The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia.
Trace amines have been implicated in a number of neuropsychiatric disorders including depression and schizophrenia. Although long known to modulate neurotransmission indirectly through the release of catecholamines, the identification of the Trace Amine 1 receptor (TA1) offers a mechanism by which trace amines can influence synaptic activity directly. TA1 binds and is activated by trace amines such as beta-phenylethylamine and tyramine. Our pharmacological characterization of mouse TA1 showed that, as in rat and primate, amphetamine is an agonist at this receptor but with surprisingly high potency. Without selective ligands for TA1 that do not also possess catecholamine-releasing properties, however, it has not been possible to study its physiological role in the central nervous system. To that end, a line of mice lacking the TA1 receptor was generated to characterize its contribution to the regulation of behavior. Compared with wild-type littermates, TA1 knockout (KO) mice displayed a deficit in prepulse inhibition. Knockout animals, in which the TA1-agonist influence of amphetamine was absent, showed enhanced sensitivity to the psychomotor-stimulating effect of this drug, which was temporally correlated with significantly larger increases in the release of both dopamine and norepinephrine in the dorsal striatum and associated with a 262% increase in the proportion of striatal high-affinity D2 receptors. TA1 therefore appears to play a modulatory role in catecholaminergic function and represents a potentially novel mechanism for the treatment of neuropsychiatric disorders. Furthermore, the TA1 KO mouse may provide a useful model for the development of treatments for some positive symptoms of schizophrenia.
Wolinsky
T D
TD
Neuroscience, Lundbeck Research USA, Inc., Paramus, NJ 07652, USA. TDW@Lundbeck.com
Swanson
C J
CJ
Smith
K E
KE
Zhong
H
H
Borowsky
B
B
Seeman
P
P
Branchek
T
T
Gerald
C P
CP
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D021641:Recognition, Psychology / Q000502:physiology; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D000095383:Trace Amine-Associated Receptors
D000661:Amphetamine; D002395:Catecholamines; D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors