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Article: Sexually dimorphic characteristics of dopamine D1 receptor-expressing neurons within the shell of the nucleus accumbens of adolescent mice.

Aziz, Heather C / Mangieri, Regina A

Research square

2023

Abstract: Background: Adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and ... ...

Abstract	Background: Adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and implicated in reward seeking and evaluation. Most neurons in the NAc are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1R+) and/or dopamine D2 receptors (D2R+). Changes in dopaminergic and glutamatergic systems occur during adolescence and converge in the NAc. While there are previous investigations into sex differences in membrane excitability and synaptic glutamate transmission in both subdivisions of the NAc, to our knowledge, none have specified NAcSh D1R+MSNs from mice during mid-adolescence. Methods: Sagittal brain slices containing the NAc were prepared from B6.Cg-Tg(Drd1a-tdTomato)6Calak/J mice of both sexes from postnatal days 35-47. Stained smears were made from vaginal samples from female mice to identify the stage of Estrous at death. Whole-cell electrophysiology recordings were collected from NAcSh D1R+MSNs in the form of membrane-voltage responses to current injections and spontaneous excitatory postsynaptic currents (sEPSCs). Results: The action potential duration was longer in males than infemales. Additionally, the frequency of sEPSCs was higher in females, and the mean event amplitude was smaller than that in males. We found no evidence of the observed sex differences being driven by the stage of the Estrous cycle and no physiological parameter significantly varied with respect to the Estrous cycle. Conclusions: Taken together, our results indicate that NAcSh D1R+MSNs exhibit sex differences during mid-adolescence that are independent of the stage of Estrous, in both AP waveform and glutamate transmission, possibly due to changes in voltage-gated potassium channels and α-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, respectively.
Language	English
Publishing date	2023-12-16
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3717874/v1
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Article: Editorial: The Jilted Brain: Neglected Structures and Functions.

Mangieri, Regina A / Allers, Kelly A / Zahr, Natalie M

Frontiers in systems neuroscience

2021 Volume 15, Page(s) 716242

Language	English
Publishing date	2021-08-11
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2453005-0
ISSN	1662-5137
ISSN	1662-5137
DOI	10.3389/fnsys.2021.716242
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Article ; Online: Compelled to drink: Why some cannot stop.

Nixon, Kimberly / Mangieri, Regina A

Science (New York, N.Y.)

2019 Volume 366, Issue 6468, Page(s) 947–948

MeSH term(s)	Alcohol Drinking ; Brain Stem ; Compulsive Behavior
Language	English
Publishing date	2019-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aaz7357
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: Effect of chronic intermittent ethanol vapor exposure on RNA content of brain-derived extracellular vesicles.

Baratta, Annalisa M / Mangieri, Regina A / Aziz, Heather C / Lopez, Marcelo F / Farris, Sean P / Homanics, Gregg E

Alcohol (Fayetteville, N.Y.)

2022 Volume 105, Page(s) 9–24

Abstract: Extracellular vesicles (EVs) are important players in normal biological function and disease pathogenesis. Of the many biomolecules packaged into EVs, coding and noncoding RNA transcripts are of particular interest for their ability to significantly ... ...

Abstract	Extracellular vesicles (EVs) are important players in normal biological function and disease pathogenesis. Of the many biomolecules packaged into EVs, coding and noncoding RNA transcripts are of particular interest for their ability to significantly alter cellular and molecular processes. Here we investigate how chronic ethanol exposure impacts EV RNA cargo and the functional outcomes of these changes. Following chronic intermittent ethanol (CIE) vapor exposure, EVs were isolated from male and female C57BL/6J mouse brain. Total RNA from EVs was analyzed by lncRNA/mRNA microarray to survey changes in RNA cargo following vapor exposure. Differential expression analysis of microarray data revealed a number of lncRNA and mRNA types differentially expressed in CIE compared to control EVs. Weighted gene co-expression network analysis identified multiple male and female specific modules related to neuroinflammation, cell death, demyelination, and synapse organization. To functionally test these changes, whole-cell voltage-clamp recordings were used to assess synaptic transmission. Incubation of nucleus accumbens brain slices with EVs led to a reduction in spontaneous excitatory postsynaptic current amplitude, although no changes in synaptic transmission were observed between control and CIE EV administration. These results indicate that CIE vapor exposure significantly changes the RNA cargo of brain-derived EVs, which have the ability to impact neuronal function.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Brain/drug effects ; Ethanol/adverse effects ; Extracellular Vesicles ; Mice, Inbred C57BL ; RNA, Long Noncoding ; RNA, Messenger
Chemical Substances	Ethanol (3K9958V90M) ; RNA, Long Noncoding ; RNA, Messenger
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605912-0
ISSN	1873-6823 ; 0741-8329
ISSN (online)	1873-6823
ISSN	0741-8329
DOI	10.1016/j.alcohol.2022.08.006
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Article: Ethanol Modulates Glutamatergic Transmission and NMDAR-Mediated Synaptic Plasticity in the Agranular Insular Cortex.

