We studied the effects of sildenafil, a selective inhibitor of PDE5, on the development and the expression of tolerance to diazepam (DZ)-induced motor impairment and sedation in mice. DZ-induced motor incoordination was assessed by the rotarod and chimney tests, and DZ-induced sedation was examined using a photocell apparatus. Sildenafil treatment enhanced the development of tolerance to the motor impairing effects, but not to the sedative effects, of DZ. Sildenafil treatment did not affect the expression of tolerance to DZ-induced motor impairment and sedation in mice. Our results suggest that sildenafil treatment, at least in part, affects the development of DZ tolerance.
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Allison C, Pratt JA: Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharmacol Ther, 2003, 98, 171–195.
Abdel-Zaher AO, Hamdy MH, Aly SA, Abdel-Hady RH, Abdel-Rahman S: Attenuation of morphine tolerance and dependence by aminoguanidine in mice. Eur J Pharmacol, 2006, 540, 60–66.
Babey AM, Kolesnikov Y, Cheng J, Inturrisi CE, Trifilletti RR, Pasternak GW: Nitric oxide and opioid tolerance. Neuropharmacology, 1994, 33, 1463–1470.
Bateson AN: Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des, 2002, 8, 5–21.
Bezerra MM, Lima V, Girao VCC, Teixeira RC, Graça JRV: Antinociceptive activity of sildenafil and adrenergic agents in the writhing test in mice. Pharmacol Rep, 2008, 60, 339–3444.
Bonavita CD, Bisagno V, Bonelli CG, Acosta GB, Rubio MC, Wikinski SI: Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate. Neuropharmacology, 2002, 42, 619–625.
Bruckdorfer R: The basics about nitric oxide. Mol Aspects Med, 2005, 26, 3–31.
Dawson TD, Snyder SH: Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci, 1994, 14, 5147–5159.
Esplugues JV: NO as a signalling molecule in the nervous system. Br J Pharmacol, 2002, 135, 1079–1095.
Fernandes C, Arnot MI, Irvine EE, Bateson AN, Martin IL, File SE: The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam. Psychopharmacology, 1999, 145, 251–259.
Fernandes C, File SE: Dizolcipine does not prevent of tolerance to the anxiolytic effects of diazepam in rats. Brain Res, 1999, 815, 431–434.
File SE: Tolerance to the behavioral actions of benzodiazepines. Neurosci Biobehav Rev 1985, 9, 113–121.
Gallager DW, Lakoski JM, Gonsalves SF, Rauch, SL: Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity. Nature, 1984, 308, 74–77.
Goldenberg MM: Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther, 1998, 20, 1033–1048.
Guevara-Guzman R, Emson CP, Kendrick KM: Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J Neurochem, 1994, 62, 807–810.
Guix FX, Uribesalgo I, Coma M, Muñoz FJ: The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol, 2005, 76, 126–152.
Ignarro LJ: Heme-dependent activation of soluble guanylate cyclase by nitric oxide: regulation of enzyme activity by porphyrins and metalloporphyrins. Seminars Haematol, 1989, 26, 63–76.
Jain NK, Patil CS, Singh A, Kulkarni SK: Sildenafilinduced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Brain Res, 2001, 170–178.
Katzung BG: Basic and clinical pharmacology. Appleton and Lange, Norwalk, CT, 1995.
Khanna JM, Morato GS, Chau A, Shah G: Influence of nitric oxide synthase inhibition on the development of rapid tolerance to ethanol. Brain Res Bull, 1995, 37, 599–604.
Kippin TE, Pinell JJP, Kornecook TJ, Kalynchuk LE: Noncontingent drug exposure facilitates the development of contingent tolerance to the anticonvulsant effects of ethanol and diazepam in kindled rats. Pharmacol Biochem Behav, 1998, 61, 143–148.
Lue WM., Su MT, Lin WB, Tao PT: The role of nitric oxide in the development of morphine tolerance in rat hippocampal slices. Eur J Pharmacol, 1999, 383, 129–135.
Majeed NH, Przewłocka B, Machelska H, Przewłocki R: Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology, 1994, 33, 189–199.
Möhler H: GABA A receptor diversity and pharmacology. Cell Tissue Res, 2006, 326, 505–516.
Nidhi G, Bhargava VK, Pandhi P: Tolerance to and withdrawal from anticonvulsant action of diazepam: role of nitric oxide. Epilepsy Behav, 2000, 1, 262–270.
