Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum

Yorgason, Jordan T.; Calipari, Erin S.; Ferris, Mark J.; Karkhanis, Anushree N.; Fordahl, Steve C.; Weiner, Jeffrey L.

doi:10.1016/j.neuropharm.2015.10.025

Cited by 89 publications

(84 citation statements)

References 52 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Extracellular levels of DA in the NAc are determined, in part, by DA transporter (DAT) activity (Ferris et al, 2014). The increased uptake of DA observed in the NAc core and shell of SI rats in the current study and in the NAc core in a previous report suggests that SI leads to augmented DAT levels in this brain region (Yorgason et al, 2015). Interestingly, other forms of chronic stress, such as repeated restraint stress, have also been shown to enhance DA uptake in the striatum (Copeland et al, 2005) and chronic ethanol exposure increases DA uptake in adult mouse, rat, and monkey models (Budygin et al, 2003;Karkhanis et al, 2015).…”

Section: Adolescent Si Disrupts Da Transmission In the Nacsupporting

confidence: 53%

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Karkhanis¹,

Rose

Weiner³

et al. 2016

Neuropsychopharmacol

106

107

View full text Add to dashboard Cite

Chronic early-life stress increases vulnerability to alcoholism and anxiety disorders during adulthood. Similarly, rats reared in social isolation (SI) during adolescence exhibit augmented ethanol intake and anxiety-like behaviors compared with group housed (GH) rats. Prior studies suggest that disruption of dopamine (DA) signaling contributes to SI-associated behaviors, although the mechanisms underlying these alterations are not fully understood. Kappa opioid receptors (KORs) have an important role in regulating mesolimbic DA signaling, and other kinds of stressors have been shown to augment KOR function. Therefore, we tested the hypothesis that SI-induced increases in KOR function contribute to the dysregulation of NAc DA and the escalation in ethanol intake associated with SI. Our ex vivo voltammetry experiments showed that the inhibitory effects of the kappa agonist U50,488 on DA release were significantly enhanced in the NAc core and shell of SI rats. Dynorphin levels in NAc tissue were observed to be lower in SI rats. Microdialysis in freely moving rats revealed that SI was also associated with reduced baseline DA levels, and pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI) increased DA levels selectively in SI subjects. Acute ethanol elevated DA in SI and GH rats and nor-BNI pretreatment augmented this effect in SI subjects, while having no effect on ethanol-stimulated DA release in GH rats. Together, these data suggest that KORs may have increased responsiveness following SI, which could lead to hypodopaminergia and contribute to an increased drive to consume ethanol. Indeed, SI rats exhibited greater ethanol intake and preference and KOR blockade selectively attenuated ethanol intake in SI rats. Collectively, the findings that nor-BNI reversed SI-mediated hypodopaminergic state and escalated ethanol intake suggest that KOR antagonists may represent a promising therapeutic strategy for the treatment of alcohol use disorders, particularly in cases linked to chronic early-life stress.

show abstract

Section: Adolescent Si Disrupts Da Transmission In the Nacsupporting

confidence: 53%

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Karkhanis¹,

Rose

Weiner³

et al. 2016

Neuropsychopharmacol

106

107

View full text Add to dashboard Cite

show abstract

“…We have recently shown that blockade of dopaminergic neurotransmission by systemic administration of α-flupenthixol reduces motivation for social play in a lever pressing task, without altering the performance of social play during reinforced periods (Achterberg et al, 2016), although systemic treatment with higher doses of α-flupenthixol does reduce social play behavior . It has been shown that long periods of social isolation after weaning affect mesolimbic dopaminergic activity (Yorgason et al, 2013(Yorgason et al, , 2016Whitaker et al, 2013). Thus, in line with the view that NAc dopaminergic neurotransmission plays a critical role in incentive motivation (Barbano and Cador, 2007;Kelley, 2004;Salamone and Correa, 2012), we hypothesized that animals highly motivated for social play as a result of longer social isolation before testing would be more sensitive to blockade of NAc dopamine receptors.…”

