Rapid desensitization of dopamine release induced by neurotensin and neurotensin fragments.
Neurotensin (NT), a tridecapeptide, induced a concentration-dependent release of dopamine (DA) from the striatum. In addition, NT8-13 and Nacetyl-NT8-13, the carboxy-terminal-containing hexapeptides, were much more effective as DA releasers than the amino-terminal, NT1-6 peptide. The potency and efficacy of NT in inducing DA release was markedly enhanced by increases in the extracellular concentration of potassium (K+). Similar to electrical stimulation and to elevated extracellular K+, NT-induced DA release was inhibited by 70% in the presence of 0.13 mM calcium. Desensitization to NT was observed after a first exposure to NT for 2.5 to 10 min, despite a 20- to 85-min washout period between exposures, with NT-free medium. The loss of response was not due to degradation or inactivation of the peptide, nor it was due to activation of DA autoreceptors or the DA transporter. NT-induced desensitization was not associated to a loss of responsiveness to DA release elicited by electrical stimulation or by high K+. In addition, desensitization occurred even if NT-induced DA release was markedly enhanced by high extracellular K+ (10 and 15 mM). Inhibition of NT-induced DA release by low calcium (on the first exposure) did not prevent the development of desensitization. Similar to the parent peptide, desensitization was observed with the active carboxy-terminal NT fragments. However, a first exposure to NT1-6 did not induce desensitization to NT8-13. These results are compatible with the view that NT-induced DA release and the development of desensitization are mediated through an action of NT on NT receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Faggin
B M
BM
University of North Carolina, Chapel Hill, Division of Clinical Pharmacology, School of Medicine 27514.
Cubeddu
L X
LX
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D046508:Culture Techniques; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D008297:Male; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014316:Tritium
D010446:Peptide Fragments; D014316:Tritium; D009496:Neurotensin; C054381:neurotensin (8-13); C058296:neurotensin (1-6); D011188:Potassium; D002118:Calcium; D004298:Dopamine