Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior

Boulougouris, Vasileios; Castañé, Anna; Robbins, Trevor W.

doi:10.1007/s00213-008-1341-2

Cited by 102 publications

(100 citation statements)

References 49 publications

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“…The impairments induced by quinpirole observed here are likely attributable to excessive activation of D 2 receptors, in light of a recent study where disruption of reversal learning induced by systemic quinpirole was ameliorated by co-administration of a D 2 but not a D 3 antagonist (Boulougouris et al, 2009). An important consideration in evaluating these findings is that activation of NAc D 2 autoreceptors can suppress DA efflux (Pierce et al, 1995).…”

Section: Excessive D 2 But Not D 1 Receptor Activation Induces Fusupporting

confidence: 59%

“…In contrast, DA depletion of the dorsolateral PFC in primates made before training impairs the acquisition of an attentional set (Crofts et al, 2001), whereas, in rats, blockade of D 1 or D 2 receptors in the medial PFC before a set-shift induces severe perseverative impairments (Ragozzino, 2002;Floresco et al, 2006b). Interestingly, stimulation of PFC DA receptors does not affect these forms of behavioral flexibility (Fletcher et al, 2005;Floresco et al, 2006b), even though systemic administration of D 2 receptor agonists does impede this form of executive functioning (Smith et al, 1999;Mehta et al, 2001;Boulougouris et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

Haluk

Floresco

2009

Neuropsychopharmacol

184

174

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Different forms of behavioral flexibility are facilitated by interactions between separate regions of the prefrontal cortex and their striatal outputs. However, the contribution of ventral striatal dopamine (DA) to these functions is unclear. The present study assessed the involvement of DA receptors in the nucleus accumbens (NAc) core on either between-or within-strategy shifts using operant chamberbased tasks. Strategy set-shifting required rats initially to learn a visual-cue discrimination and, on the following day, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were initially trained on a response discrimination and then required to select the opposite lever to receive food reward. Intra-NAc microinfusions of D 1 (SCH23390) but not D 2 (eticlopride) receptor antagonists impaired set-shifting, disrupting the maintenance of a new strategy. Conversely, supranormal activation of D 2 (quinpirole) but not D 1 (SKF81297) receptors also impaired set-shifting, inducing perseverative deficits. However, only infusions of the D 2 agonist impaired reversal learning, but did so without disrupting initial response learning. Thus, mesoaccumbens DA, acting on D 1 receptors, selectively facilitates complex forms of flexibility requiring shifts between different strategies, but does not appear to contribute to simpler forms of flexibility entailing shifts of specific stimulus-reward associations. In contrast, abnormal increases in D 2 receptor activity cause a more general impairment in behavioral flexibility. These findings suggest that deficits in these forms of executive functioning observed in disorders linked to dysfunction of the DA system may be attributable in part to aberrant increases or decreases in mesoaccumbens DA activity.

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Section: Excessive D 2 But Not D 1 Receptor Activation Induces Fusupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

Haluk

Floresco

2009

Neuropsychopharmacol

184

174

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“…Therefore, we think it is justified to state that the deficits in reversal learning, probabilistic discounting and punished reward taking evoked by chemogenetic mesoaccumbens stimulation is the result of increased DA signaling in the NAc. Reversal learning impairments have previously been reported after systemic or intra-NAc treatment with a DA D2 receptor agonist in rats and humans [47][48][49] , whereas probabilistic discounting seems to be dependent on DA D1 rather than D2 receptor stimulation in the NAc 50 . Together, this suggests that the behavioral effects of mesoaccumbens hyperactivity observed here rely on stimulation of both DA receptor subtypes, depending on the task structure.…”

Section: Discussionmentioning

confidence: 77%

A neuronal mechanism underlying decision-making deficits during hyperdopaminergic states

