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18 results on '"Vickstrom, Casey R."'

8. Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.

Author

Xiaojie Liu, Vickstrom, Casey R., Hao Yu, Shuai Liu, Snarrenberg, Shana Terai, Friedman, Vladislav, Lianwei Mu, Bixuan Chen, Kelly, Thomas J., Baker, David A., and Qing-song Liu

Subjects
*REINFORCEMENT (Psychology), *DOPAMINERGIC neurons, *DOPAMINE, *MESENCEPHALON, *COCAINE, *NUCLEUS accumbens
Abstract

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum123

Author

Chen, Yao, Liu, Xiaojie, Vickstrom, Casey R., Liu, Michelle J., Zhao, Li, Viader, Andreu, Cravatt, Benjamin F., and Liu, Qing-song

Subjects
Cannabinoid Receptor Agonists, Mice, Knockout, Neurons, Patch-Clamp Techniques, cerebellum, Amino Acid Transport System X-AG, Glutamic Acid, Neuronal Excitability, endocannabinoid, Arachidonic Acids, New Research, Synaptic Transmission, Monoacylglycerol Lipases, 2-arachidonoylglycerol, Glycerides, Membrane Potentials, Tissue Culture Techniques, astrocyte, monoacylglycerol lipase, nervous system, Purkinje cells, Astrocytes, Animals, Endocannabinoids
Abstract

Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.

Published
2016

17. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress.

Author

Peng Zhong, Vickstrom, Casey R., Xiaojie Liu, Ying Hu, Laikang Yu, Han-Gang Yu, and Qing-song Liu

Subjects
*DOPAMINERGIC neurons, *MENTAL depression, *VOLTAGE-gated ion channels, *HYPERPOLARIZATION (Cytology), *CYCLIC nucleotides
Abstract

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization- activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety- like behavior in stress-naıve mice, whereas VTA HCN2 overexpression largely prevented CMS- induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors. [ABSTRACT FROM AUTHOR]

Published
2017
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18. VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward

Author

Liu, Xiaojie, Li, Yan, Yu, Laikang, Vickstrom, Casey R, and Liu, Qing-song

Abstract

Mechanistic target of rapamycin (mTOR) regulates long-term synaptic plasticity, learning, and memory by controlling dendritic protein synthesis. The mTOR inhibitor rapamycin has been shown to attenuate the behavioral effects of drugs of abuse, including cocaine. Using viral vectors to selectively delete mTOR in the ventral tegmental area (VTA) in adult male mTORloxP/loxPmice, we investigated the role of mTOR in regulating neuronal morphology, basal synaptic transmission, dopamine dynamics, and cocaine-induced synaptic plasticity and rewarding effects. We find that targeted deletion of mTOR in the VTA had no significant effects on soma size and dendritic morphology of VTA neurons but significantly decreased dopamine release and reuptake in the nucleus accumbens (NAc) shell, a major target region. Western blot analysis revealed that mTOR deletion led to decreases in phosphorylated tyrosine hydroxylase (pTH-Ser40) levels in the VTA and dopamine transporter expression in the NAc. mTOR deletion had no significant effects on basal excitatory transmission in VTA dopamine neurons but caused an increase in GABAergic inhibition because of an increase in VTA GABAergic neuron firing. Furthermore, mTOR deletion attenuated conditioned place preference to cocaine and cocaine-induced potentiation of excitation and reduction of GABAergic inhibition in VTA dopamine neurons. Taken together, these results suggest that loss of mTOR in the VTA shifts the balance of excitatory and inhibitory synaptic transmission and decreases dopamine release and reuptake in the NAc. In addition, VTA mTOR signaling regulates cocaine-cue associative learning and cocaine-induced synaptic plasticity in VTA dopamine neurons.

Published
2018
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