Duke University

Martin Beaulieu

Marc G Caron

Raul R Gainetdinov

Tatiana D Sotnikova

Xiaodong Zhang

Ranga R Krishnan

Sébastien Marion

David A Schwartz

Tatyana D Sotnikova

Redford B Williams

Lauranell Burch

Raul R Gainetdinova

Recombinant or transgenic non-human mammals are described having a mutant tryptophan hydroxylase 2 (Tph2) gene resulting in altered synthesis of 5-hydroxytryptophan and serotonin in the brain. In some embodiments the mutant tryptophan hydroxylase 2 gene contains mouse R439H and/or P447R functional mutations, or their corresponding mutations in other species. Congenic non-human mammals having mutant tryptophan hydroxylase 2 genes are also provided. Methods of screening a compound for serotonergic activity or activity in treating a serotonergic neurotransmission dysregulation disorder are provided, which include administering a test compound to a recombinant non-human mammal and then detecting the presence or absence of serotonergic activity, or activity in treating a serotonergic neurotransmission dysregulation disorder, in the mammal. A cell such as a nerve cell (e.g., a central nervous system neuron) isolated from a transgenic or congenic mammal is also disclosed, along with cell cultures containing these cells.

Transgenic mice carrying functional single nucleotide polymorphisms in brain-specific tryptophan hydroxylase

A method of screening a candidate compound for &#x3b2;Arrestin mediated anti-G protein coupled receptor signaling activity is comprises: (a) contacting said candidate compound to a &#x3b2;Arrestin signaling complex or a constituent thereof, under conditions in which a signaling complex is formed; and then (b) detecting the presence or absence of disruption of said signaling complex, disruption of said complex indicating said compound has &#x3b2;Arrestin mediated anti-G protein coupled receptor signaling activity. Compositions and kits for carrying out the method are also described.

Methods for identifying compounds that regulate beta-arrestin signaling complexes

Methods for identifying compounds that regulate &#x3b2;-Arrestin signaling complexes

A method of screening a subject for a serotonergic neurotransmission dysregulation disorder comprises detecting the presence or absence of an Tph2 mutation in the subject; and then determining that the subject is at increased risk of a serotonergic neurotransmission dysregulation disorder due to the presence or absence of the Tph2 mutation.

Polymorphism in tryptophan hydroxylase-2 controls brain serotonin synthesis

A method of treating a subject for a serotonergic neurotransmission dysregulation disorder, comprises administering the subject a serotonin enhancer (e.g., a serotonin reuptake inhibitor) in an amount effective to treat the disorder; and concurrently administering the subject 5-hydroxytryptophan in an amount effective to enhance the activity of the serotonin enahancer, (e.g., serotonin reuptake inhibitor). In preferred embodiments the disorder is depression, anxiety, or substance abuse.

Method for augmenting the effects of serotonin reuptake inhibitors

Growing community of inventors

Durham, NC, United States of America

Martin Beaulieu