Amanda Shaw

Mayo Foundation for Medical Education and Research, Рочестер, Michigan, United States

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Publications (8)24.77 Total impact

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    ABSTRACT: NT69L is a neurotensin analog that blocks nicotine-induced locomotor activity and has sustained efficacy in a rat model of nicotine-induced sensitization when administered peripherally. Additionally, NT69L attenuates food-reinforcement in rats. The present study tested the effect of acute administration of NT69L on nicotine self-infusion in Sprague-Dawley rats. Rats were trained to self-infuse nicotine intravenously (0.03mg/kg per infusion) following operant training. Once the rats acquired stable responding to nicotine self-infusion they were pretreated with NT69L (1mg/kg, i.p.) or saline 30min before being assessed for nicotine self-infusion. Pretreatment with NT69L significantly attenuated nicotine self-infusion under FR1 (fixed ratio of 1) and FR5 schedule of reinforcement as compared to saline pretreatment. Control rats that were response-independent "yoked" as well as rats that self-infused saline or NT69L showed minimal responses, indicating that nicotine served as a reinforcer. Additionally, NT69L modulated serum corticosterone; brain norepinephrine serotonin; and dopamine receptors mRNA levels altered in the nicotine self-infused rats after a 24h withdrawal period. Pretreatment with NT69L significantly decreased the nicotine-induced increase in serum corticosterone levels and striatal norepinephrine and increased the nicotine-induced reduction in serotonin in both the striatum and the prefrontal cortex (PFC). NT69L might modulate dopamine neurotransmission implicated in the reinforcing effects of nicotine by modulating tyrosine hydroxylase and dopamine receptor mRNA levels in the PFC and striatum. These data support further study of the effects of NT analogs on attenuating the reinforcing effects of psychostimulants.
    Neuropeptides 11/2010; 45(1):9-16. DOI:10.1016/j.npep.2010.09.003 · 2.55 Impact Factor
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    ABSTRACT: Neurotensin (NT) is a neuropeptide with antinociceptive effects that are mediated through NT receptors, of which there are three known subtypes (NTS1, NTS2, and NTS3). Morphine is a mu-opioid receptor agonist commonly used for pain treatment but is associated with side effects that can be serious. We hypothesize that selective NT receptor agonists may represent a novel class of analgesics and their use in conjunction with morphine will have synergistic properties which may reduce the dose of morphine administered and its side effects. The antinociceptive activity of an NT agonist (NT69L) and morphine was studied in rats using the hot plate test to determine if there is synergism between the two drugs in reducing pain. The NTS2 receptor antagonist, levocabastine, was used to determine the receptor subtype involved in the analgesic effect of NT69L and morphine. The administration of both NT69L and morphine resulted in a dose-dependent analgesic effect. The isobolographic analysis demonstrated that the combination of sub-analgesic doses of NT69L and morphine was synergistic in the hot plate test. Pretreatment with the NTS2 receptor antagonist, levocabastine attenuated the antinociceptive effect of NT69L and the combined effect of NT69L and morphine in the hot plate test. The results support the hypothesis that the synergistic combination of NT69L and morphine would improve the pharmacological treatment of pain while minimizing specific adverse effects of each of the drugs at a higher dose. NTS2 is important for the antinociceptive effect of NT69L and morphine.
    Brain research 08/2009; 1294:22-8. DOI:10.1016/j.brainres.2009.07.086 · 2.83 Impact Factor
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    ABSTRACT: A series of recent studies has demonstrated that the molecules involved in regulation of neuronal plasticity are also involved in the mode of action of antidepressants and mood stabilizer drugs. Intracellular calcium signaling, energy metabolism, and neuronal plasticity can be influenced by inducing axonal remodeling and increasing levels of certain synaptic proteins. Because antipsychotic drugs are used as mood stabilizers our studies focused on a newly-marketed antipsychotic drug, paliperidone. We determined changes in rat synaptoneurosomal proteins after chronic treatment with paliperidone, lithium salt, or valproic acid in order to find similarities or differences between the mode of action of paliperidone and these two classical mood stabilizers. We determined differential protein expression profiles in prefrontal cortex (PFC) of male Sprague-Dawley rats (n = 4/group). Synaptoneurosomal-enriched preparations were obtained from PFC after chronic treatment with these three drugs. Proteins were separated by 2D-DIGE and identified by nano-LC-MS/MS. We observed similar protein expression profiles at the synaptoneurosomal level, suggesting that the mode of action for paliperidone is similar to that of lithium and valproic acid. However, the expression profile for paliperidone was more similar to that of lithium. Pathways affected in common by these two drugs included oxidative phosphorylation, electron transport, carbohydrate metabolism, and post-synaptic cytokinesis implicating the effects of these drugs in signaling pathways, energy metabolism, and synaptic plasticity.
    Brain Research 10/2008; 1233:8-19. DOI:10.1016/j.brainres.2008.07.021 · 2.83 Impact Factor
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    ABSTRACT: NT69L, is a novel neurotensin (8-13) analog that participates in the modulation of the dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system, with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is involved in nicotine's reinforcing properties. The aim of the present study was to investigate the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2 weeks) administration of nicotine elicited increases in extracellular levels of dopamine, dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotine-evoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction.
    Brain Research 10/2008; 1231:6-15. DOI:10.1016/j.brainres.2008.07.037 · 2.83 Impact Factor
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    ABSTRACT: Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.
    Journal of Pharmacology and Experimental Therapeutics 09/2008; 327(2):573-83. DOI:10.1124/jpet.108.143610 · 3.86 Impact Factor
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    ABSTRACT: NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.
    Brain Research 02/2007; 1127(1):90-8. DOI:10.1016/j.brainres.2006.10.025 · 2.83 Impact Factor
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    ABSTRACT: Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2'-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2'-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.
    European Journal of Pharmacology 02/2007; 555(1):30-6. DOI:10.1016/j.ejphar.2006.10.004 · 2.68 Impact Factor
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    ABSTRACT: Neurotensin (NT) is a neuropeptide that, for decades, has been implicated in the biology of schizophrenia. It is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various neuropsychiatric diseases, including schizophrenia. This review outlines the neurochemistry and function of the NT system and the data implicating its role in schizophrenia. The data suggest that NT receptor agonists have the potential to be used as novel therapeutic agents for the treatment of schizophrenia, with the added benefits of (i) not causing weight gain, an adverse effect that is problematic with some of the currently used atypical antipsychotic drugs; and (ii) helping patients to stop smoking, a behaviour that is highly prevalent in those with schizophrenia.
    CNS Drugs 02/2007; 21(1):13-23. · 4.38 Impact Factor