Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders

ABSTRACT

Introduction: Alterations in dopamine neurotransmission has been implicated in pathophysiology of neuropsychiatric and neurodegenerative disorders, and DARPP-32 plays a pivotal role in dopamine neurotransmission. DARPP-32 likely influences dopamine-mediated behaviors in animal models of neuropsychiatric and neurodegenerative disorders and therapeutic effects of pharmacological treatment.

Areas covered: We will review animal studies on the biochemical and behavioral roles of DARPP-32 in drug addiction, schizophrenia and Parkinson’s disease. In general, under physiological and pathophysiological conditions, DARPP-32 in D1 receptor expressing (D1R) -medium spiny neurons (MSNs) promotes dopamine/D1 receptor/PKA signaling, whereas DARPP-32 in D2 receptor expressing (D2R)-MSNs counteracts dopamine/D2 receptor signaling. However, the function of DARPP-32 is differentially regulated in acute and chronic phases of drug addiction; DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase through homeostatic mechanisms. Therefore, DARPP-32 plays a bidirectional role in dopamine neurotransmission, depending on the cell type and experimental conditions, and is involved in dopamine-related behavioral abnormalities.

Expert opinion: DARPP-32 differentially regulates dopamine signaling in D1R- and D2R-MSNs, and a shift of balance between D1R- and D2R-MSN function is associated with behavioral abnormalities. An adjustment of this imbalance is achieved by therapeutic approaches targeting DARPP-32-related signaling molecules.

KEYWORDS:

• DARPP-32
• dopamine
• drug addiction
• D1 receptor
• D2 receptor

Article highlights

• In neuropsychiatric and neurodegenerative disorders such as drug addiction, schizophrenia and Parkinson’s disease, dopamine dysregulation induces a shift of balance between the function of D1R- and D2R-MSNs in the striatum and NAc. DARPP-32 contributes to the dysregulation of dopamine.

• DARPP-32 (P-Thr34 DARPP-32) in D1R-MSNs promotes dopamine/D1 receptor/PKA signaling, which is associated with the rewarding and reinforcing effects of psychostimulants and L-DOPA-induced dyskinesia in animal models of Parkinson’s disease.

• DARPP-32 (P-Thr34 DARPP-32) in D2R-MSNs counteracts dopamine/D2 receptor signaling, which is associated with the effects of antipsychotics.

• In drug addiction, DARPP-32 enhances D1 receptor/PKA signaling in the acute phase, whereas DARPP-32 suppresses D1 receptor/PKA signaling in the chronic phase.

• An adjustment of imbalance between D1R- and D2R-MSN function can be achieved by therapeutic approaches targeting dopamine- and DARPP-32-related signaling molecules. However, cell type-specific approach needs to be developed.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.