Repeated social defeat and the rewarding effects of cocaine in adult and adolescent mice: dopamine transcription factors, proBDNF signaling pathways, and the TrkB receptor in the mesolimbic system

Montagud‐Romero, Sandra; Núñez, Cristina; Blanco-Gandía, M. Carmen; Martínez-Laorden, Elena; Aguilar, M.A.; Navarro‐Zaragoza, Javier; Almela, Pilar; Milanés, M. Victoria; Laorden, María‐Luisa; Miñarro, José; Rodrı́guez-Arias, Marta

doi:10.1007/s00213-017-4612-y

Cited by 46 publications

(32 citation statements)

References 77 publications

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“…A recent study found that mice exhibited decreased levels of the transcription actors Pitx3 and Nurr1 in the VTA when they were defeated during adolescence, but not in adulthood. This confirms that the genetic control of DA markers is altered only when social stress occurs during adolescence (Montagud‐Romero et al., ). The molecular processes underlying the different effects of SD on transcriptional factors are difficult to determine.…”

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onsupporting

confidence: 78%

“…Although adolescents display a higher release of adrenocorticotropic hormone (ACTH) and corticosterone in response to an acute stressor than adults (Bingham et al., ; Doremus‐Fitzwater, Varlinskaya, & Spear, ), their response to SD evolves with the repetition of the encounters. Adolescent mice experience the first SD as play‐fighting rather than social stress, as male aggression during this phase is not experienced in the same way as during maturity (Montagud‐Romero et al., ; Rodríguez‐Arias et al., ). With the repetition of the defeat experience and the maturation of their hormonal profile, adolescent animals exhibit higher corticosterone responses with respect to their first agonistic encounter, thus displaying an increasingly adult response (Romeo et al., ; Lui et al., ; Wright, Muir, & Perrot, ).…”

Section: Social Defeat Stress During Adolescencementioning

confidence: 99%

“…In response to a stressful experience, CRF release in the VTA can cause synaptic neuroadaptations of DA neurons along the mesolimbic pathway (Borgland, Malenka, & Bonci, ; Saal, Dong, Bonci, & Malenka, ; Ungless et al., ). The greater plasticity of the adolescent brain explains why mice exposed to repeated social stress during adolescence and cocaine exhibit lower expression of Pitx3 in the VTA (Montagud‐Romero et al., ). In line with this, mice separated from their mother and treated with cocaine exhibit decreased Nurr1 and Pitx3 protein expression levels in the VTA (Gracia‐Rubio et al., ).…”

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

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Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Montagud‐Romero

Blanco-Gandía

Reguilón

et al. 2018

Eur J of Neuroscience

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Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces long-lasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short- and long-term consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

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Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onsupporting

confidence: 78%

Section: Social Defeat Stress During Adolescencementioning

confidence: 99%

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

See 1 more Smart Citation

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Montagud‐Romero

Blanco-Gandía

Reguilón

et al. 2018

Eur J of Neuroscience

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“…(Xu et al, 2011;Benarroch, 2015;Borodinova and Salozhin, 2016). These opposite effects have been hypothesized specifically in the NAcc in the context of animal models of depression as learned helplessness and social defeat stress, where BDNF content is increased while proBDNF content is decreased compared to control animals in this brain area (Shirayama et al, 2015;Yang et al, 2016;Montagud-Romero et al, 2017). In this regard, since it is well-documented that an increase in BDNF content in the NAcc increases cocaine-seeking behavior and vulnerability to substance abuse (Krishnan et al, 2007;Burke and Miczek, 2015), an increase in proBDNF in this brain area could have an opposite impact.…”

Section: Discussionmentioning

confidence: 99%

Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

Marton¹,

Gonzalez²,

Rodríguez³

et al. 2018

Preprint

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Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I40 selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I40. Finally, NGF was found to be upregulated in all regions after I40, while a selective upregulation was found in PFC and VTA for the I20 treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine.1.

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“…In particular, numerous studies have demonstrated that adolescent social defeat increases addictive-like phenotypes in male rodents. Specifically, increased conditioned place preference to cocaine and MDMA is seen following adolescent social defeat stress (Garcia-Pardo et al, 2015;Montagud-Romero et al, 2017). Similarly, both adolescent social defeat and social isolation increase cocaine self-administration in male rats (Burke and Miczek, 2015;Yajie et al, 2005).…”

Section: Adolescent Social Isolation Promotes Vulnerability To Addictmentioning

confidence: 99%

Adolescent Social Isolation Increases Vulnerability to Cocaine

Aq¹,

As³

et al. 2018

Preprint

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Childhood and adolescent adversity is associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the molecular mechanisms underlying how chronic stress during adolescence alters reward signaling remains largely unexplored. Understanding how adolescent stress increases addictionlike phenotypes could inform the development of targeted interventions both before and after drug use. The current study examined how adolescent-onset isolation stress affected behavioral, molecular, and physiological responses to cocaine in male and female mice. Adolescent-onset social isolation did not alter the ability of mice to learn an operant response for food, nor influence food self-administration or motivation for food on a progressive ratio schedule. However, male and female socially stressed mice exhibited an increase in motivation for cocaine and cocaine seeking during a cueinduced reinstatement session. Additionally, we demonstrated that adolescent-onset social isolation increased cocaine-induced neuronal activation, as assessed by Fos expression, within the nucleus accumbens core and shell, ventral pallidum, dorsal bed nucleus of the stria terminalis, lateral septum and basolateral amygdala. Taken together, the present studies demonstrate that social stress during adolescence augments the behavioral responses to cocaine during adulthood and alters the responsiveness of reward-related brain circuitry.

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Repeated social defeat and the rewarding effects of cocaine in adult and adolescent mice: dopamine transcription factors, proBDNF signaling pathways, and the TrkB receptor in the mesolimbic system

Abstract: Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine.

Cited by 46 publications

References 77 publications

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

Adolescent Social Isolation Increases Vulnerability to Cocaine

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