ABSTRACT
Modafinil was compared to the indirect dopaminergic drugs, dexamphetamine and methylphenidate, using in vivo differential normal pulse voltammetry with carbon fibre electrodes located in the caudate nucleus to study extracellular catechol level in anaesthetized mice. Modafinil (16-256 mg kg-1) failed to modify the catechol oxidation peak height (peak 2). Dexamphetamine at low doses (2 and 4 mg kg-1) decreased, while at a higher dose (8 mg kg-1) did not modify peak 2 height. A low dose of methylphenidate (16 mg kg-1) did not display any effect, while higher doses (32 and 64 mg kg-1) increased peak 2 height. Pargyline-induced monoamine oxidase inhibition elicited a rapid and dramatic decrease in peak 2 height (related to the decrease of catechol levels). In these conditions modafinil (64 and 256 mg kg-1) did not modify, while dexamphetamine (2, 4 and 8 mg kg-1) and methylphenidate (16, 32 and 64 mg kg-1) increased peak 2 height in relation to synaptic dopamine level increase. This study, in mice, demonstrated the lack of effects of modafinil on nigro-striatal function, at the pre-synaptic level, as opposed to dexamphetamine and methylphenidate.
Subject(s)
Benzhydryl Compounds/pharmacology , Central Nervous System Stimulants/pharmacology , Dopamine/physiology , Receptors, Presynaptic/physiology , Anesthesia , Animals , Caudate Nucleus/drug effects , Caudate Nucleus/physiology , Dextroamphetamine/pharmacology , Electrophysiology , Male , Membrane Potentials/drug effects , Methylphenidate/pharmacology , Methyltyrosines/pharmacology , Mice , Modafinil , Monoamine Oxidase Inhibitors/pharmacology , Pargyline/pharmacology , Tyrosine 3-Monooxygenase/antagonists & inhibitors , alpha-MethyltyrosineSubject(s)
Corpus Striatum/physiology , Dopamine/metabolism , Methylphenidate/pharmacology , Monoamine Oxidase Inhibitors , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Male , Pargyline/pharmacology , Rats , Rats, Inbred F344 , Rats, Inbred Strains , Stereotyped Behavior/drug effects , Substantia Nigra/physiologyABSTRACT
The following psychopharmacological effects of adrafinil have been observed in mice: increase in locomotor activity (64-256 mg.kg-1), antagonism (16-128 mg.kg-1) of the hypnotic effects of barbitone but not of pentobarbitone, reduction of immobility duration in the forced swimming test (16-256 mg.kg-1); slight antagonism (256 mg.kg-1) of electroshock-induced convulsions; no modification of rectal temperature; no stereotyped or climbing behaviour; no increase in lethality in aggregated mice (LD50 isolated = 1022 mg.kg-1, LD50 aggregated = 859 mg.kg-1); lack of effects on the provisional tests for antidepressants: no interaction with reserpine-, oxotremorine-, or apomorphine-induced hypothermia but potentiation of yohimbine-induced toxicity; lack of peripheral sympathetic effects (no mydriasis, no salivation, no contraction of the pilomotor muscles, no antagonism of reserpine-induced ptosis); lack of peripheral anticholinergic effects (no mydriasis, no antagonism of oxotremorine-induced salivation or lacrimation). As compared to no analeptic, anticholinergic or antidepressant drugs, adrafinil shows a unique behavioural profile in mice defined on the one hand by a specific stimulant activity associated with antidepressant-like effects that do no seem related to a beta-adrenergic mechanism and on the other hand by a lack of dopaminergic effects. Most adrafinil-induced effects (increase in locomotor activity, reduction of immobility duration in the forced swimming test) may correspond to a central alpha 1-adrenergic stimulation, but the unexpected lack of peripheral sympathetic effects remains unexplained.
