ABSTRACT
BACKGROUND: Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. METHODS: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4min was evaluated. All drugs were given intraperitoneally (ip). RESULTS: Selegiline (10mg/kg) decreased the immobility time in the FST similar to fluoxetine (20mg/kg). Pretreatment with l-arginine (NO precursor, 750mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. CONCLUSIONS: It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.
Subject(s)
Antidepressive Agents/pharmacology , Cyclic GMP/metabolism , Immobility Response, Tonic/drug effects , Nitric Oxide/metabolism , Selegiline/pharmacology , Swimming , Animals , Arginine/pharmacology , Drug Synergism , Fluoxetine/pharmacology , Guanidines/pharmacology , Hippocampus/metabolism , Indazoles/pharmacology , Male , Methylene Blue/pharmacology , Mice , Motor Activity/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Nitrites/metabolism , Prefrontal Cortex/metabolism , Selegiline/antagonists & inhibitors , Signal Transduction/drug effects , Sildenafil Citrate/pharmacologyABSTRACT
1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.
Subject(s)
Dopamine/physiology , Mesencephalon/cytology , Monoamine Oxidase Inhibitors/pharmacology , Neurons/drug effects , Animals , Clorgyline/antagonists & inhibitors , Clorgyline/pharmacology , Dopamine Antagonists/pharmacology , Electrophysiology , Evoked Potentials/drug effects , In Vitro Techniques , Mesencephalon/drug effects , Pargyline/antagonists & inhibitors , Pargyline/pharmacology , Patch-Clamp Techniques , Rats , Rats, Wistar , Selegiline/antagonists & inhibitors , Selegiline/pharmacology , Substantia Nigra/cytology , Substantia Nigra/drug effects , Ventral Tegmental Area/cytology , Ventral Tegmental Area/drug effectsABSTRACT
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 90 mg kg-1 s.c., a dose lethal in non-pretreated mice, was well tolerated in selegiline [-)-deprenyl)-pretreated mice and produced persistent depletion of striatal dopamine and its metabolites one week after the last of four daily injections. The protective effect of selegiline against dopaminergic neurotoxicity of MPTP can thus be overridden by a high dose of MPTP that would be lethal without selegiline pretreatment.
