Presynaptic action of neurotensin on dopamine release through inhibition of D(2) receptor function.
BACKGROUND
Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).


RESULTS
DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D2 autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D2 autoreceptors, quinpirole (1 microM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D2 receptor antagonist, sulpiride (5 microM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8-13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D2 autoreceptors. In addition, initial blockade of D2 autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8-13).


CONCLUSIONS
Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D2 autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.
Fawaz
Charbel S
CS
Department of Pharmacology, Groupe de Recherche sur le Système Nerveux Central, Faculty of Medicine, Université de Montréal, Quebec, H3C 3J7, Canada. charbelf@total.net
Martel
Philippe
P
Leo
Damiana
D
Trudeau
Louis-Eric
LE
D000818:Animals; D017660:Autoreceptors / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004558:Electric Stimulation; D004563:Electrochemistry; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D009496:Neurotensin / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D018028:Receptors, Neurotensin / Q000502:physiology; D017661:Receptors, Presynaptic / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D017660:Autoreceptors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; D017661:Receptors, Presynaptic; D019257:Quinpirole; D009496:Neurotensin; D013469:Sulpiride; D004298:Dopamine
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