Psychomotor activity and body weight gain after exposure to low ribavirin doses in rats: Role of treatment duration
Keywords:
ribavirin, amphetamine, motor activity, body weight, ratsAbstract
Paper description:
- Ribavirin is an antiviral agent showing side effects associated with use of high doses and/or long-term application.
- This study examined the effects of single or repeated application of low ribavirin doses (10, 20 and 30 mg/kg/day, i.p.) on dopamine-mediated behaviors, novelty-induced investigation and d-amphetamine-induced motor activity, and on body weight gain in adult male rats. Hypolocomotion and reduced weight gain in a U-shaped dose-response related manner were observed after repeated ribavirin treatment.
- The findings contribute to an improved understanding of the psychomotor and physiological responses to low ribavirin doses in the rodent model with regard to treatment duration.
Abstract: Clinically-related basic studies on the behavioral effects of ribavirin treatment are still lacking despite its wide use as an antiviral medication. This paper considers the effects of low ribavirin doses (10, 20 and 30 mg/kg/day) on psychomotor activity (novelty-induced exploratory behavior, d-amphetamine (AMPH, 1.5 mg/kg, intraperitoneal)-induced motor activity), and body weight gain in socially undisturbed adult male Wistar rats 24 h after the first, seventh and fourteenth once-a-day injection. Low doses of ribavirin were tested in an attempt to avoid the recognized systemic side effects related to high-dose usage. None of the singly applied ribavirin doses affected exploratory/spontaneous and AMPH-induced motor behavior (locomotion, stereotypy-like and vertical activity), however, body weight gain was significantly lower after treatment with 30 mg/kg of ribavirin. The 7- and 14-day treatments with 10 and 30 mg/kg/day of ribavirin significantly suppressed novelty-induced locomotion and body weight gain; the 14-day treatment with ribavirin at a dose of 30 mg/kg/day decreased AMPH-induced stereotypy. These findings indicate that repeated application (up to 14 days) of low ribavirin doses results in low novelty-induced locomotion along with reduced weight gain, accentuating the existence of a U-shaped dose-response relationship with a prolonged duration of ribavirin treatment.
https://doi.org/10.2298/ABS190205018P
Received: February 5, 2019; Revised: March 13, 2019; Accepted: March 22, 2019; Published online: March 25, 2019
How to cite this article: Petković B, Stojadinović G, Kesić S, Ristić S, Martać Lj, Podgorac J, Pešić V. Psychomotor activity and body weight gain after exposure to low ribavirin doses in rats: role of treatment duration Arch Biol Sci. 2019;71(2):357-68.
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References
Esmat G, El Kassas M, Elbaz T, El Raziky M. Ribavirin and its great potentials in infectious diseases. In: Buskirk J, editor. Ribavirin: biochemistry, clinical applications and potential side effects. New York: Nova Science Publishers Inc; 2013. p. 37-57.
Thomas E, Ghany MG, Liang TJ. The application and mechanism of action of ribavirin in therapy of hepatitis C. Antivir Chem Chemother. 2012;23(1):1-12.
Cattie JE, Letendre SL, Woods SP, Barakat F, Perry W, Cherner M, Umlauf A, Franklin D, Heaton RK, Hassanein T, Grant I; Translational Methamphetamine AIDS Research Center (TMARC) Group. Persistent neurocognitive decline in a clinic sample of hepatitis C virus-infected persons receiving interferon and ribavirin treatment. J Neurovirol. 2014;20(6):561-70.
de Knegt RJ, Bezemer G, Van Gool AR, Drenth JP, Hansen BE, Droogleever Fortuyn HA, Weegink CJ, Hengeveld MW, Janssen HL. Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C. Aliment Pharmacol Ther. 2011;34(11-12):1306-17.
Fioravante M, Alegre SM, Marin DM, Lorena SL, Pereira TS, Soares EC. Weight loss and resting energy expenditure in patients with chronic hepatitis C before and during standard treatment. Nutrition. 2012;28(6):630-4.
Mahajan S, Avasthi A, Grover S, Chawla YK. Role of baseline depressive symptoms in the development of depressive episode in patients receiving antiviral therapy for hepatitis C infection. J Psychosom Res. 2014;77(2):109-15.
Kamei S, Sakai T, Matsuura M, Tanaka N, Kojima T, Arakawa Y, Matsukawa Y, Mizutani T, Oga K, Ohkubo H, Matsumura H, Hirayanagi K. Alterations of quantitative EEG and mini-mental state examination in interferon-alpha-treated hepatitis C. Eur Neurol. 2002;48(2):102-7.
