Operant model of frustrated expected reward in mice

Burokas, Aurelijus; Gutiérrez‐Cuesta, Javier; Martín‐García, Elena; Maldonado, Rafaël

doi:10.1111/j.1369-1600.2011.00423.x

Cited by 43 publications

(50 citation statements)

References 29 publications

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“…Nociception (1), physical dependence and withdrawal (1, 26), locomotor activity (20), locomotor sensitization (27), bar test (28), conditioned place preference (CPP) (29) and SA procedures (20, 30, 31) are described in Supplemental Information.…”

Section: Methodsmentioning

confidence: 99%

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Charbogne

Gardon

Martín‐García

et al. 2017

Biological Psychiatry

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BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.

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Section: Methodsmentioning

confidence: 99%

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Charbogne

Gardon

Martín‐García

et al. 2017

Biological Psychiatry

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“…In an extension of Amsel’s work, one study demonstrated an interaction between FNR and threat processing, in that frustrated mice exhibited increased aggressive responses in an intruder paradigm ([12], Figure 1). Indeed, based on other rodent research, Gray [13] proposed the “fear=frustration” hypothesis, suggesting that frustration is processed as a threat and responses to both are mediated by the behavioral inhibition system.…”

Section: The Neuroscience Of Irritabilitymentioning

confidence: 99%

“…Top left: When exposed to the threat of a conspecific in a resident intruder paradigm, frustrated mice show increased aggressive behavior. This aggression is greater than that exhibited by non-frustrated mice (not shown) [12]. Bottom left: Irritability in youth is associated with aberrant amygdala-prefrontal cortex connectivity when viewing threatening faces [37]; see Figure 2 for details.…”

Section: Figure 1 (Key Figure)mentioning

confidence: 99%

“…Experimental manipulations that expose an organism to threat can be used to study between-strain or between-subject differences in response to frustration, in the form of irritable behavior. Top right: Frustration is induced in a mouse by withholding food reward when the appearance of the conditioned stimulus (light cue) signals the opportunity to obtain reward through lever press [12]. Bottom right: Frustration is induced in a child by a game that is rigged so that the child does not receive an expected reward [74]; see also Figure 3.…”

Section: Figure 1 (Key Figure)mentioning

confidence: 99%

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Pediatric Irritability: A Systems Neuroscience Approach

Leibenluft

2017

Trends in Cognitive Sciences

146

129

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Irritability, defined as an increased propensity to exhibit increased anger relative to one’s peers, is a common clinical problem in youth. Irritability can be conceptualized as aberrant responses to frustration (where frustration is the emotional response to blocked goal attainment) and/or aberrant “approach” responses to threat. Irritable youth show hyper-reactivity to threat mediated by dysfunction in amygdala, medial prefrontal cortex, ACC, insula, striatum, and association cortex. Irritable youth also show abnormalities in reward learning, cognitive control, and responses to frustration. These abnormalities are mediated by circuitry that includes the inferior frontal gyrus, striatum, anterior cingulate and parietal cortices. Effective treatments for irritability are lacking; pathophysiological research can lead to more precisely targeted interventions.

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“…Nicotine self-administration sessions were performed in accordance to protocols previously described (Burokas et al, 2012;Martin-Garcia et al, 2009;Soria et al, 2008;Soria et al, 2005). Details of the apparatus, surgery, and the nicotine self-administration procedure are included in the Supplementary Information.…”

Section: Intravenous Nicotine Self-administrationmentioning

confidence: 99%

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

Navarrete

Rodrı́guez-Arias

Martín‐García

et al. 2013

Neuropsychopharmacol

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108

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This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and a3-and a4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with a3-and a4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and selfadministered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, a3-nAChR, and a4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with a3-and a4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.

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Operant model of frustrated expected reward in mice

Cited by 43 publications

References 29 publications

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Pediatric Irritability: A Systems Neuroscience Approach

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

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