Shillinglaw, Joel E / Morrisett, Richard A / Mangieri, Regina A

Frontiers in pharmacology

2018 Volume 9, Page(s) 1458

Abstract: The agranular insular cortex (AIC) has recently been investigated by the alcohol field because of its connectivity to and modulatory control over limbic and brainstem regions implicated in alcohol use disorder (AUD), and because it has shown involvement ... ...

Abstract	The agranular insular cortex (AIC) has recently been investigated by the alcohol field because of its connectivity to and modulatory control over limbic and brainstem regions implicated in alcohol use disorder (AUD), and because it has shown involvement in animal models of alcohol drinking. Despite evidence of AIC involvement in AUD, there has not yet been an examination of whether ethanol modulates glutamatergic and γ-amino-butyric acid (GABA)ergic synaptic transmission and plasticity in the AIC. Characterizing how the synaptic transmission and plasticity states of AIC cortical processing neurons are modulated by acute ethanol will likely reveal the molecular targets by which chronic ethanol alters AIC function as alcohol drinking transitions from controlled to problematic. Therefore, we collected brain slices from ethanol-naïve adult male mice, obtained whole-cell recording configuration in layer 2/3 AIC pyramidal neurons, and bath-applied ethanol at pharmacologically relevant concentrations during electrophysiological assays of glutamatergic and GABAergic synaptic transmission and plasticity. We found that ethanol inhibited electrically evoked N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory post-synaptic currents (EPSCs) in a concentration-related fashion, and had little effect on evoked α-amino-3-hydrox-5-methylisoxazole-4-propionic acid-type receptor (AMPAR)-mediated EPSCs. Ethanol had no effect on spontaneous excitatory post-synaptic currents (sEPSCs) or inhibitory GABA
Language	English
Publishing date	2018-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2018.01458
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Article: Do Alcohol-Related AMPA-Type Glutamate Receptor Adaptations Promote Intake?

Woodward Hopf, F / Mangieri, Regina A

Handbook of experimental pharmacology

2018 Volume 248, Page(s) 157–186

Abstract: Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to ... ...

Abstract	Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence. Alcohol- and drug-related adaptations in NMDARs have been recently reviewed, while less is known about kainate receptor adaptations. Thus, we focus here on functional changes in AMPARs, tetramers composed of GluA1-4 subunits. Long-lasting increases or decreases in AMPAR function, the so-called long-term potentiation or depression, have widely been considered to contribute to normal and pathological memory states. In addition, a great deal has been learned about the acute regulation of AMPARs by signaling pathways, scaffolding and auxiliary proteins, intracellular trafficking, and other mechanisms. One important common adaptation is a shift in AMPAR subunit composition from GluA2-containing, calcium-impermeable AMPARs (CIARs) to GluA2-lacking, calcium-permeable AMPARs (CPARs), which is observed under a broad range of conditions including intoxicant exposure or intake, stress, novelty, food deprivation, and ischemia. This shift has the potential to facilitate AMPAR currents, since CPARs have much greater single-channel currents than CIARs, as well as faster AMPAR activation kinetics (although with faster inactivation) and calcium-related activity. Many tools have been developed to interrogate particular aspects of AMPAR signaling, including compounds that selectively inhibit CPARs, raising exciting translational possibilities. In addition, recent studies have used transgenic animals and/or optogenetics to identify AMPAR adaptations in particular cell types and glutamatergic projections, which will provide critical information about the specific circuits that CPARs act within. Also, less is known about the specific nature of alcohol-related AMPAR adaptations, and thus we use other examples that illustrate more fully how particular AMPAR changes might influence intoxicant-related behavior. Thus, by identifying alcohol-related AMPAR adaptations, the specific molecular events that underlie them, and the cells and projections in which they occur, we hope to better inform the development of new therapeutic interventions for addiction.
MeSH term(s)	Animals ; Ethanol/pharmacology ; Humans ; Neurons/drug effects ; Receptors, AMPA/physiology ; Receptors, N-Methyl-D-Aspartate
Chemical Substances	Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate ; Ethanol (3K9958V90M)
Language	English
Publishing date	2018-04-20
Publishing country	Germany
Document type	Journal Article
ISSN	0171-2004
ISSN	0171-2004
DOI	10.1007/164_2018_105
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Article ; Online: Ethanol Experience Enhances Glutamatergic Ventral Hippocampal Inputs to D1 Receptor-Expressing Medium Spiny Neurons in the Nucleus Accumbens Shell.