Malaguarnera M, Laurino A, Di Fazio I, Pistone G, Castorina M, Guccione N, Rampello L. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res. 2001;21(5):273-8.
Schmidt F, Janssen G, Martin G, Lorenz R, Loeschke K, Soyka M, Folwaczny C, Schaefer M. Factors influencing long-term changes in mental health after interferon-alpha treatment of chronic hepatitis C. Aliment Pharmacol Ther. 2009;30(10):1049-59.
Seyam MS, Freshwater DA, O'Donnell K, Mutimer DJ. Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C*. J Viral Hepat. 2005;12(5):531-5.
Reddy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J Hepatol. 2009;50(2):402-11.
Ferrara EA, Oishi JS, Wannemacher RW, Jr., Stephen EL. Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys. Antimicrob Agents Chemother. 1981;19(6):1042-9.
Jeulin H, Venard V, Carapito D, Finance C, Kedzierewicz F. Effective ribavirin concentration in mice brain using cyclodextrin as a drug carrier: evaluation in a measles encephalitis model. Antiviral Res. 2009;81(3):261-6.
Crumpacker C, Bubley G, Lucey D, Hussey S, Connor J. Ribavirin enters cerebrospinal fluid. Lancet. 1986;2(8497):45-6.
Franchetti P, Cappellacci L, Grifantini M, Senatore G, Martini C, Lucacchini A. Tiazofurin analogues as selective agonists of A1 adenosine receptors. Res Commun Mol Pathol Pharmacol. 1995;87(1):103-5.
Fastbom J, Pazos A, Palacios JM. The distribution of adenosine A1 receptors and 5'-nucleotidase in the brain of some commonly used experimental animals. Neuroscience. 1987;22(3):813-26.
Franco R, Ferre S, Agnati L, Torvinen M, Gines S, Hillion J, Casadó V, Lledó P, Zoli M, Lluis C, Fuxe K. Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology. 2000;23(4 Suppl):S50-9.
Ferre S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20(10):482-7.
Schwienbacher I, Fendt M, Hauber W, Koch M. Dopamine D1 receptors and adenosine A1 receptors in the rat nucleus accumbens regulate motor activity but not prepulse inhibition. Eur J Pharmacol. 2002;444(3):161-9.
Janać B, Pešić V, Peković S, Rakić L, Stojiljković M. The time-course of ribavirin-provoked changes of basal and AMPH-induced motor activities in rats. Exp Brain Res. 2005;165(3):402-6.
Sellings LH, Clarke PB. Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial shell and core. J Neurosci. 2003;23(15):6295-303.
Jacobson KA, von Lubitz DK, Daly JW, Fredholm BB. Adenosine receptor ligands: differences with acute versus chronic treatment. Trends Pharmacol Sci. 1996;17(3):108-13.
Kawashimo A, Shimazoe T, Yoshimatsu A, Watanabe S. Repeated adenosine pre-treatment potentiates the acute effect of methamphetamine in rats. Jpn J Pharmacol. 2000;84(1):78-81.
Poleszak E, Malec D. Influence of adenosine receptor agonists and antagonists on amphetamine-induced stereotypy in rats. Pol J Pharmacol. 2000;52(6):423-9.
Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nat Neurosci. 2015;18(10):1394-404.
Hughes RN. Neotic preferences in laboratory rodents: issues, assessment and substrates. Neurosci Biobehav Rev. 2007;31(3):441-64.
Faurholt-Jepsen M, Brage S, Vinberg M, Kessing LV. State-related differences in the level of psychomotor activity in patients with bipolar disorder - Continuous heart rate and movement monitoring. Psychiatry Res. 2016;237:166-74.
Flagel SB, Robinson TE. Quantifying the psychomotor activating effects of cocaine in the rat. Behav Pharmacol. 2007;18(4):297-302.
Jain MK, Zoellner C. Role of ribavirin in HCV treatment response: now and in the future. Expert Opin Pharmacother. 2010;11(4):673-83.
Horvitz JC. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience. 2000;96(4):651-6.
Legault M, Wise RA. Novelty-evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area. Eur J Neurosci. 2001;13(4):819-28.
Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14(4):402-12.
Abenavoli L, Mazza M, Almasio PL. The optimal dose of ribavirin for chronic hepatitis C: From literature evidence to clinical practice: The optimal dose of ribavirin for chronic hepatitis C. Hepat Mon. 2011;11(4):240-6.
