scholarly journals PDE10A Inhibitors—Clinical Failure or Window Into Antipsychotic Drug Action?

2021 ◽  
Vol 14 ◽  
Author(s):  
Frank S. Menniti ◽  
Thomas A. Chappie ◽  
Christopher J. Schmidt
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Standard Of Care ◽  
Medium Spiny Neurons ◽  
Indirect Pathway ◽  
Dopamine D2 ◽  
Spiny Neurons ◽  
Antipsychotic Efficacy ◽  
Antipsychotic Activity ◽  
D2 Antagonists

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

scholarly journals Restoration of KCC2 Membrane Localization in Striatal Dopamine D2 Receptor-Expressing Medium Spiny Neurons Rescues Locomotor Deficits in HIV Tat-Transgenic Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110220
Author(s):  
Aaron J. Barbour ◽  
Sara R. Nass ◽  
Yun K. Hahn ◽  
Kurt F. Hauser ◽  
Pamela E. Knapp
Keyword(s):  
Transgenic Mice ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Brain Regions ◽  
D1 Receptor ◽  
Membrane Localization ◽  
Hippocampal Damage ◽  
Medium Spiny Neurons ◽  
Dopamine D2 ◽  
Spiny Neurons

People infected with HIV (PWH) are highly susceptible to striatal and hippocampal damage. Motor and memory impairments are common among these patients, likely as behavioral manifestations of damage to these brain regions. GABAergic dysfunction from HIV infection and viral proteins such as transactivator of transcription (Tat) have been well documented. We recently demonstrated that the neuron specific Cl− extruder, K+ Cl− cotransporter 2 (KCC2), is diminished after exposure to HIV proteins, including Tat, resulting in disrupted GABAAR-mediated hyperpolarization and inhibition. Here, we utilized doxycycline (DOX)-inducible, GFAP-driven HIV-1 Tat transgenic mice to further explore this phenomenon. After two weeks of Tat expression, we found no changes in hippocampal KCC2 levels, but a significant decrease in the striatum that was associated with hyperlocomotion in the open field assay. We were able to restore KCC2 activity and baseline locomotion with the KCC2 enhancer, CLP290. Additionally, we found that CLP290, whose mechanism of action has yet to be described, acts to restore phosphorylation of serine 940 resulting in increased KCC2 membrane localization. We also examined neuronal subpopulation contributions to the noted effects and found significant differences. Dopamine D2 receptor-expressing medium spiny neurons (MSNs) were selectively vulnerable to Tat-induced KCC2 loss, with no changes observed in dopamine D1 receptor-expressing MSNs. These results suggest that disinhibition/diminished hyperpolarization of dopamine D2 receptor-expressing MSNs can manifest as increased locomotion in this context. They further suggest that KCC2 activity might be a therapeutic target to alleviate motor disturbances related to HIV.

scholarly journals Effect of Zishenpingchan Granule on Neurobehavioral Manifestations and the Activity and Gene Expression of Striatal Dopamine D1 and D2 Receptors of Rats with Levodopa-Induced Dyskinesias

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Qing Ye ◽  
Xiao-Lei Yuan ◽  
Jie Zhou ◽  
Can-xing Yuan ◽  
Xu-ming Yang
Keyword(s):  
Gene Expression ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
D2 Receptors ◽  
Striatal Dopamine ◽  
Control Group ◽  
Indirect Pathway ◽  
Dopamine D2 ◽  
D1 And D2 Receptors ◽  
Neurobehavioral Manifestations

This study was performed to observe the effects of Zishenpingchan granule on neurobehavioral manifestations and the activity and gene expression of striatal dopamine D1 and D2 receptors of rats with levodopa-induced dyskinesias (LID). We established normal control group, LID model group, and TCM intervention group. Each group received treatment for 4 weeks. Artificial neural network (ANN) was applied to excavate the main factor influencing variation in neurobehavioral manifestations of rats with LID. The results showed that overactivation in direct pathway mediated by dopamine D1 receptor and overinhibition in indirect pathway mediated by dopamine D2 receptor may be the main mechanism of LID. TCM increased the efficacy time of LD to ameliorate LID symptoms effectively mainly by upregulating dopamine D2 receptor gene expression.

scholarly journals α4-containing GABAA receptors on dopamine D2 receptor-expressing neurons mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine

2016 ◽  
Author(s):  
Tom Macpherson ◽  
Claire I Dixon ◽  
Patricia H. Janak ◽  
Delia Belelli ◽  
Jeremy J. Lambert ◽  
...  
Keyword(s):  
Drugs Of Abuse ◽  
Dopamine D2 Receptor ◽  
Conditioned Reinforcer ◽  
D2 Receptor ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Conditioned Reinforcers ◽  
Behavioural Responses ◽  
Dopamine D2 ◽  
Specific Deletion

Abstract:Extrasynaptic GABAA receptors (GABAARs) composed of α4, β and δ subunits mediate GABAergic tonic inhibition and are pertinent molecular targets in the modulation of behavioural responses to drugs of abuse, including ethanol and cocaine. These GABAARs are highly expressed within the nucleus accumbens (NAc) where they influence the excitability of the medium spiny neurons (MSNs). Here we explore their role in modulating behavioural responses to reward-conditioned cues and the behaviour-potentiating effects of cocaine. α4-subunit constitutive knockout mice (α4-/-) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen following viral knockdown of GABAAR α4 subunits within the NAc. Local infusion of the δ-GABAAR-preferring agonist, THIP, into the NAc had no effect on responding when given alone, but reduced cocaine potentiation of responding for conditioned reinforcers in wildtype but not α4-/- mice. Finally, specific deletion of α4-subunits from dopamine D2-, but not D1-receptor-expressing neurons, mimicked the phenotype of the constitutive knockout, potentiating CRf responding and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that α4-GABAAR mediated inhibition of dopamine D2 receptor-expressing neurons reduces instrumental-responding for a conditioned reinforcer, and its potentiation by cocaine, and emphasise the potential importance of GABAergic signalling within the NAc in mediating cocaine’s effects.

scholarly journals Morphine differentially alters the synaptic and intrinsic properties of D1R- and D2R-expressing medium spiny neurons in the nucleus accumbens

2019 ◽  
Author(s):  
Dillon S. McDevitt ◽  
Benjamin Jonik ◽  
Nicholas M. Graziane
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Nucleus Accumbens Shell ◽  
Membrane Excitability ◽  
Action Potential Firing ◽  
Spiny Neurons ◽  
Functional Output

AbstractExposure to opioids reshapes future reward and motivated behaviors partially by altering the functional output of medium spiny neurons (MSNs) in the nucleus accumbens shell. Here, we investigated how morphine, a highly addictive opioid, alters synaptic transmission and intrinsic excitability on dopamine D1-receptor (D1R) expressing and dopamine D2-receptor (D2R) expressing MSNs, the two main output neurons in the nucleus accumbens shell. Using whole-cell electrophysiology recordings, we show, that 24 h abstinence following repeated non-contingent administration of morphine (10 mg/kg, i.p.) in mice reduces miniature excitatory postsynaptic current (mEPSC) frequency and miniature inhibitory postsynaptic current (mIPSC) frequency on D2R-MSNs, with concomitant increases in D2R-MSN intrinsic membrane excitability. We did not observe any changes on synaptic or intrinsic changes on D1R-MSNs. Lastly, in an attempt to determine the integrated effect of the synaptic and intrinsic alterations on the overall functional output of D2R-MSNs, we measured the input-output efficacy by measuring synaptically-driven action potential firing. We found that both D1R-MSN and D2R-MSN output was unchanged following morphine treatment.

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