High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens

Chen, R.; McIntosh, Scot; Hemby, Scott E.; Sun, Haiguo; Sexton, Tammy; Martin, Thomas J.; Childers, Steven R.

doi:10.1016/j.neulet.2018.02.026

Cited by 14 publications

(15 citation statements)

References 45 publications

(60 reference statements)

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“…Dopamine binding on VTA D2 receptors is negatively correlated with cocaine and amphetamine seeking and consumption ( Buckholtz et al, 2010 ; Bello et al, 2011 ). Further, elevating VTA DA neuron activity via D2 knockdown increases cocaine self administration ( Chen et al, 2018 ) and blocking the negative feedback activity of these receptors increases cocaine self administration ( McCall et al, 2017 ). Additionally, rats with knockdown D2Rs will also work harder for sucrose and cocaine ( de Jong et al, 2015 ).…”

Section: Category I – Impaired Control Of Substance Usementioning

confidence: 99%

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

Poisson

Engel

Saunders

2021

Front. Neural Circuits

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Addiction is a complex disease that impacts millions of people around the world. Clinically, addiction is formalized as substance use disorder (SUD), with three primary symptom categories: exaggerated substance use, social or lifestyle impairment, and risky substance use. Considerable efforts have been made to model features of these criteria in non-human animal research subjects, for insight into the underlying neurobiological mechanisms. Here we review evidence from rodent models of SUD-inspired criteria, focusing on the role of the striatal dopamine system. We identify distinct mesostriatal and nigrostriatal dopamine circuit functions in behavioral outcomes that are relevant to addictions and SUDs. This work suggests that striatal dopamine is essential for not only positive symptom features of SUDs, such as elevated intake and craving, but also for impairments in decision making that underlie compulsive behavior, reduced sociality, and risk taking. Understanding the functional heterogeneity of the dopamine system and related networks can offer insight into this complex symptomatology and may lead to more targeted treatments.

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Section: Category I – Impaired Control Of Substance Usementioning

confidence: 99%

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

Poisson

Engel

Saunders

2021

Front. Neural Circuits

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“…Similarly, intra-VTA infusion of the GABA B R agonist baclofen blocked the locomotor-stimulatory effect of psychostimulants and opioids ( Kalivas et al, 1990 ; Steketee and Kalivas, 1991 ; Chen and Reith, 1994 ; Leite-Morris et al, 2002 , 2004 ) and attenuated self-administration of cocaine, opioids, and other drugs of abuse ( Xi and Stein, 1999 ; Brebner et al, 2000 ; Leite-Morris et al, 2004 ; Backes and Hemby, 2008 ). RNAi-mediated suppression of D 2 R in the rat VTA (cell non-selective) enhanced cocaine-related behavior ( de Jong et al, 2015 ; Chen et al, 2018 ), enhanced choice impulsivity ( Bernosky-Smith et al, 2018 ), and increased functional brain activity ( Martin et al, 2020 ). Ablation of D 2 R in DA neurons throughout the mouse brain correlated with enhanced cocaine-induced activity ( Bello et al, 2011 ), as well as acquisition of cocaine self-administration and reactivity to drug-paired cues ( Holroyd et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine

DeBaker

Velasco

McCall

et al. 2021

eNeuro

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Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G protein-dependent feedback pathways, mediated by GABA B receptors (GABA B Rs) and D 2 DA receptors (D 2 Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G protein signaling in these neurons on this addictionrelated behavior. To resolve the relative influence of GABA B R-and D 2 R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D 2 R and GABA B R in VTA DA neurons. Ablation of GABA B R or D 2 R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABA B R or D 2 R activation. D 2 R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABA B R ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D 2 R nor GABA B R ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction. SIGNIFICANCE STATEMENT Although inhibitory G protein-dependent signaling involving the GABA B (GABA B R) and D 2 dopamine receptor (D 2 R) in VTA DA neurons is thought to limit DA neurotransmission evoked by drugs of abuse, their relative impact on behavioral sensitivity to such drugs is unclear. Using a neuron-specific viral CRISPR/Cas9 approach, we show that that loss of D 2 R in VTA DA neurons enhances behavioral sensitivity to systemic administration of cocaine in male and female mice, whereas loss of GABA B R enhances cocaine sensitivity only in males. Neither GABA B R nor D 2 R ablation impacted behavioral sensitivity to morphine. Thus, differential engagement of inhibitory feedback pathways in VTA DA neurons likely contributes to drug-specific neurophysiological and behavioral effects and may underlie sex differences associated 84 with some facets of addiction.

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“…Decreased DA in the brain may result in abnormalities of dopaminergic pathways, leading to psychiatric complications such as depression and bipolar disorder [42][43][44]. The D2 receptor is present in higher concentration in the striatum and nucleus accumbens, and its stimulation has been associated with psychotic behavior [45][46][47].…”

Section: Pharmacological Mechanismsmentioning

confidence: 99%

Cocaine and Its Variations in Forms of Presentation and Addiction

Neto¹,

Figueiroa²,

Almeida³

et al. 2020

Psychopathology - An International and Interdisciplinary Perspective

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This chapter intends to show cocaine variations in its forms of presentation, chemical forms, pharmacology, use forms, and contexts of use to understand how these factors can influence drug addiction. Furthermore, a discussion on the most expected psychoactive effects will take place during this chapter, based on different forms of use, treatment possibilities, and possible harm reduction strategies. Above all, the discussion considers the recursive movement of people who abuse the drug or became dependent. Therefore, the authors will discourse about these aspects using some singular and illustrative cases, from the biographical trajectory of people in their contexts related to the substance use, aborting the recursive movement of the drug user.

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High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens

Cited by 14 publications

References 45 publications

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine

Cocaine and Its Variations in Forms of Presentation and Addiction

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