Compositions and methods for modulating dopamine neurotransmission

Abstract

The present invention provides for diagnosis or treatment of neurological or neuropsychiatric disorders involving abnormal dopamine neurotransmission. Methods and agents are provided for modulating dopamine transporter activity and modulating dopaminergic neurotransmission. Agents of the present invention include fragments of D2 receptor or dopamine transporter (DAT) that can disrupt D2-DAT coupling.

What is claimed is: 
     
         1 . An isolated polypeptide of between 34 and 110 amino acids in length comprising SEQ ID NO:1. 
     
     
         2 . The isolated polypeptide of  claim 1  having the ability to disrupt D2-DAT coupling in a mammal. 
     
     
         3 . The isolated polypeptide of  claim 1 , comprising SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         4 . The isolated polypeptide of  claim 1 , which is fused to a protein transduction domain. 
     
     
         5 . The isolated polypeptide of  claim 6 , wherein the protein transduction domain is SEQ ID NO:14. 
     
     
         6 . A method for increasing dopaminergic neurotransmission in a mammal in need of such treatment comprising administering a therapeutically effective amount of the isolated polypeptide according to  claim 1 . 
     
     
         7 . A method for increasing dopaminergic neurotransmission in a mammal in need of such treatment comprising administering a therapeutically effective amount of an isolated polypeptide according to  claim 1 , wherein the isolated polypeptide disrupts dopamine D2 receptor-dopamine transporter (D2-DAT) coupling in the mammal. 
     
     
         8 . The method of  claim 7 , wherein the agent is administered for treating a disease selected from the group consisting of psychostimulant addiction including cocaine addiction or amphetamine addiction, depression, obesity, ADHD, narcolepsy and Parkinson's disease. 
     
     
         9 . The method of  claim 7 , wherein the agent is administered to localize DAT at the cell surface. 
     
     
         10 . The method of  claim 9 , wherein the agent is administered for treating a disease selected from the group consisting of schizophrenia, and Tourette's syndrome. 
     
     
         11 . The method of  claim 9 , wherein cell surface localization of DAT is determined by quantifying dopamine uptake. 
     
     
         12 . The method of  claim 9 , wherein cell surface localization of DAT is determined by immunolabeling with an antibody specific for DAT. 
     
     
         13 . The method of  claim 9 , wherein cell surface localization of DAT is determined by coimmunoprecipitation of DAT with an antibody specific for D2 receptor. 
     
     
         14 . The method of  claim 9 , wherein cell surface localization of DAT is determined by affinity precipitation of DAT with a D2 receptor. 
     
     
         15 . The method of  claim 9 , wherein cell surface localization of DAT is determined by quantifying DAT ligand binding. 
     
     
         16 . The isolated polypeptide of  claim 1  defined by SEQ ID NO:1. 
     
     
         17 . The isolated polypeptide of  claim 1  defined by SEQ ID NO:3 or SEQ ID NO:4.