Section: Discussionmentioning

confidence: 86%

Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats

Manduca

Servadio

Damsteegt

et al. 2016

Neuropsychopharmacol

120

107

View full text Add to dashboard Cite

Social play behavior is a highly rewarding form of social interaction displayed by young mammals. Social play is important for neurobehavioral development and it has been found to be impaired in several developmental psychiatric disorders. In line with the rewarding properties of social play, we have previously identified the nucleus accumbens (NAc) as an important site of action for endocannabinoid and opioid modulation of this behavior. NAc dopamine has a well-known role in certain components of reward processes, such as incentive motivation. However, its contribution to the positive emotional aspects of social interactions is less clear. Therefore, we investigated the role of dopaminergic neurotransmission in the NAc in social play behavior in rats. We found that intra-NAc infusion of the dopamine releaser/ reuptake inhibitor amphetamine increased social play behavior that was dependent on activation of both D1 and D2 dopamine receptors. This increase in social play behavior was mimicked by intra-NAc infusion of the dopamine receptor agonist apomorphine, but not of the dopamine reuptake inhibitor GBR-12909. Blockade of either D1 or D2 NAc dopamine receptors reduced social play in animals highly motivated to play as a result of longer social isolation before testing. Last, blockade of NAc dopamine receptors prevented the playenhancing effects of endocannabinoid and opioid receptor stimulation. These findings demonstrate an important modulatory role of NAc dopaminergic neurotransmission in social play. Thus, functional activity in the mesolimbic dopamine pathway plays an important role in adaptive social development, whereas abnormal NAc dopamine function may underlie the social impairments observed in developmental psychiatric disorders such as autism, attention deficit hyperactivity disorder or early-onset schizophrenia.

show abstract

“…These perturbations in accumbal dopamine release dynamics also persisted well into adulthood. Subsequent studies have now confirmed that aSI also leads to increased dopamine release and uptake in the dorsal striatum (Yorgason et al, 2016). This study also reported higher dopamine transporter levels in ventral and dorsal striatal tissue extracts from aSI rats, providing a possible mechanism that may contribute to the increased rate of dopamine uptake.…”

Section: Nucleus Accumbensmentioning

confidence: 88%

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

Butler

Karkhanis

Jones

et al. 2016

Alcoholism Clin & Exp Res

Self Cite

View full text Add to dashboard Cite

Individuals diagnosed with anxiety-related illnesses are at increased risk of developing alcoholism, exhibit a telescoped progression of this disease and fare worse in recovery, relative to alcoholics that do not suffer from a comorbid anxiety disorder. Similarly, preclinical evidence supports the notion that stress and anxiety represent major risk factors for the development of alcohol use disorder (AUD). Despite the importance of understanding the link between anxiety and alcoholism, much remains unknown about the neurobiological substrates underlying this relationship. One stumbling block has been the lack of animal models that reliably reproduce the spectrum of behaviors associated with increased vulnerability to these diseases. Here, we review the literature that has examined the behavioral and neurobiological outcomes of a simple rodent adolescent social isolation procedure and discuss its validity as a model of vulnerability to comorbid anxiety disorders and alcoholism. Recent studies have provided strong evidence that adolescent social isolation of male rats leads to the expression of a variety of behaviors linked with increased vulnerability to anxiety and/or AUD, including deficits in sensory gating and fear extinction, and increases in anxiety measures and ethanol drinking. Neurobiological studies are beginning to identify mesolimbic adaptations that may contribute to the behavioral phenotype engendered by this model. Some of these changes include increased excitability of ventral tegmental area dopamine neurons and pyramidal cells in the basolateral amygdala and significant alterations in baseline and stimulated catecholamine signaling. A growing body of evidence suggests that adolescent social isolation may represent a reliable rodent model of heightened vulnerability to anxiety disorders and alcoholism in male rats. These studies provide initial support for the face, construct, and predictive validity of this model and highlight its utility in identifying neurobiological adaptations associated with increased risk of developing these disorders.

show abstract

Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum

Cited by 89 publications

References 52 publications

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

Contact Info

Product

Resources

About