Phosphodiesterase acitvity and regulation of phosphodiesterase 1-B-mediated signaling in brain

A method of identifying a compound that modulates PDE1B activity in a dopamine D1 receptor intracellular signaling pathway in a cell or tissue comprising:

• (a) determining a first level of PDE1B activity in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of PDE1B activity in said cell or tissue,
• wherein a difference in said first level and said second level of PDE1B activity is indicative of the ability of said test compound to modulate PDE1B activity.

A method of identifying a compound that modulates activity of a dopamine D1 receptor intracellular signaling pathway in a cell or tissue comprising:

• (a) determining a first level of activity of PDE1B in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of activity of PDE1B in said cell or tissue,
• wherein a difference in said first level and said second level of PDE1B activity is indicative of the ability of said test compound to modulate activity of said pathway.

A method of identifying a compound that modulates activity of a dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate, GABA, acetylcholine, adenosine, cannabinoid receptor, natriuretic peptide or endorphin intracellular signaling pathway in a cell or tissue comprising:

• (a) determining a first level of activity of PDE1B in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of activity of PDE1B in said cell or tissue,
• wherein a difference in said first level and said second level of PDE1B activity is indicative of the ability of said test compound to modulate activity of said pathway.

A method of identifying a compound that modulates activity of a dopamine D1 receptor intracellular signaling pathway in a cell or tissue comprising:

• (a) contacting said cell or tissue with a test compound;
• and
• (b) determining a level of activity of PDE1B in said cell or tissue;
• wherein a difference in said level and a control level of PDE1B activity in a comparable cell or tissue not contacted with the test compound is indicative of the ability of said test compound to modulate activity of said pathway.

A method of identifying a compound that modulates PDE1B activity in a dopamine D1 receptor intracellular signaling pathway in a cell or, tissue comprising:

• (a) contacting said cell or tissue with a test compound;
• and
• (b) determining a level of PDE1B activity in said cell or tissue;
• wherein a difference in said level and a control level of PDE1B activity in a comparable cell or tissue not contacted with the test compound is indicative of the ability of said test compound to modulate PDE1B activity.

A method for identifying an agent to be tested for an ability to treat a PDE1B-related or dopamine D1-receptor intracellular signaling pathway disorder in a patient in need of such treatment comprising:

• (a) contacting in a cell or tissue PDE1B and Thr34-dephosphorylated DARPP-32 with a potential agent;
• and
• (b) detecting the amount of phosphorylation of Thr34-dephosphorylated DARPP-32,
• wherein the agent is identified if an increase in the phosphorylation of Thr34-dephosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a PDE1B-related or dopamine D1 receptor intracellular signaling pathway disorder in a patient in need of such treatment comprising:

• (a) contacting in a cell or tissue PDE1B and Ser845-dephosphorylated GluR1 AMPA receptor with a potential agent;
• and
• (b) detecting the amount of phosphorylation of Ser845-dephosphorylated GluR1 AMPA receptor,
• wherein the agent is identified if an increase in the phosphorylation of Ser845-dephosphorylated GluR1 AMPA receptor is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to modulate activity of a dopamine D1 receptor intracellular signaling pathway in a cell or tissue comprising:

• (a) determining a first level of PDE1B activity in said cell or tissue;
• (b) contacting said cell or tissue with a potential agent;
• and
• (c) determining a second level of PDE1B activity in said cell or tissue,
• wherein a difference in said first level and said second level of PDE1B activity is indicative of the ability of said potential agent to modulate activity of the dopamine D1 receptor intracellular signaling pathway.

A method for identifying an agent to be tested for an ability to modulate activity of a dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate, GABA, acetylcholine, adenosine, cannabinoid receptor, natriuretic peptide or endorphin intracellular signaling pathway intracellular signaling pathway in a cell or tissue comprising:

• (a) determining a first level of PDE1B activity in said cell or tissue;
• (b) contacting said cell or tissue with a potential agent;
• and
• (c) determining a second level of PDE1B activity in said cell or tissue,
• wherein a difference in said first level and said second level of PDE1B activity is indicative of the ability of said potential agent to modulate activity of said intracellular signaling pathway.

A method for identifying an agent to be tested for an ability to modulate activity of a dopamine D1 receptor intracellular signaling pathway in a cell or tissue comprising:

• (a) contacting said cell or tissue with a potential agent;
• and
• (b) determining a level of PDE1B activity in said cell or tissue;
• wherein a difference in said level and a control level of PDE1B activity in a comparable cell or tissue not contacted with the test compound is indicative of the ability of said test compound to modulate activity of the dopamine D1 receptor intracellular signaling pathway.

A method for identifying an agent to be tested for an ability to modulate activity of a dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate, GABA, acetylcholine, adenosine, cannabinoid receptor, natriuretic peptide or endorphin intracellular signaling pathway intracellular signaling pathway in a cell or tissue comprising:

• (a) contacting said cell or tissue with a potential agent;
• and
• (b) determining a level of PDE1B activity in said cell or tissue,
• wherein a difference in said level and a control level of PDE1B activity in a comparable cell or tissue not contacted with the test compound is indicative of the ability of said test compound to modulate activity of said intracellular signaling pathway.

A method for selecting a potential therapeutic agent for use in the treatment of a PDE1B-related or dopamine D1 receptor intracellular signaling pathway disorder, comprising:

• (a) administering a potential therapeutic agent to an animal;
• (b) measuring the response of said animal to said potential therapeutic agent;
• (c) comparing the response of said animal with that of a control animal to which the potential therapeutic agent has not been administered;
• and
• (d) selecting a potential therapeutic agent based on the difference in responses observed between said animal and said control animal.

A method for selecting a potential therapeutic agent for use in the treatment of a PDE1B-related or dopamine D1 receptor intracellular signaling pathway disorder, comprising:

• (a) administering a potential therapeutic agent to an animal;
• (b) measuring the response of said animal to administration of a neurotransmitter that interacts with a dopamine D1 receptor intracellular signaling pathway;
• (c) comparing the response of said animal with that of a control animal to which the potential therapeutic agent has not been administered;
• and
• (d) selecting a potential therapeutic agent based on the difference in responses observed between said animal and said control animal.

A method for selecting a potential therapeutic agent for use in the treatment of a PDE1B-related or dopamine D1 receptor intracellular signaling pathway disorder, comprising:

• (a) administering a potential therapeutic agent to an animal;
• (b) measuring the response of said animal to dopamine administration;
• (c) comparing the response to dopamine administration of said animal with that of a control animal to which the potential therapeutic agent has not been administered;
• and
• (d) selecting a potential therapeutic agent based on the difference in responses observed between said animal and said control animal.

A method for selecting a potential therapeutic agent for use in the treatment of a PDE1B-related or dopamine D1 receptor intracellular signaling pathway disorder, comprising:

• (a) administering a potential therapeutic agent to an animal;
• (b) measuring the response of said animal, wherein the response is selected from the group consisting of:
• (i) exhibition of exploratory behavior during a test period for horizontal locomotor activity;
• (ii) exhibition of hyperactivity after administration of methamphetamine treatment;
• (iii) path length in acquisition of a Morris water maze;
• (iv) change in level of phospho-Thr34 or phospho-Ser845 in striatal slices from said animal;
• and
• (v) change in level of phospho-Thr34 or phospho-Ser845 in nucleus accumbens slices from said animal,
• (c) comparing the response of said animal with that of a control animal to which the potential therapeutic agent has not been administered;
• and
• (d) selecting a potential therapeutic agent based on the difference in responses observed between said animal and said control animal.