Nicole M Enman

Drexel University, Filadelfia, Pennsylvania, United States

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Publications (8)22.52 Total impact

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    Full-text · Article · Dec 2015
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    ABSTRACT: Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Biological Psychiatry
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    ABSTRACT: Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Behavioural Brain Research
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    ABSTRACT: Repeated, extreme, or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes. Stressors can precipitate the onset of psychiatric diseases, or exacerbate pre-existing disorders including various anxiety and mood disorders. As stressors can negatively impact human psychiatric health, it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure. Elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to, or recovery from, stress-related psychiatric disease. Herein, we will review the evidence for neuropeptide Y as an endogenous mediator of resilience and its potential relevance for the treatment of stress-related psychiatric diseases.
    Full-text · Article · Jan 2015

  • No preview · Article · Jan 2015 · Drug and Alcohol Dependence
  • Nicole M Enman · Yong Zhang · Ellen M Unterwald
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    ABSTRACT: Posttraumatic stress disorder (PTSD) co-occurs highly with substance use disorders (SUD), yet the neurobiological basis for this comorbid relationship remains unclear. PTSD and SUDs result in similar pathological states including impulsive behavior, reward deficiency, and heightened stress sensitivity. Hence, PTSD and SUD may depend on overlapping dysfunctional neurocircuitry. Here we provide a short overview of the relationship between comorbid PTSD and SUD, as well as the potential role of select neurotransmitter systems that may underlie enhanced vulnerability to drug abuse in the context of PTSD.
    No preview · Article · Dec 2013 · Pharmacology Biochemistry and Behavior
  • C.P. Craige · N.M. Enman · E.M. Unterwald
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    ABSTRACT: Heightened anxiety and sensitivity to stress following chronic cocaine use are likely to increase an individual's susceptibility for relapse to drug-seeking behavior. Thus, it is important to investigate the neural mechanisms responsible for the regulation of anxiety during cocaine withdrawal and stress-induced relapse in order to identify potential targets for pharmacological intervention. This chapter will address the involvement of several neurotransmitter systems in regulating anxiety during cocaine withdrawal and stress-induced relapse mechanisms. The distinct roles of the dopamine, serotonin, corticotropin releasing factor, norepinephrine, and opioid systems in regulating the negative consequences of cocaine withdrawal and the effects of stress in eliciting relapse to drug use will be discussed. In addition, a section detailing the potential role of other neuropeptides like cholecystokinin and neuropeptide Y in cocaine withdrawal-induced anxiety and stress-induced relapse is included. It is important to consider the roles of these brain-signaling systems separately, as well as integrated in a network that functions in regulating anxiety during cocaine withdrawal and the effects of stress on drug abuse and relapse to drug use. By targeting these regulatory mechanisms, potential pharmacological targets may be identified in support of the prevention of relapse to drug use.
    No preview · Article · Dec 2013
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    Nicole M Enman · Ellen M Unterwald
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    ABSTRACT: Glycogen synthase kinase 3 (GSK3) is implicated in mediating dopamine-dependent behaviors. Previous studies have demonstrated the ability of amphetamine, which increases extracellular dopamine levels and influences behavior, to regulate the activity of GSK3. This study used valproic acid and the selective GSK3 inhibitor, SB 216763, to examine the role of GSK3 in amphetamine-induced hyperactivity and the development of sensitized stereotypic behavior. Pretreatment with valproic acid (50-300 mg/kg, i.p.) or SB 216763 (2.5-5 mg/kg, i.p.) prior to amphetamine (2 mg/kg, i.p.) significantly reduced amphetamineinduced ambulation and stereotypy. To assess the development of sensitization to the stereotypic effects of amphetamine, mice were pretreated daily with valproic acid (300 mg/kg) or SB 216763 (5 mg/kg) prior to amphetamine (2 mg/kg) for 5 days. Upon amphetamine challenge (1 mg/kg) 7 days later, mice pretreated with valproate or SB 216763 showed a significant attenuation of amphetamine-induced sensitization of stereotypy. To determine whether regulation of GSK3 activity was associated with attenuation of acute amphetamine-induced hyperactivity by valproic acid, valproate (300 mg/kg) or vehicle was injected prior to amphetamine (2 mg/kg) or saline and brain tissue obtained. Analysis of the levels of phospho-GSK3α and β by immunoblot indicated that valproate increased phosphorylation of ser²¹-GSK3α in the frontal cortex, as well as ser⁹-GSK3β in the frontal cortex and caudate putamen of amphetamine-injected mice. These data support a role for GSK3 in acute amphetamine-induced hyperactivity and the development of sensitization to amphetamine-induced stereotypy.
    Preview · Article · May 2012 · Behavioural brain research