Gara N, Ghany MG. What the infectious disease physician needs to know about pegylated interferon and ribavirin. Clin Infect Dis. 2013;56(11):1629-36.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27-31.
Sanson-Fisher RW, Poole AD, Dunn J. An empirical method for determining an appropriate interval length for recording behavior. J Appl Behav Anal. 1980;13(3):493-500.
Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75(6):406-33.
Steel RGD. A multiple comparison rank sum test - treatments versus control. Biometrics. 1959;15(4):560-72.
Hothorn LA. The two-step approach – a significant ANOVA F-test before Dunnett’s comparisons against a control – is not recommended. Commun Stat Theory Methods. 2016;45(11):3332-43.
Hamada C. Statistical analysis for toxicity studies. J Toxicol Pathol. 2018;31(1):15-22.
Harvie P, Omar RF, Dusserre N, Lansac N, Desormeaux A, Gourde P, Simard M, Tremblay M, Beauchamp D, Bergeron MG. Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model. J Pharmacol Exp Ther. 1996;279(2):1009-17.
Stojkov D, Lavrnja I, Pekovic S, Dacic S, Bjelobaba I, Mostarica-Stojkovic M, Stosic-Grujicic S, Jovanovic S, Nedeljkovic N, Rakic L, Stojiljkovic M. Therapeutic effects of combined treatment with ribavirin and tiazofurin on experimental autoimmune encephalomyelitis development: clinical and histopathological evaluation. J Neurol Sci. 2008;267(1-2):76-85.
Safronetz D, Haddock E, Feldmann F, Ebihara H, Feldmann H. In vitro and in vivo activity of ribavirin against Andes virus infection. PLoS One. 2011;6(8):e23560.
Fernandez M, Svenningsson P, Fredholm BB. Adaptive changes in adenosine receptors following long-term treatment with the adenosine receptor agonist R-phenylisopropyl adenosine. Life Sci. 1996;58(9):769-76.
Roman V, Keijser JN, Luiten PG, Meerlo P. Repetitive stimulation of adenosine A1 receptors in vivo: changes in receptor numbers, G-proteins and A1 receptor agonist-induced hypothermia. Brain Res. 2008;1191:69-74.
Lin CC, Yeh LT, Luu T, Lourenco D, Lau JY. Pharmacokinetics and metabolism of [(14)C]ribavirin in rats and cynomolgus monkeys. Antimicrob Agents Chemother. 2003;47(4):1395-8.
Colombo G, Lorenzini L, Zironi E, Galligioni V, Sonvico F, Balducci AG, Pagliuca G, Giuliani A, Calzà L, Scagliarini A. Brain distribution of ribavirin after intranasal administration. Antiviral Res. 2011;92(3):408-14.
Jones GH, Robbins TW. Differential effects of mesocortical, mesolimbic, and mesostriatal dopamine depletion on spontaneous, conditioned, and drug-induced locomotor activity. Pharmacol Biochem Behav. 1992;43(3):887-95.
Kaplan GB, Leite-Morris KA, Klufas MA, Fan W. Intra-VTA adenosine A1 receptor activation blocks morphine stimulation of motor behavior and cortical and limbic Fos immunoreactivity. Eur J Pharmacol. 2009;602(2-3):268-76.
Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998;28(3):309-69.
Kim DS, Palmiter RD. Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice. Proc Natl Acad Sci U S A. 2003;100(3):1346-51.
Szczypka MS, Kwok K, Brot MD, Marck BT, Matsumoto AM, Donahue BA, Palmiter RD. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron. 2001;30(3):819-28.
Kim DS, Szczypka MS, Palmiter RD. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists. J Neurosci. 2000;20(12):4405-13.
Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci. 2007;30(8):375-81.
Yang GK, Yip L, Fredholm BB, Kieffer TJ, Kwok YN. Involvement of adenosine signaling in controlling the release of ghrelin from the mouse stomach. J Pharmacol Exp Ther. 2011;336(1):77-86.
Olsson IAS, Westlund K. More than numbers matter: the effect of social factors on behaviour and welfare of laboratory rodents and non-human primates. Appl Anim Behav Sci. 2007;103(3-4):229-54.
Ramsay DS, Woods SC. Clarifying the roles of homeostasis and allostasis in physiological regulation. Psychol Rev. 2014;121(2):225-47.
Meijer MK, Spruijt BM, van Zutphen LF, Baumans V. Effect of restraint and injection methods on heart rate and body temperature in mice. Lab Anim. 2006;40(4):382-91.
Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci. 2001;24:31-55.
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