Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction

Alonso, I. Pamela; Pino, José A.; Kortagere, Sandhya; Torres, Gonzalo E.; España, Rodrigo A.

doi:10.1038/s41386-020-00879-2

Cited by 27 publications

(24 citation statements)

References 109 publications

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“…Proteins were transferred to nitrocellulose membrane (Cat# 88018, 0.45-μm pore, Thermo Scientific TM , Rockford, IL, United States) at 350 mA for 1.5 h. Non-specific sites of membrane binding were blocked with 5% skim milk in T-TBS (0.1% Tween-20, 20 mM TBS, 137 mM NaCl) for 1 h at room temperature. Primary antibodies for immunodetection of dopamine system proteins were selected based on previously published data: 1:1,000 of rabbit anti-D1R (AB1765P, Merck Millipore, Darmstadt, Germany) ( Huang et al, 1992 ; Graham et al, 2015 ); 1:1,000 of rabbit anti-D2R (AB5084P, Merck Millipore, Darmstadt, Germany) ( Galvan et al, 2014 ; Graham et al, 2015 ); 1:10,000 of rabbit anti-TH (657012, Merck Millipore, Darmstadt, Germany) ( Espinosa et al, 2016 ); 1:2,000 of rabbit anti-DAT (434-DATEL2, Phosphosolutions, Aurora, CO, United States) ( Dib et al, 2018 ; Alonso et al, 2021 ). Rabbit anti-GAPDH (G9545, Sigma-Aldrich, St. Louis, MO, United States) at 1:10,000 was used as loading control.…”

Section: Methodsmentioning

confidence: 99%

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

Escobar

Martínez-Pinto

Silva-Olivares

et al. 2021

Front. Cell. Neurosci.

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The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive–compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3glo/CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3glo/CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3glo/CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3glo/CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3glo/CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3glo/CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3glo/CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3glo/CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.

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Section: Methodsmentioning

confidence: 99%

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

Escobar

Martínez-Pinto

Silva-Olivares

et al. 2021

Front. Cell. Neurosci.

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“…Strikingly, the VTA transcriptome exhibited robust rhythms in gene expression; roughly 10% of the 2,643 transcripts investigated had significant rhythms with peaks in expression primarily clustering at ZT3 (inactive/light phase) and even more so at ZT16 (active/dark phase) ( Koch et al, 2020 ). In particular, several studies have shown VTA dopamine-related genes diurnally vary in expression and function, and/or maybe directly regulated by the circadian molecular clock, including TH, DAT, and the dopamine degradation enzyme monoamine oxidase A (MAOA) ( Figure 1B) ( McClung et al, 2005 ; Hampp et al, 2008 ; Chung et al, 2014 ; Ferris et al, 2014 ; Logan et al, 2019 ; Alonso et al, 2021 ). Together, these findings point to a functional circadian clock system within the VTA that organizes its function on a 24-h timescale.…”

Section: The Ventral Tegmental Area As a Circadian Oscillatormentioning

confidence: 99%

The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

2022

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Circadian rhythms convergently evolved to allow for optimal synchronization of individuals’ physiological and behavioral processes with the Earth’s 24-h periodic cycling of environmental light and temperature. Whereas the suprachiasmatic nucleus (SCN) is considered the primary pacemaker of the mammalian circadian system, many extra-SCN oscillatory brain regions have been identified to not only exhibit sustainable rhythms in circadian molecular clock function, but also rhythms in overall region activity/function and mediated behaviors. In this review, we present the most recent evidence for the ventral tegmental area (VTA) and nucleus accumbens (NAc) to serve as extra-SCN oscillators and highlight studies that illustrate the functional significance of the VTA’s and NAc’s inherent circadian properties as they relate to reward-processing, drug abuse, and vulnerability to develop substance use disorders (SUDs).

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“…The neuromodulator dopamine (DA) has well established roles in SUDs [42,43], behavioral alterations during drug withdrawal [44,45], and sleep [46][47][48].There is considerable evidence that exogenous cannabinoids indirectly modulate DA activity [49][50][51] with ramifications for development of CUD and CWS. The striatum, comprised of subregions including the nucleus accumbens (NAc), dorsal medial (DMS) and dorsal lateral striatum (DLS), is a major site of DA action in the brain and is involved in many behaviors associated with drug abuse and withdrawal symptoms [52], as well as sleep [53], making it an interesting nexus of the actions of THC and withdrawal phenomena.…”

Section: Dopamine Cud and Cwsmentioning

confidence: 99%

“…Striatal DA is known to play a role in sleep-state architecture [46], so further studies are needed to investigate the causal role of enhanced striatal DA release observed in female mice in alleviating sleep disruption during early chronic THC abstinence.…”

Section: Conclusion and Caveatsmentioning

confidence: 99%

Sex-dependent changes in murine striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence

Kesner

Mateo

Abrahao

et al. 2021

Preprint

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Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is known to be affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors, e.g., irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during withdrawal in a mouse chronic cannabis exposure model. Using a THC treatment regimen known to produce tolerance we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance inducing THC treatment. Sex differences were observed in nearly all metrics. Altered striatal DA release, sleep and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. To our knowledge these findings provide the first model of directly translatable non-precipitated cannabis withdrawal symptoms, in particular, sleep disruption.

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Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction

Cited by 27 publications

References 109 publications

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice

The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

Sex-dependent changes in murine striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence

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