Atypical antipsychotics and dopamine D1 receptor agonism: an in vivo experimental study using core temperature measurements in the rat

SUMMARYUltrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

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Dopamine receptor occupancy in vivo: behavioral correlates using NNC-112, NNC-687 and NNC-756, new selective dopamine D1 receptor antagonists

European Journal of Pharmacology ◽

10.1016/0014-2999(92)90577-q ◽

1992 ◽

Vol 219 (1) ◽

pp. 35-44 ◽

Cited By ~ 28

Author(s):

Erik B. Nielsen ◽

Peter H. Andersen

Keyword(s):

Dopamine Receptor ◽

Receptor Occupancy ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

Receptor Antagonists ◽

Behavioral Correlates ◽

Nnc 756 ◽

Selective Dopamine

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Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

10.1101/2020.03.12.989103 ◽

2020 ◽

Author(s):

Jace Jones-Tabah ◽

Hanan Mohammad ◽

Shadi Hadj-Youssef ◽

Lucy Kim ◽

Ryan D. Martin ◽

...

Keyword(s):

Resonance Energy Transfer ◽

Resonance Energy ◽

Dopamine D1 Receptor ◽

D1 Receptor ◽

Striatal Neurons ◽

Dynamic Cell ◽

Cell Type Specific ◽

Fret Biosensors ◽

Optically Detected

AbstractLike many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell-type specific, and can change in response to disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson’s disease (PD), alterations in this pathway lead to activation of extracellular regulated kinases (ERK1/2), contributing to L-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with L-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia.

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