Kircher, Daniel M / Aziz, Heather C / Mangieri, Regina A / Morrisett, Richard A

The Journal of neuroscience : the official journal of the Society for Neuroscience

2019 Volume 39, Issue 13, Page(s) 2459–2469

Abstract: A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling in the reward circuit is the nucleus accumbens, more ... ...

Abstract	A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling in the reward circuit is the nucleus accumbens, more specifically, the dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) within this region, which have been implicated in the formation of dependence to many drugs of abuse including alcohol. D1-MSNs receive glutamatergic input from several brain regions; however, it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. Here, we investigate input-specific adaptations in glutamatergic transmission in response to varying levels of alcohol experience. Virally mediated expression of Channelrhodopsin in ventral hippocampal (vHipp) glutamate neurons of male mice allowed for selective activation of vHipp to D1-MSN synapses. Therefore, we were able to compare synaptic adaptations in response to low and high alcohol experience
MeSH term(s)	Animals ; Ethanol/administration & dosage ; Glutamic Acid/physiology ; Hippocampus/drug effects ; Hippocampus/physiology ; Long-Term Synaptic Depression ; Male ; Mice, Inbred C57BL ; Neural Pathways/drug effects ; Neural Pathways/physiology ; Neurons/drug effects ; Neurons/physiology ; Nucleus Accumbens/drug effects ; Nucleus Accumbens/physiology ; Optogenetics ; Receptors, AMPA/physiology ; Receptors, Dopamine D1/physiology ; Receptors, N-Methyl-D-Aspartate/physiology ; Synapses/drug effects ; Synapses/physiology
Chemical Substances	Receptors, AMPA ; Receptors, Dopamine D1 ; Receptors, N-Methyl-D-Aspartate ; Ethanol (3K9958V90M) ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2019-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.3051-18.2019
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Article ; Online: Regional Analysis of the Pharmacological Effects of Acute Ethanol on Extracellular Striatal Dopamine Activity.

Vena, Ashley A / Mangieri, Regina / Gonzales, Rueben A

Alcoholism, clinical and experimental research

2016 Volume 40, Issue 12, Page(s) 2528–2536

Abstract: Background: The objective of this study was to characterize the acute pharmacological effects of ethanol (EtOH) on extracellular dopamine in the dorsomedial and dorsolateral striata. This is the first study to quantify and directly compare the effects ... ...

