A role for presynaptic mechanisms in the actions of nomifensine and haloperidol

Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in...

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Bibliographic Details
Published in:Neuroscience 2003-05, Vol.118 (3), p.819-829
Main Authors: GARRIS, P. A, BUDYGIN, E. A, PHILLIPS, P. E. M, VENTON, B. J, ROBINSON, D. L, BERGSTROM, B. P, REBEC, G. V, WIGHTMAN, R. M
Format: Article
Language:English
Subjects:
Animals
Autoreceptors - drug effects
Autoreceptors - metabolism
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Brain - physiopathology
Catalepsy - chemically induced
Catalepsy - metabolism
Catalepsy - physiopathology
Dopamine - metabolism
Dopamine Antagonists - pharmacology
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors - pharmacology
Haloperidol - pharmacology
Hyperkinesis - chemically induced
Hyperkinesis - metabolism
Hyperkinesis - physiopathology
Male
Medical sciences
Membrane Glycoproteins
Membrane Transport Proteins - drug effects
Membrane Transport Proteins - metabolism
Nerve Tissue Proteins
Neuropharmacology
nomifensine
Nomifensine - pharmacology
Pharmacology. Drug treatments
Presynaptic Terminals - drug effects
Presynaptic Terminals - metabolism
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Rats
Rats, Sprague-Dawley
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
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Summary:Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA](max)) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA](max) and motor activation following nomifensine (r=0.99) and a negative correlation was found between [DA](max) and catalepsy following haloperidol (r=-0.96) in the second experiment. Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.
ISSN:0306-4522
1873-7544
DOI:10.1016/s0306-4522(03)00005-8