Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors

Lu, Chen; Zhu, Xiaona; Feng, Yifan; Ao, Weizhen; Li, Jie; Gao, Zilong; Luo, Huoqing; Chen, Ming; Cai, Fang; Zhan, Shulu; Li, Hongxia; Duan, Shumin; Hu, Ji

doi:10.1038/s41380-023-01982-8

Cited by 6 publications

(3 citation statements)

References 102 publications

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“…This view has been challenged recently by the observation that applying in vivo fiber photometry and chemogenetics antipsychotics (i.e., olanzapine and clozapine) may directly bind and work as antagonist GABA A receptors in ventral tegmental area (VTA). As a consequence, GABA neurons are activated, and the GABAergic projection from VTA to the NAc is involved in such antipsychotic effects [ 132 ].…”

Section: Resultsmentioning

confidence: 99%

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Bartolomeis¹,

Ciccarelli²,

Simone³

et al. 2023

IJMS

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Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.

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Section: Resultsmentioning

confidence: 99%

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Bartolomeis¹,

Ciccarelli²,

Simone³

et al. 2023

IJMS

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“…Stereotaxic Viral Injections: Mice were anesthetized with isoflurane and mounted on a stereotaxic instrument (RWD, ShenZhen, China). [33] Each virus solution was slowly injected (30 nL min −1 ) into the PVN either unilaterally (for fiber photometry) or bilaterally (for chemogenetic experiments). The PVN coordinates relative to the bregma were -0.65 mm AP, ±0.25 mm ML, -4.67 mm DV.…”

Section: Methodsmentioning

confidence: 99%

Propofol Alleviates Anxiety‐Like Behaviors Associated with Pain by Inhibiting the Hyperactivity of PVN^CRH Neurons via GABA_A Receptor β3 Subunits

Yu,

Zhu,

Peng

et al. 2024

Advanced Science

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Pain, a comorbidity of anxiety disorders, causes substantial clinical, social, and economic burdens. Emerging evidence suggests that propofol, the most commonly used general anesthetic, may regulate psychological disorders; however, its role in pain‐associated anxiety is not yet described. This study investigates the therapeutic potential of a single dose of propofol (100 mg kg−1) in alleviating pain‐associated anxiety and examines the underlying neural mechanisms. In acute and chronic pain models, propofol decreased anxiety‐like behaviors in the elevated plus maze (EPM) and open field (OF) tests. Propofol also reduced the serum levels of stress‐related hormones including corticosterone, corticotropin‐releasing hormone (CRH), and norepinephrine. Fiber photometry recordings indicated that the calcium signaling activity of CRH neurons in the paraventricular nucleus (PVNCRH) is reduced after propofol treatment. Interestingly, artificially activating PVNCRH neurons through chemogenetics interfered with the anxiety‐reducing effects of propofol. Electrophysiological recordings indicated that propofol decreases the activity of PVNCRH neurons by increasing spontaneous inhibitory postsynaptic currents (sIPSCs). Further, reducing the levels of γ‐aminobutyric acid type A receptor β3 (GABAAβ3) subunits in PVNCRH neurons diminished the anxiety‐relieving effects of propofol. In conclusion, this study provides a mechanistic and preclinical rationale to treat pain‐associated anxiety‐like behaviors using a single dose of propofol.

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“…These systems and directions of signalling overlap with the dopaminergic abnormalities seen in psychosis. There is some evidence that some antipsychotic medications may reduce the severity of psychotic symptoms through blocking GABA A receptors on GABAergic neurons in the VTA ( Lu et al, 2023 ), inhibiting dopaminergic innervation of the NAc, which in turn leads to disinhibition of the ventral pallidum and decreased dopaminergic activity in the midbrain which projects back to the dorsal striatum, overall reducing pathology.…”

Section: Behavioural Manifestations Of Neurochemical Alterationsmentioning

confidence: 99%

Exploring causal mechanisms of psychosis risk

Oliver,

Chesney,

Cullen

et al. 2024

Neuroscience & Biobehavioral Reviews

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Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors

Cited by 6 publications

References 102 publications

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Propofol Alleviates Anxiety‐Like Behaviors Associated with Pain by Inhibiting the Hyperactivity of PVN^CRH Neurons via GABA_A Receptor β3 Subunits

Exploring causal mechanisms of psychosis risk

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Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors

Cited by 6 publications

References 102 publications

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Propofol Alleviates Anxiety‐Like Behaviors Associated with Pain by Inhibiting the Hyperactivity of PVNCRH Neurons via GABAA Receptor β3 Subunits

Exploring causal mechanisms of psychosis risk

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Propofol Alleviates Anxiety‐Like Behaviors Associated with Pain by Inhibiting the Hyperactivity of PVN^CRH Neurons via GABA_A Receptor β3 Subunits