Compositions and Methods For Modulating Dopamine Nerutransmission

Abstract

The present invention provides for diagnosis or treatment of neurological or neuropsyciatric 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.

Description

FIELD OF INVENTION[0001]The present invention relates to compositions and methods for diagnosis or treatment of diseases or disorders involving abnormal dopamine neurotransmission. More particularly, the present invention relates to modulating dopamine transporter activity.BACKGROUND OF THE INVENTION[0002]The monoamine neurotransmitter dopamine (DA) plays a major role in regulating motor behavior, learning, reward and emotion (1, 2). Many neurological / neuropsychiatric disorders implicate a hyper-dopaminergic state in the etiology and / or maintenance of the disease (2-5). For example, U.S. Publication 2005 / 0048042 describes modulation of dopamine levels in the treatment of schizophrenia and addictive disorders. Recent SPECT and PET studies have confirmed an abnormally heightened level of synaptic dopamine in schizophrenia (6, 7).[0003]Regulation of synaptic dopamine (DA) levels is predominantly regulated through active re-uptake by the dopamine transporter (DAT). Although previous stu...

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Benefits of technology

[0118]Previous studies have shown the DAT knock-out mice display significant spontaneous hyperlocomotion, reproduce several features of the amphetamine animal model of schizophrenia, are hyperactive, stereotypic, and show significant deficits in sensimotor gating and spatial cognitive function (26-29).

[0119]Since an impaired D2-DAT interaction would be expected to lead to decreased DAT mediated DA, which in turn would be expected to potentiate locomotor activity, mice treated with TAT-DAT[NT1-1] peptides (SEQ ID NO:12) to interfere with the D2-DAT interaction were examined for locomotor activity. One consequence of elevated dopaminergic transmission is behavioral activation (26-28).

[0120]Previous studies have shown that systemically injected TAT peptide penetrates the blood-brain barrier 1 hour after IP injection (21, 30). In the present work, injection of purified TAT-DAT[NT1-1] (SEQ ID NO:12) (3 mM/g, 0.3 mL, IP), but not the TAT-DAT[NT1-2] peptide (SEQ ID NO:13), significantly blocked the D2-DAT protein-protein interaction as illustrated in the co-immunoprecipitation results (data not shown). Consistent with the finding that TAT-DAT[NT1-1] (SEQ ID NO: 12) abolished the enhancement of DAT uptake induced by the co-expression of D2 receptors (FIG. 2E), TAT-DAT[NT1-1] (SEQ ID NO: 12) increased distance traveled and rearing (P<0.01) compared to treatment with TAT peptide (SEQ ID NO:14) or TATDAT[NT1-2] (SEQ ID NO:13) (FIG. 4C-F). The observed increase in distance traveled and rearing is reminiscent of the DAT knockout mice (26).

[0121]DA receptors exert their physiological functions upon agonist stimulation and thus the modulation of DAT uptake by activation of D2 was tested.

Problems solved by technology

However, in recent years, traditional concepts have been challenged with the identification of direct protein-protein interactions between two structurally and functionally distinct receptor families (12, 13).

However, neither of these patent documents disclose a practical means for modulating dopamine activity.

However, none of the described compounds are shown to be selective for dop

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