Nicole A Northrop

Medical University of Ohio at Toledo, Toledo, Ohio, United States

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Publications (7)29.72 Total impact

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    Nicole A Northrop · Bryan K Yamamoto
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    ABSTRACT: Methamphetamine (Meth) is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB) is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth (McCann et al., 1998) on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed toward the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction.
    Frontiers in Neuroscience 03/2015; 9:69. DOI:10.3389/fnins.2015.00069 · 3.70 Impact Factor
  • Laura E Halpin · Nicole A Northrop · Bryan K Yamamoto
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    ABSTRACT: Ammonia has been identified to play a significant role in the long term damage to dopamine and serotonin terminals produced by methamphetamine (METH), but how ammonia contributes to this damage is unknown. Experiments were conducted to identify whether increases in brain ammonia affect METH-induced increases in glutamate and subsequent excitotoxicity. Increases in striatal glutamate were measured using in-vivo microdialysis. To examine the role of ammonia in mediating changes in extracellular glutamate after METH exposure, lactulose was used to decrease plasma and brain ammonia. Lactulose is a non-absorbable disaccharide which alters the intestinal lumen through multiple mechanisms that lead to the increased peripheral excretion of ammonia. METH caused a significant increase in extracellular glutamate that was prevented by lactulose. Lactulose had no effect on METH-induced hyperthermia. To determine if ammonia contributed to excitotoxicity, the effect of METH and lactulose treatment on calpain-mediated spectrin proteolysis was measured. METH significantly increased calpain-specific spectrin breakdown products, and this increase was prevented with lactulose treatment. To examine if ammonia-induced increases in extracellular glutamate were mediated by excitatory amino acid transporters, the reverse dialysis of ammonia, the glutamate transporter inhibitor, DL-threo-β-benzyloxyaspartic acid (TBOA), or the combination of the two directly into the striatum of awake, freely moving rats was conducted. TBOA blocked the increases in extracellular glutamate produced by the reverse dialysis of ammonia. These findings demonstrate that ammonia mediates METH-induced increases in extracellular glutamate through an excitatory amino acid transporter to cause excitotoxicity.Neuropsychopharmacology accepted article preview online, 29 October 2013; doi:10.1038/npp.2013.306.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; 39(4). DOI:10.1038/npp.2013.306 · 7.83 Impact Factor
  • Nicole A Northrop · Bryan K Yamamoto
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    ABSTRACT: Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth.
    Neuropharmacology 05/2013; DOI:10.1016/j.neuropharm.2013.04.040 · 4.82 Impact Factor
  • Nicole A Northrop · Bryan K Yamamoto
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    ABSTRACT: Studies of methamphetamine (Meth)-induced neurotoxicity have traditionally focused on monoaminergic terminal damage while more recent studies have found that stress exacerbates these damaging effects of Meth. Similarities that exist between the mechanisms that cause monoaminergic terminal damage in response to stress and Meth and those capable of producing a disruption of the blood-brain barrier (BBB) suggest that the well-known high co-morbidity of stress and Meth could produce long-lasting structural and functional BBB disruption. The current studies examined the role of neuroinflammation in mediating the effects of exposure to chronic stress and/or Meth on BBB structure and function. Rats were pre-exposed to chronic unpredictable stress (CUS) and/or challenged with Meth. Twenty-four hours after the treatment of Meth in rats pre-exposed to CUS, occludin and claudin-5 immunoreactivity were decreased while truncation of β-dystroglycan, as well as FITC-dextran and water extravasation was increased. All changes other than β-dystroglycan and edema persisted 7 days later, occurred with increases in GFAP and COX-2, and were blocked by ketoprofen after Meth treatment. In addition, persistent increases in FITC-dextran extravasation were prevented by treatment with an EP1 receptor antagonist after Meth exposure. The results indicate that CUS and Meth synergize to produce long-lasting structural and functional BBB disruptions that are mediated by cyclooxygenase and protracted increases in inflammation. These results suggest that stress and Meth can synergize to produce a long-lasting vulnerability of the brain to subsequent environmental insults resulting from the persistent breach of the BBB.
    Journal of Neuroimmune Pharmacology 07/2012; 7(4). DOI:10.1007/s11481-012-9391-y · 3.17 Impact Factor
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    Nicole A Northrop · Laura P Smith · Bryan K Yamamoto · David J Eyerman
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    ABSTRACT: Regulation of glutamate release is an important underlying mechanism in mediating excitotoxic events such as damage to dopamine (DA) and serotonin (5-HT) neurons observed after exposure to methamphetamine (Meth). One way to regulate glutamate release may be through the modulation of α7 nicotinic acetylcholine (nACh) receptors. Meth administration is known to increase acetylcholine release; however, it is unknown whether Meth increases glutamate release and causes long-term damage to both DA and 5-HT terminals through the activation of α7 nACh receptors. To test this hypothesis, the α7 nACh receptor antagonist, methyllycaconitine (MLA), was administered before the administration of repeated doses of Meth while simultaneously monitoring extracellular striatal glutamate with in vivo microdialysis. In addition, the subsequent long-term decreases in markers of dopaminergic and serotonergic terminals, including DA reuptake transporter (DAT), serotonin reuptake transporter (SERT), vesicular monoamine transporter-2, vesicular DA, and vesicular 5-HT content in the rat striatum, were measured. The results show that MLA pretreatment prevented Meth-induced increases in striatal glutamate and protected against the subsequent long-term decreases in striatal DAT and vesicular DA content without affecting the hyperthermia produced by Meth. In contrast, the Meth-induced decreases in striatal SERT immunoreactivity and vesicular 5-HT content were not affected by MLA. This suggests that the α7 nACh receptor differentially mediates glutamate-dependent damage to DA but not 5-HT terminals in a manner that is independent of hyperthermia. Furthermore, antagonism of α7 nACh receptors may be a possible therapeutic strategy for decreasing extracellular glutamate and preventing the excitotoxic damage observed in other DA-related neurodegenerative disorders.
    Journal of Pharmacology and Experimental Therapeutics 03/2011; 336(3):900-7. DOI:10.1124/jpet.110.177287 · 3.86 Impact Factor
  • Nicole A Northrop · Nicole A Northrup · Bryan K Yamamoto
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    ABSTRACT: The focus of this commentary is to describe how neuroscience, immunology, and pharmacology intersect and how interdisciplinary research involving these areas has expanded knowledge in the area of neuroscience, in particular. Examples are presented to illustrate that the brain can react to the peripheral immune system and possesses immune function and that resident immune molecules play a role in normal brain physiology. In addition, evidence is presented that the brain immune system plays an important role in mediating neurodegenerative diseases, the aging process, and neurodevelopment and synaptic plasticity. The identification of these mechanisms has been facilitated by pharmacological studies and has opened new possibilities for pharmacotherapeutic approaches to the treatment of brain disorders. The emerging field of neuroimmune pharmacology exemplifies this interdisciplinary approach and has facilitated the study of basic cellular and molecular events and disease states and opens avenues for novel therapies.
    Journal of Neuroimmune Pharmacology 03/2011; 6(1):10-9. DOI:10.1007/s11481-010-9239-2 · 3.17 Impact Factor
  • Source
    Nicole A Northrop · Bryan K Yamamoto
    Journal of Neuroimmune Pharmacology 09/2010; 6(1). DOI:10.1007/s11481-010-9244-5 · 3.17 Impact Factor