Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice.
Drugs that facilitate dopaminergic neurotransmission induce cognitive and attentional deficits which include inability to filter sensory input measured by prepulse inhibition (PPI). Methylphenidate, an amphetamine analog is used in the treatment of attention deficit hyperactivity disorder. Given that nitric oxide (NO) modulates dopamine effect our aim is to analyze the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) inhibitors effect on PPI disruption induced by methylphenidate. The inhibitors effects were compared to those produced by haloperidol and clozapine. Male Swiss mice received a first i.p. injection (one hour before testing), of either saline, or N(G) nitro l-arginine (10, 40 or 90 mg/kg), or 7-Nitroindazole (3, 10, 30 or 60 mg/kg), or oxadiazolo-quinoxalin (5 or 10 mg/kg), or haloperidol (1 mg/kg), or clozapine (5 mg/kg). Thirty min later mice received the second injection of either saline or methylphenidate (20 or 30 mg/kg) or amphetamine (5 or 10 mg/kg). One group of mice received intracerebroventricular 7-Nitroindazole (50 or 100 nM) followed by systemic administration of saline or methylphenidate (30 mg/kg). The results revealed a methylphenidate dose-dependent disruption of PPI comparable to amphetamine. The effect was prevented by either nitric oxide synthase or guanilate cyclase inhibitors or clozapine or haloperidol. In conclusion, methylphenidate induced a dose-dependent PPI disruption in Swiss mice modulated by dopamine and NO/sGC. The results corroborate the hypothesis of dopamine and NO interacting to modulate sensorimotor gating through central nervous system. It may be useful to understand methylphenidate and other psychostimulants effects.
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Department of Pharmacology, FMRP, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, Brazil.
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D000818:Animals; D001307:Auditory Perception / Q000187:drug effects* / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D007191:Indazoles; D010069:Oxadiazoles; D011810:Quinoxalines; D008774:Methylphenidate; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D003024:Clozapine; D006220:Haloperidol; C080122:7-nitroindazole