Sex differences in dopamine release regulation in the striatum

Zachry, Jennifer E.; Nolan, Suzanne O.; Brady, Lillian J.; Kelly, Shannon; Siciliano, Cody A.; Calipari, Erin S.

doi:10.1038/s41386-020-00915-1

Cited by 99 publications

(70 citation statements)

References 125 publications

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“…Enhanced D 2 R-dependent signaling in VTA DA neurons from female mice may compensate for the loss of GABA B R signaling, explaining the weak influence of GABA B R on cocaine-induced activity in females. Alternatively, there may be reduced GABAergic feedback to VTA DA neurons in females, rendering the loss of GABA B R less effective ( Zachry et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…This difference could reflect elevated D 2 R expression and/or function in VTA DA neurons from females and is predicted to decrease cocaine sensitivity. Indeed, females exhibit elevated D 2 R-dependent signaling at baseline as compared with males ( Walker et al, 2006 ; Zachry et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cocaine-induced activity was characterized by a more rapid and sharp peak in females as compared with males, which could be explained by a tighter regulation of synaptic DA by DAT in females compared with males ( Zachry et al, 2021 ). D 2 R ablation in VTA DA neurons in male mice yielded a temporal profile comparable to that seen in female mice.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Estrogens are known to have a facilitatory influence on some reward-seeking behaviors, an effect mediated at least in part by actions on striatal dopamine signaling [93][94][95]. In addition to the important role that sex hormones play during brain development (i.e., organizational influences) [96], there are two ways in which circulating hormones such as estrogen can have ongoing (activational) influences on alcohol drinking and other behaviors.…”

Section: Ovarian Hormones Promote Binge Alcohol Drinkingmentioning

confidence: 99%

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

Radke

Sneddon

Frasier

et al. 2021

IJMS

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Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.

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“…Sex differences have been described regarding the structure and function of adult pre- and postsynaptic components of DA circuitries, including differences in structural organization, DA content, and regulation of local DA release (Becker et al, 2001 , 2012 ; Becker, 2009 ; Gillies et al, 2014 ; Walker et al, 2017 ; Becker and Chartoff, 2018 ; Kokane and Perrotti, 2020 ; Zachry et al, 2020 ). Ovarian hormones are key regulators of some of these observed sex differences, notably DA neuron firing rates (Zhang et al, 2008 ; Calipari et al, 2017 ) and striatal DA release (Xiao and Becker, 1994 ; Castner et al, 2005 ; Calipari et al, 2017 ; Yoest et al, 2019 ).…”

Section: Mechanisms Underlying Mesocorticolimbic Dopamine Circuit Organization In Adolescencementioning

confidence: 99%

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

Reynolds

Flores²

2021

Front. Neural Circuits

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Mesocorticolimbic dopamine circuity undergoes a protracted maturation during adolescent life. Stable adult levels of behavioral functioning in reward, motivational, and cognitive domains are established as these pathways are refined, however, their extended developmental window also leaves them vulnerable to perturbation by environmental factors. In this review, we highlight recent advances in understanding the mechanisms underlying dopamine pathway development in the adolescent brain, and how the environment influences these processes to establish or disrupt neurocircuit diversity. We further integrate these recent studies into the larger historical framework of anatomical and neurochemical changes occurring during adolescence in the mesocorticolimbic dopamine system. While dopamine neuron heterogeneity is increasingly appreciated at molecular, physiological, and anatomical levels, we suggest that a developmental facet may play a key role in establishing vulnerability or resilience to environmental stimuli and experience in distinct dopamine circuits, shifting the balance between healthy brain development and susceptibility to psychiatric disease.

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Sex differences in dopamine release regulation in the striatum

Cited by 99 publications

References 125 publications

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

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

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

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