Sensorimotor gating in neurotensin-1 receptor null mice.
BACKGROUND
Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist PD149163, known to increase PPI in rats.


METHODS
Baseline PPI and acoustic startle response were measured in WT and NT1 KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days.


RESULTS
Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice.


CONCLUSIONS
The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists.
Feifel
D
D
Department of Psychiatry, University of California, San Diego, Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8218, USA. dfeifel@ucsd.edu
Pang
Z
Z
Shilling
P D
PD
Melendez
G
G
Schreiber
R
R
Button
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D
D000161:Acoustic Stimulation / Q000009:adverse effects; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000172:deficiency*; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics*; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics*
D000697:Central Nervous System Stimulants; D007211:Indoles; D018696:Neuroprotective Agents; C103205:PD 149164; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D016291:Dizocilpine Maleate; D000661:Amphetamine; D000218:Adamantane