Dopamine D2L Receptor Is Required for Visual Discrimination and Reversal Learning

Morita, Maki; Wang, Yanyan; Sasaoka, Toshikuni; Okada, Kinya; Niwa, Minae; Sawa, Akira; Hikida, Takatoshi

doi:10.1159/000447970

Cited by 17 publications

(12 citation statements)

References 56 publications

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“…As noted above, lower availability, levels and/or functionality of striatal dopaminergic D2 receptors have been consistently linked to impulsive behavioral phenotypes in laboratory rodents and human or nonhuman primates ( Kruzich and Grandy, 2004 ; Kruzich et al, 2006 ; Dalley et al, 2007 ; Boulougouris et al, 2009 ; De Steno and Schmauss, 2009 ; Buckholtz et al, 2010 ; Groman et al, 2011 ; Laughlin et al, 2011 ; Morita et al, 2016 ). D2 receptors are located within multiple cellular compartments within the striatum, including postsynaptic medium spiny neurons that project to the pallidum, as well as on dopamine-releasing terminals where they regulate dopamine synthesis and release ( Jentsch and Roth, 2000 ).…”

Section: Discussionmentioning

confidence: 91%

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Linden

James

McDaniel

et al. 2018

eNeuro

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Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2-KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms.

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Section: Discussionmentioning

confidence: 91%

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Linden

James

McDaniel

et al. 2018

eNeuro

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“…Our findings suggest therefore that interactive effects between trait anxiety and cocaine exposure were somehow responsible for the inability of HE rats to exploit reward value during the reversal session. Reversal learning has been widely shown to depend on monoaminergic mechanisms in the OFC and striatum [75][76][77][78][79][80] with substantial evidence implicating D2 receptors in the striatal indirect pathway [81][82][83][84][85]. However, rather than decreasing DRD2 expression in the striatum, as predicted from prior positron emission tomography imaging studies in humans and other rats, [86][87][88], striatal DRD2 expression increased significantly in the DMS after 8 days of abstinence from cocaine in LE and HE rats.…”

Section: Discussionmentioning

confidence: 82%

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

Zhukovsky

Puaud

Jupp

et al. 2019

Neuropsychopharmacol.

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Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA). Twenty-four rats were screened for anxiety in an open field prior to acquisition of cocaine SA over six daily sessions with subsequent long-access cocaine SA for 7 days. Control rats (n = 24) were trained to lever-press for food under a yoked schedule of reinforcement. Higher rates of cocaine SA were predicted by increased anxiety and preceded impaired reversal learning, expressed by a decrease in lose-shift as opposed to win-stay probability. A model-free reinforcement learning algorithm revealed that rats with high, but not low cocaine escalation failed to exploit previous reward learning and were more likely to repeat the same response as the previous trial. Eight-day withdrawal from high cocaine escalation was associated, respectively, with increased and decreased dopamine receptor D2 (DRD2) and serotonin receptor 2C (HTR2C) expression in the ventral striatum compared with controls. Dopamine receptor D1 (DRD1) expression was also significantly reduced in the orbitofrontal cortex of high cocaine-escalating rats. These findings indicate that withdrawal from escalated cocaine SA disrupts how negative feedback is used to guide goal-directed behavior for natural reinforcers and that trait anxiety may be a latent variable underlying this interaction.

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“…Morita et al 49 reported impaired VD learning in dopamine D 2 long receptor-deficient mice. Disc1 has been shown to associate with dopamine D 2 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…A disruption in this circuitry and/or the dopaminergic system in Disc1 Δ2‐3/Δ2‐3 mice may impair VD learning. Morita et al reported impaired VD learning in dopamine D 2 long receptor‐deficient mice. Disc1 has been shown to associate with dopamine D 2 receptors .…”

Section: Discussionmentioning

confidence: 99%

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice

Wulaer

Nagai

Sobue

et al. 2018

Genes Brain and Behavior

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Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1 mice are associated with hyperactivity of the DMS.

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Dopamine D2L Receptor Is Required for Visual Discrimination and Reversal Learning

Cited by 17 publications

References 56 publications

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice

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Dopamine D2L Receptor Is Required for Visual Discrimination and Reversal Learning

Cited by 17 publications

References 56 publications

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1Δ2‐3/Δ2‐3 mice

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Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice