Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala

Larkin, Joshua D.; Jenni, Nicole L; Floresco, Stan B.

doi:10.1007/s00213-015-4094-8

Cited by 39 publications

(30 citation statements)

References 49 publications

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“…It should be noted, that the distributions of the WT and KD mice are even across groups (table 2) because group assignments were conducted within each genotype so as not to skew group conditions. In other studies, D 2 receptor activation in the basolateral amygdala attenuated risky choices in risk-prone rats leading to a behavioral profile of decision-making that resembled risk-aversive rats (Larkin et al 2015). A similar trend can be observed in the present study in which risk-preferring mice switch to an increased preference for the advantageous choices when treated with brexpiprazole.…”

Section: Discussionmentioning

confidence: 85%

“…Thus, selectively reducing DAT function recreates altered exploration in mania patients, which can be partially ameliorated by antimanic treatments such as valproate (van Enkhuizen et al 2013) and lithium (van Enkhuizen et al 2015b). It should be noted, however, that valproate increased rather than ameliorated exploration of specific stimuli, which could be linked to the deleterious effects it reportedly has on aspects of cognition such as decision-making (Larkin et al 2015). Clearly, a strong need still exists for therapies that do not negatively impact cognition while specifically treating the behavioral deficits seen in BD mania.…”

Section: Discussionmentioning

confidence: 99%

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Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

Milienne-Petiot

Geyer

Arnt³

et al. 2017

Psychopharmacology

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Rationale Bipolar Disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient’s quality of life, better treatments are needed. Objectives Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3 and 5-HT1A receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania. Methods The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the Behavioral Pattern Monitor (BPM) and Iowa Gambling Task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively. Results DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice. Conclusions Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

Milienne-Petiot

Geyer

Arnt³

et al. 2017

Psychopharmacology

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“…whether D1 vs. D2 in prefrontal cortex; Floresco, 2013). For example, local infusions of MPH in the (baso)lateral amygdala (BLA) enhance cue-reward learning through a D1 mechanism and suppress task-irrelevant behaviors through a D2 mechanism (Tye et al 2010; Larkin et al 2015). Therefore, chronic administration of MPH may result in striatal downregulation of D1 receptors in the short term, but when assessed after prolonged drug-withdrawal and upon conditions of reward learning, may be upregulated in the long-term.…”

Section: Discussionmentioning

confidence: 99%

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Izquierdo

Pozos

Torre

et al. 2016

Behavioural Brain Research

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Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner.

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“…On the other hand, it is important to note that stress-induced increases in choice times appear to be mediated by enhanced dopamine transmission, as this effect was blocked by the administration of a dopamine antagonist prior to stress exposure (Shafiei et al, 2012). Although the terminal region(s) where increased dopamine may mediate this effect is unclear, stimulation of D 2 receptors in the prefrontal cortex or basolateral amygdala increases choice latencies during other types of cost/benefit decision-making (St. Onge et al, 2011;Larkin et al, 2015). It is interesting to note that acute stress potentiates DOPAC metabolism and extracellular dopamine levels in the nucleus accumbens and prefrontal cortex (Abercrombie et al, 1989;Dunn and Berridge, 1990;Holly et al, 2015;Imperato et al, 1991;Matsuzaki et al, 1989) in a manner similar to ICV CRF infusion (0.2-20 μg ;Dunn, 1988;Dunn and Berridge, 1987).…”

Section: Crf Actions In the Vta And Effort-related Decision-makingmentioning

confidence: 99%

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor

Bryce

Floresco

2016

Neuropsychopharmacol

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Acute stress activates numerous systems in a coordinated effort to promote homeostasis, and can exert differential effects on mnemonic and cognitive functions depending on a myriad of factors. Stress can alter different forms of cost/benefit decision-making, yet the mechanisms that drive these effects remain unclear. In the present study, we probed how corticotropin-releasing factor (CRF) may contribute to stress-induced alterations in cost/benefit decision-making, using an task where well-trained rats chose between a low effort/ low reward lever (LR; two pellets) and a high effort/high reward lever (HR; four pellets), with the effort requirement increasing over a session (2, 5, 10, and 20 presses). One-hour restraint stress markedly reduced preference for the HR option, but this effect was attenuated by infusions of the CRF antagonist, alpha-helical CRF. Conversely, central CRF infusion mimicked the effect of stress on decision-making, as well as increased decision latencies and reduced response vigor. CRF infusions did not alter preference for larger vs smaller rewards, but did reduce responding for food delivered on a progressive ratio, suggesting that these treatments may amplify perceived effort costs that may be required to obtain rewards. CRF infusions into the ventral tegmental area recapitulated the effect of central CRF treatment and restraint on choice behavior, suggesting that these effects may be mediated by perturbations in dopamine transmission. These findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression.

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Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala

Abstract: These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.

Cited by 39 publications

References 49 publications

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor

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