Verharen

Jong

Roelofs

et al. 2017

Preprint

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Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision-making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to faulty decision-making in rats. Activation of the VTA-nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTAprefrontal cortex pathway promotes risky decision-making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision-making, providing a mechanistic understanding of the reckless behaviors seen in substance abuse, mania, and after dopamine replacement therapy in Parkinson's disease.Impaired decision-making can have profound negative consequences, both in the short and in the long term. As such, it is observed in a variety of mental disorders, such as mania 1,2 , substance addiction [3][4][5][6] , and as a side effect of dopamine (DA) replacement therapy in Parkinson's disease 7,8 . Importantly, these disorders are associated with aberrations in DAergic neurotransmission 9,10 , and DA has been implicated in decision-making processes [11][12][13] . However, ascending DAergic projections from the ventral mesencephalon are anatomically and functionally heterogeneous [14][15][16] and the contribution of these distinct DA pathways to decision-making processes remains elusive.The mesocorticolimbic system, comprising DA cells within the ventral tegmental area (VTA) that mainly project to the nucleus accumbens (NAc; mesoaccumbens pathway) and medial prefrontal cortex (mPFC; mesocortical pathway), has an important role in value-based learning and decision-making [14][15][16] . When an experienced reward is better than expected, the firing of VTA DA neurons increases, thereby signaling a discrepancy between anticipated and experienced reward to downstream regions. Conversely, when a reward does not fulfill expectations, DA neuronal activity decreases. This pattern of DA cell activity is the basis of reward prediction error (RPE) theory [17][18][19][20] , which describes an essential mechanism through which organisms learn to flexibly alter their behavior when the costs and benefits associated with different courses of action shift. Although the relevance of RPEs in value-based learning is widely acknowledged, little is known about how different VTA target regions process these DA-mediated error signals, and how this ultimately leads to adaptations in behavior.Here, we used projection-specific chemogenetics combined with behavioral tasks, pharmacological interventions, computational modelling, in vivo microdialysis and in vivo neuronal population recordings to investigate how different ascending V...

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“…Nafadotride and aripiprazole were injected 20 min before behavioral testing according to a Latin-square design (veh, 1 and 3 mg/ kg) with a wash-out period of 1 week between both drugs. The doses were based on previously published research (Boulougouris et al, 2008;Nordquist et al, 2008;St Onge and Floresco, 2009). All drug testing was performed with sessions comprising a fixed ITI of 5 s.…”

Section: Systemic Drug Administrationmentioning

confidence: 99%

“…The apparent lack of effect of systemic nafadotride on impulsivity might result from these opposing actions in both the NAcbS and NAcbC, and not because an insufficient dose of nafadotride was used (see also Boulougouris et al (2008);St Onge and Floresco (2009)). It is also conceivable that brain regions other than the NAcb mediate in part the effects of the systemically administered drugs, potentially through opponent interactions between the PFC and striatum.…”

Section: Dopamine Receptor Modulation Of Impulsivity M Besson Et Almentioning

confidence: 99%

Dissociable Control of Impulsivity in Rats by Dopamine D2/3 Receptors in the Core and Shell Subregions of the Nucleus Accumbens

Besson

Belin

McNamara

et al. 2009

Neuropsychopharmacol

122

111

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Previous research has identified the nucleus accumbens (NAcb) as an important brain region underlying inter-individual variation in impulsive behavior. Such variation has been linked to decreased dopamine (DA) D2/3 receptor availability in the ventral striatum of rats exhibiting spontaneously high levels of impulsivity on a 5-choice serial reaction time (5-CSRT) test of sustained visual attention. This study investigated the involvement of DA D2/3 receptors in the NAcb core (NAcbC) and the NAcb shell (NAcbS) in impulsivity. We investigated the effects of a DA D2/3 receptor antagonist (nafadotride) and a DA D2/3 partial agonist (aripiprazole) infused directly into either the NAcbC or NAcbS of rats selected for high (HI) and low (LI) impulsivity on the 5-CSRT task. Nafadotride increased significantly the level of impulsivity when infused into the NAcbS, but decreased impulsivity when infused into the NAcbC of HI rats. By contrast, intraNAcb microinfusions of aripiprazole did not affect impulsivity. Systemic administration of nafadotride had no effect on impulsive behavior but increased the number of omissions and correct response latencies, whereas systemic injections of aripiprazole decreased impulsive and perseverative behavior, and increased the number of omissions and correct response latencies. These findings indicate an opponent modulation of impulsive behavior by DA D2/3 receptors in the NAcbS and NAcbC. Such divergent roles may have relevance for the etiology and treatment of clinical disorders of behavioral control, including attention-deficit hyperactivity disorder and drug addiction.

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Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior

Abstract: Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.

Cited by 102 publications

References 49 publications

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

A neuronal mechanism underlying decision-making deficits during hyperdopaminergic states

Dissociable Control of Impulsivity in Rats by Dopamine D2/3 Receptors in the Core and Shell Subregions of the Nucleus Accumbens

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