Phillips BG, Kato M, Pesek CA, Winnicki M, Narkiewicz K, Davison D, Somers VK: Sympathetic activation by sildenafil. Circulation, 2000, 102, 3068–3073.
Quock RM, Nquyen E: Possible involvement of nitric oxide in chlordiazepoxide-induced anxiolysis in mice. Life Sci, 1992, 51, PL255–260.
Riazi K, Roshanpour M, Rafiei-Tabatabei N, Homayoun H, Ebrahimi F, Dehpour AR: The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway. Br J Pharmacol, 2006, 147, 935–943.
Segovia G, Porras A, Mora F: Effects of a nitric oxide donor on glutamate and GABA release in striatum and hippocampus of the conscious rat. NeuroReport, 1994, 5, 1937–1940.
Smith RL, Barrett RJ: Tolerance to the anticonflict effects of diazepam: Importance of methodological considerations. Pharmacol Biochem Behav, 1997, 58, 61–66.
Stephens DN: A glutamatergic hypothesis of drug dependence: extrapolations from benzodiazepine receptor ligands. Behav Pharmacol, 1995, 6, 425–446.
Tahsili-Fahadan P, Yahyavi-Firouz-Abadi N, Orandi AH, Esmaeili B, Basseda Z, Dehpour AR: Rewarding properties of sildenafil citrate in mice: role of the nitric oxidecyclic GMP pathway. Psychopharmacology, 2006, 185, 201–207.
Talarek S, Fidecka S: Involvement of nitricoxidergic system in the hypnotic effects of benzodiazepines in mice. Pol J Pharmacol, 2004, 56, 719–726.
Talarek S, Fidecka S: Role of nitric oxide in anticonvulsant effects of benzodiazepines in mice. Pol J Pharmacol, 2003, 55, 181–191.
Talarek S, Fidecka S: Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol, 2002, 54, 27–34.
Talarek S, Listos J, Fidecka S: Role of nitric oxide in the development of tolerance to diazepam-induced motor impairment in mice. Pharmacol Rep, 2008, 60, 475–482.
Tallman JF, Gallager DW: The GABAergic system: a locus of benzodiazepine action. Annu Rev Neurosci, 1985, 8, 21–44.
Tietz EI, Rosenberg HC, Chiu TH: Audiographic localization of benzodiazepine receptor down regulation. J Pharmacol Exp Ther, 1986, 236, 284–292.
Ulhayathas S, Karuppagounder SS, Thrash BM, Parameshwaran K, Suppiramaniam V, Dhanasekaran M: Versatile effects of sildenafil: recent pharmacological applications. Pharmacol Rep, 2007, 59, 150–163.
Uzbay IT, Oglesby MW: Nitric oxide and substance dependence. Neurosci Biobehav Rev, 2001, 25, 43–52.
van Rijnsoever C, Täuber M, Choulli MK, Keist R, Rudolph U, Möhler H, Fritschy JM, Crestani F: Requirement of α5-GABAA receptors for the development of tolerance to the sedative action of diazepam in mice. J Neurosci, 2004, 24, 6785–6790.
Valtschanoff JG, Weinberg RJ, Rustioni A, Schmidt HHHW: Nitric oxide synthase and GABAcolocalize in lamina 2 of rat spinal cord. Neurosci Lett, 1992, 148, 6–10.
Vogel HG, Vogel WH: Psychotropic and neurotropic activity. In: Drug discovery and evaluation. Pharmacological assays. Ed. Vogel HG, Vogel WH, Springer-Verlag, Berlin, Heidelberg, New York, 1997, 204–213.
Wafford KA: GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr Opin Pharmacol, 2005, 5, 47–52.
Wazlawik E, Morato GS: Effect of intracerebroventricular administration of 7-nitroindazole on tolerance to ethanol. Brain Res Bull, 2002, 57, 165–170.
Zarri I, Bucossi G, Cupello A, Rapallino MV, Robello M: Modulation by nitric oxide of rat brain GABAA receptors. Neurosci Lett, 1994, 180, 239–242.
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Talarek, S., Orzelska, J., Listos, J. et al. Effects of sildenafil treatment on the development of tolerance to diazepam-induced motor impairment and sedation in mice. Pharmacol. Rep 62, 627–634 (2010). https://doi.org/10.1016/S1734-1140(10)70320-0
- motor impairment