of acute VPA on seizure severity.
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http://dx.doi.org/10.1016/j.eplepsyres.2005.03.010DOI Listing
June 2005