New therapeutic strategies targeting D1-type dopamine receptors for neuropsychiatric disease

Abstract

The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson's disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.

Keywords: D1DR; cognition; dopamine D1 receptor; dyskinesia.

Figure 1

Schematic diagram shows projections of midbrain dopaminergic projections (ventral tegmental area or substantia nigra) to the frontal cortex and striatum and intracellular signaling pathway in a D1 receptor synapse. Midbrain dopaminergic neurons (red) project to both glutamatergic pyramidal neurons (purple) and GABAergic interneurons (gray) in prefrontal cortex. Some midbrain dopaminergic neurons project to medium spiny neurons in the striatum that express either D1 dopamine receptors (blue) or D2 dopamine receptors (green). Dopamine synthesis in dopaminergic neurons requires two key proteins, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC), which are target molecules for dopaminergic degenerating diseases (PD). D1DRs in post-synaptic neurons are coupled with G-proteins. Activation of D1DRs stimulates adenylate cyclase (AC) which results in increased cAMP levels. Increasing PKA activity with cAMP changes subsequently induces phosphorylation of DARPP-32.