NT79: A novel neurotensin analog with selective behavioral effects.
Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79, which exhibits selective behavioral effects. NT79 was tested in animal models for pain (thermal-hot plate test; visceral-acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphine-induced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79. Binding data at molecularly cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED(50) of 0.14 microg/kg while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, d-amphetamine-induced hyperactivity, and reducing d-amphetamine- and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.
Boules
Mona
M
Neuropsychopharmacology Laboratory, Mayo Clinic Florida, Jacksonville, FL 32224, USA. boules.mona@mayo.edu
Liang
Yanqi
Y
Briody
Siobhan
S
Miura
Tomofumi
T
Fauq
Irfan
I
Oliveros
Alfredo
A
Wilson
Mina
M
Khaniyev
Shaheen
S
Williams
Katrina
K
Li
Zhimin
Z
Qi
Yanfei
Y
Katovich
Michael
M
Richelson
Elliott
E
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000161:Acoustic Stimulation; D000698:Analgesia; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055139:Sensory Gating / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism
D010446:Peptide Fragments; C547346:neurotensin NT79; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D009496:Neurotensin; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid