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Positive Modulator (positive + modulator)
Selected AbstractsPRECLINICAL STUDY: Pavlovian drug discrimination with bupropion as a feature positive occasion setter: substitution by methamphetamine and nicotine, but not cocaineADDICTION BIOLOGY, Issue 2 2009Jamie L. Wilkinson ABSTRACT Bupropion can serve as a discriminative stimulus (SD) in an operant drug discrimination task, and a variety of stimulants substitute for the bupropion SD. There are no reports, however, of bupropion functioning as a Pavlovian occasion setter (i.e. feature positive modulator). The present experiment seeks to fill this gap in the literature by training bupropion in rats as a feature positive modulator that disambiguates when a light will be paired with sucrose. Specifically, on bupropion (10 mg/kg intraperitoneal) sessions, offset of 15-second cue lights were followed by brief delivery of liquid sucrose; saline sessions were similar except no sucrose was available. Rats readily acquired the discrimination with more conditioned responding to the light on bupropion sessions. Bupropion is approved for use as a smoking cessation aid, and more recently has drawn attention as a potential pharmacotherapy for cocaine and methamphetamine abuse. Accordingly, after discrimination training, we tested the ability of cocaine (1,10 mg/kg), methamphetamine (0.1 to 1 mg/kg) and nicotine (0.00625 to 0.2 mg/kg) to substitute for the bupropion feature. Nicotine (0.05 mg/kg) and methamphetamine (0.3 mg/kg) substituted fully for bupropion; cocaine did not substitute. These results extend previous research on shared stimulus properties between bupropion and other stimulants to a Pavlovian occasion setting function. Further, this is the first report of nicotine and methamphetamine substitution for bupropion. The overlap in stimulus properties might explain the effectiveness of bupropion as a smoking cessation aid and highlight the possible utility of bupropion for treatment of stimulant use disorder. [source] 1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABAA receptor-mediated currents in acutely dissociated dopaminergic neuronsJOURNAL OF NEUROCHEMISTRY, Issue 1 2002Jie Wu Abstract We have evaluated GABAA receptor function during treatment of 1-methyl-4-phenylpridinium (MPP+) using patch-clamp perforated whole-cell recording techniques in acutely dissociated dopaminergic (DAergic) neurons from rat substantia nigra compacta (SNc). ,-Aminobutyric acid (GABA), glutamate or glycine induced inward currents (IGABA, IGlu, IGly) at a holding potential (VH) of ,45 mV. The IGABA was reversibly blocked by the GABAA receptor antagonist, bicuculline, suggesting that IGABA is mediated through the activation of GABAA receptors. During extracellular perfusion of MPP+ (1,10 ,m), IGABA, but neither IGlu nor IGly, declined (termed run-down) with repetitive agonist applications, indicating that the MPP+ -induced IGABA run-down occurred earlier than IGly or IGlu under our experimental conditions. The MPP+ -induced IGABA run-down can be prevented by a DA transporter inhibitor, mazindol, and can be mimicked by a metabolic inhibitor, rotenone. Using conventional whole-cell recording with different concentrations of ATP in the pipette solution, IGABA run-down can be induced by decreasing intracellular ATP concentrations, or prevented by supplying intracellular ATP, indicating that IGABA run-down is dependent on intracellular ATP concentrations. A GABAA receptor positive modulator, pentobarbital (PB), potentiated the declined IGABA and eliminated IGABA run-down. Corresponding to these patch-clamp data, tyrosine hydroxylase (TH) immunohistochemical staining showed that TH-positive cell loss was protected by PB during MPP+ perfusion. It is concluded that extracellular perfusion of MPP+ induces a functional run-down of GABAA receptors, which may cause an imbalance of excitation and inhibition of DAergic neurons. [source] Metabolic pathway of magnetized fluid-induced relaxation effects on heart muscleBIOELECTROMAGNETICS, Issue 8 2005Gayane Ayrapetyan Abstract The effect of magnetized physiological solution (MPS) on isolated, perfused snail heart muscle contractility, 45Ca uptake and intracellular level of cAMP, and cGMP was studied. The existence of the relaxing effect of MPS on heart muscle at room temperature (22 °C) and its absence in cold medium (4 °C) was shown. The MPS had a depressing effect on 45Ca uptake by muscles and intracellular cAMP content and an elevating effect on intracellular cGMP level. It is suggested that the relaxing effect of MPS on heart muscle is due to the decrease of intracellular Ca ions as the result of activation of cGMP-dependent Ca efflux. The MPS induced decrease of intracellular cAMP content can be considered as a consequence of intracellular Ca loss, leading to the Na,+,K-ATPase reactivation, and causing the decrease of the intracellular level of ATP, serving as a substrate and positive modulator of cyclase activity. Bioelectromagnetics © 2005 Wiley-Liss, Inc. [source] Contribution of Kv4 channels toward the A-type potassium current in murine colonic myocytesTHE JOURNAL OF PHYSIOLOGY, Issue 2 2002Gregory C. Amberg A rapidly inactivating K+ current (A-type current; IA) present in murine colonic myocytes is important in maintaining physiological patterns of slow wave electrical activity. The kinetic profile of colonic IA resembles that of Kv4-derived currents. We examined the contribution of Kv4 ,-subunits to IA in the murine colon using pharmacological, molecular and immunohistochemical approaches. The divalent cation Cd2+ decreased peak IA and shifted the voltage dependence of activation and inactivation to more depolarized potentials. Similar results were observed with La3+. Colonic IA was sensitive to low micromolar concentrations of flecainide (IC50= 11 ,M). Quantitative PCR indicated that in colonic and jejunal tissue, Kv4.3 transcripts demonstrate greater relative abundance than transcripts encoding Kv4.1 or Kv4.2. Antibodies revealed greater Kv4.3-like immunoreactivity than Kv4.2-like immunoreactivity in colonic myocytes. Kv4-like immunoreactivity was less evident in jejunal myocytes. To address this finding, we examined the expression of K+ channel-interacting proteins (KChIPs), which act as positive modulators of Kv4-mediated currents. Qualitative PCR identified transcripts encoding the four known members of the KChIP family in isolated colonic and jejunal myocytes. However, the relative abundance of KChIP transcript was 2.6-fold greater in colon tissue than in jejunum, as assessed by quantitative PCR, with KChIP1 showing predominance. This observation is in accordance with the amplitude of the A-type current present in these two tissues, where colonic myocytes possess densities twice that of jejunal myocytes. From this we conclude that Kv4.3, in association with KChIP1, is the major molecular determinant of IA in murine colonic myocytes. [source] | ||||||||||