Abstract	Background: The objective of this study was to characterize the acute pharmacological effects of ethanol (EtOH) on extracellular dopamine in the dorsomedial and dorsolateral striata. This is the first study to quantify and directly compare the effects of acute EtOH on dopamine in these subregions. Therefore, we also tested the nucleus accumbens as a positive control. We hypothesized that while EtOH may increase extracellular dopamine in the dorsomedial striatum and dorsolateral striatum, the magnitude of this increase and the temporal profiles of extracellular dopamine concentrations would differ among the dorsomedial striatum, dorsolateral striatum, and nucleus accumbens. Methods: We performed in vivo microdialysis in adult, male Long Evans rats as they received a single (experiment 1) or repeated (experiment 2) doses of EtOH. Results: The results of our positive control study validate earlier work by our laboratory demonstrating that acute intravenous EtOH immediately and robustly increases extracellular dopamine in the nucleus accumbens (Howard et al., ). In contrast, a single 1-g/kg dose of intravenous EtOH did not significantly affect extracellular dopamine in the dorsomedial striatum or the dorsolateral striatum. However, following a cumulative EtOH dosing protocol, we observed a ramping up of tonic dopamine activity in both the dorsomedial striatum and dorsolateral striatum over the course of the experiment, but this effect was more robust in the dorsomedial striatum. Conclusions: These results suggest that distinct mechanisms underlie the stimulating effects of acute EtOH on extracellular dopamine in striatal subregions. Additionally, our findings suggest a role for the dorsomedial striatum and minimal-to-no role for the dorsolateral striatum in mediating the intoxicating effects of acute moderate to high doses of EtOH.
MeSH term(s)	Administration, Intravenous ; Animals ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Dopamine/metabolism ; Ethanol/administration & dosage ; Ethanol/pharmacology ; Extracellular Fluid/metabolism ; Male ; Microdialysis ; Nucleus Accumbens/metabolism ; Rats
Chemical Substances	Ethanol (3K9958V90M) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2016-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	428999-7
ISSN	1530-0277 ; 0145-6008
ISSN (online)	1530-0277
ISSN	0145-6008
DOI	10.1111/acer.13246
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Article ; Online: Preclinical and clinical evidence for suppression of alcohol intake by apremilast.

The Journal of clinical investigation

2023 Volume 133, Issue 6

Abstract: Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 ... ...

Abstract	Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.
MeSH term(s)	Humans ; Mice ; Animals ; Alcoholism ; Thalidomide/pharmacology ; Phosphodiesterase 4 Inhibitors/pharmacology ; Phosphodiesterase 4 Inhibitors/therapeutic use ; Psoriasis/drug therapy ; Ethanol ; Alcohol Drinking/genetics
Chemical Substances	apremilast (UP7QBP99PN) ; Thalidomide (4Z8R6ORS6L) ; Phosphodiesterase 4 Inhibitors ; Ethanol (3K9958V90M)
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI159103
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Article: Ethanol exposure interacts with training conditions to influence behavioral adaptation to a negative instrumental contingency.

Mangieri, Regina A / Cofresí, Roberto U / Gonzales, Rueben A

Frontiers in behavioral neuroscience

2014 Volume 8, Page(s) 220

Abstract: We previously reported that, in male, Long Evans rats, instrumental lever pressing that had been reinforced during limited training under a variable interval (VI) schedule by oral self-administration of a 10% sucrose/10% ethanol (10S10E) solution was ... ...

Abstract	We previously reported that, in male, Long Evans rats, instrumental lever pressing that had been reinforced during limited training under a variable interval (VI) schedule by oral self-administration of a 10% sucrose/10% ethanol (10S10E) solution was insensitive to devaluation of 10S10E. In contrast, lever pressing that had been reinforced under a variable ratio (VR) schedule, or by self-administration of 10% sucrose (10S) alone, was sensitive to outcome devaluation. The relative insensitivity to outcome devaluation indicated that seeking of 10S10E by the VI-trained rats had become an instrumental habit. In the present study we employed an alternative operational definition of an instrumental habit and compared the effect of reversing the action-outcome contingency on lever press performance by rats trained under the same experimental conditions. Male Long Evans rats received daily operant training, in which lever presses were reinforced by 10S10E or 10S, under VI or VR schedules. After nine sessions of VI or VR training, rats were tested over four sessions in which the instrumental contingency was changed so that a lever press would prevent reinforcer delivery for 120 s. We found that rats that had been trained to lever press for 10S10E under the VR schedule showed a greater change in lever pressing across testing sessions than those that had received 10S10E reinforcement under the VI schedule. There was no such interaction with reinforcement schedule for rats that had received only 10S reinforcement during training. These findings are consistent with those of our previous study, and provide further evidence that addition of ethanol to sucrose may promote habitual responding in an instrumental task.
Language	English
Publishing date	2014-06-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2014.00220
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