Involvement of the neurotensin receptor 1 in the behavioral effects of two neurotensin agonists, NT-2 and NT69L: lack of hypothermic, antinociceptive and antipsychotic actions in receptor knockout mice.
Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia and in mediating the efficacy of antipsychotic drugs. NT is also involved in the regulation of body temperature and pain sensitivity. Using neurotensin receptor 1 (NTR1) knockout (KO) and wild-type (WT) mice, these studies evaluated the involvement of NTR1 in the behavioral responses produced by peripheral administration of NT agonists (NT-2 and NT69L). Animals were characterized in paradigms designed to assess hypothermia, antinociception, and antipsychotic-like effects. Under basal conditions, there were no phenotypic differences between NTR1 KO and WT mice. In WT mice, both NTR1 agonists decreased core body temperature (active doses in mg/kg, i.p., for NT-2 and NT69L, respectively: 1 and 3), increased tail withdrawal latencies (1 and 3), produced decreased spontaneous climbing (0.1, 0.3, 1 and 1, 3, 10) and reversed apomorphine-induced climbing (0.3, 1 and 1, 3). In contrast, none of the effects of either agonist were present in KO mice. These results suggest that NTR1: (1) does not play a major role in the control of basal thermoregulation, nociception or psychomotor stimulation in mice (barring possible developmental plasticity), (2) does mediate these behavioral responses to NT agonists, and (3) may play a role in the potential antipsychotic effects of these agonists.
Mechanic
Jordan A
JA
Roche Palo Alto, Neurobehavior, Molecular Biology, and Pharmacology and Cell Sciences, 3431 Hillview Ave., Palo Alto, CA 94304, USA.
Sutton
Janette E
JE
Berson
Amy E
AE
Wu
Xiaosu
X
Kwan
Joyce
J
Schreiber
Rudy
R
Pang
Zhen
Z
Button
Donald C
DC
D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009496:Neurotensin / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D011930:Reaction Time / Q000187:drug effects; D018028:Receptors, Neurotensin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects
D018491:Dopamine Agonists; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D018028:Receptors, Neurotensin; C068951:methyl(arginyl)-lysyl-prolyl-tryptophyl-tert-leucyl-leucine; C407426:neurotensin 69L; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D001058:Apomorphine