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
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.