Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity

Citation
P. Hertel et al., Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity, EUR J PHARM, 422(1-3), 2001, pp. 77-81
Citations number
26
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN journal
00142999 → ACNP
Volume
422
Issue
1-3
Year of publication
2001
Pages
77 - 81
Database
ISI
SICI code
0014-2999(20010622)422:1-3<77:IOTTTS>2.0.ZU;2-W
Abstract
Although several studies have indicated that neurotensin administered acute ly has several pharmacological properties common with those of antipsychoti c drugs, the effects of repeated exposure to neurotensin receptor agonism h ave been less well characterised. Here. we investigated the effect of the n ovel neurotensin-(8-13) analogue NT69L [(N-methyl-Arg), Lys, Pro, L-neo-Trp , tert-Leu, Leu] in animal models sensitive to central neurotensin receptor stimulation as well as in predictive models for antipsychotic activity and motor side-effect liability. Acute injection of NT69L (0.19-6.1 mu mol/kg, s.c./i.p.) caused hypothermia (> 2.5 degreesC) and reduction in spontaneou s locomotor activity but failed to induce catalepsy. Furthermore, NT69L (0. 10 mu mol/kg, s.c.) counteracted the hyperlocomotion elicited by amphetamin e (0.5 mg/kg, s.c.). However, repeated injections of NT69L (0.19 mu mol/kg, s.c. for 6 days, twice daily) significantly reduced its effect on spontane ous locomotor activity and completely abolished its effect on amphetamine-e licited hyperactivity. Our data obtained after single injections of NT69L i ndicate that this drug stimulates central neurotensin receptors after perip heral administration and collectively support the notion that neurotensin r eceptor agonism is associated with an attractive pre-clinical profile as re gards both antipsychotic activity and motor side-effect liability. However, the present results also indicate that repeated neurotensin receptor stimu lation may cause a desensitisation of neurotensin receptor mediated effects . (C) 2001 Elsevier Science B.V. All rights reserved.