Deletion of the δ Opioid Receptor Gene Impairs Place Conditioning But Preserves Morphine Reinforcement

Merrer, Julie Le; Plaza-Zabala, Ainhoa; Boca, Carolina Del; Matifas, Audrey; Maldonado, Rafaël; Kieffer, Brigitte L.

doi:10.1016/j.biopsych.2010.10.021

Cited by 71 publications

(88 citation statements)

References 18 publications

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Section: Introductionsupporting

confidence: 65%

“…Others and we showed that morphine-induced place conditioning is reduced in these animals (Chefer and Shippenberg, 2009;Le Merrer et al, 2012b;Le Merrer et al, 2011). Our results (Le Merrer et al, 2012b;Le Merrer et al, 2011) further suggested that this phenotype may reflect deficient ability to form drug-context associations rather than deficient reward processes, leading us to speculate that hippocampal function is altered in Oprd1 À / À mice. Finally, previous experiments showed increased break points for morphine self-administration under a progressive-ratio schedule of reinforcement (Le Merrer et al, 2011), as well as increased motor impulsivity (Olmstead et al, 2009) in Oprd1 À / À mice, suggesting that striatal function may also be modified in these animals.…”

Section: Introductionsupporting

confidence: 65%

“…Our results (Le Merrer et al, 2012b;Le Merrer et al, 2011) further suggested that this phenotype may reflect deficient ability to form drug-context associations rather than deficient reward processes, leading us to speculate that hippocampal function is altered in Oprd1 À / À mice. Finally, previous experiments showed increased break points for morphine self-administration under a progressive-ratio schedule of reinforcement (Le Merrer et al, 2011), as well as increased motor impulsivity (Olmstead et al, 2009) in Oprd1 À / À mice, suggesting that striatal function may also be modified in these animals. We therefore designed the present study to characterize learning and memory abilities in Oprd1 À / À animals, and examined both HPC-dependent and striatum-dependent responses.…”

Section: Introductionsupporting

confidence: 57%

“…We had previously observed that delta opioid receptor knockout mice show reduced ability to form drug-context but not drug-cue associations in a place-conditioning task, suggesting that hippocampal-dependent learning may be deficient in these animals (Le Merrer et al, 2012b;Le Merrer et al, 2011). Here, we demonstrate a key role for delta A total of 67 genes encoding actors of GABA, glutamate or monoamine signaling, and neuronal markers (see Supplementary Table S2), were tested and only genes showing a significant fold-change difference are shown.…”

Section: Discussionmentioning

confidence: 99%

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Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

Merrer

Rezaï

Scherrer

et al. 2013

Neuropsychopharmacol

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Pharmacological data suggest that delta opioid receptors modulate learning and memory processes. In the present study, we investigated whether inactivation of the delta opioid receptor modifies hippocampus (HPC)-and striatum-dependent behaviors. We first assessed HPC-dependent learning in mice lacking the receptor (Oprd1 À / À mice) or wild-type (WT) mice treated with the delta opioid antagonist naltrindole using novel object recognition, and a dual-solution cross-maze task. Second, we subjected mutant animals to memory tests addressing striatum-dependent learning using a single-solution response cross-maze task and a motor skill-learning task. Genetic and pharmacological inactivation of delta opioid receptors reduced performance in HPC-dependent object place recognition. Place learning was also altered in Oprd1 À / À animals, whereas striatum-dependent response and procedural learning were facilitated. Third, we investigated the expression levels for a large set of genes involved in neurotransmission in both HPC and striatum of Oprd1 À / À mice. Gene expression was modified for several key genes that may contribute to alter hippocampal and striatal functions, and bias striatal output towards striatonigral activity. To test this hypothesis, we finally examined locomotor effects of dopamine receptor agonists. We found that Oprd1 À / À and naltrindole-treated WT mice were more sensitive to the stimulant locomotor effect of SKF-81297 (D1/D5), supporting the hypothesis of facilitated striatonigral output. These data suggest, for the first time, that delta receptor activity tonically inhibits striatal function, and demonstrate that delta opioid receptors modulate learning and memory performance by regulating the HPC/striatum balance.

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Section: Introductionsupporting

confidence: 65%

Section: Introductionsupporting

confidence: 65%

Section: Introductionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

Merrer

Rezaï

Scherrer

et al. 2013

Neuropsychopharmacol

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“…The importance of hippocampal delta (d)-opioid receptors to learning and memory (but not morphine reinforcement) has recently been demonstrated [36,37]. Mice lacking d-opioid receptors (Oprd1 2/2 ), for example, exhibit increased motor impulsivity, but no obvious alteration of pain perception [38].…”

Section: Introductionmentioning

confidence: 99%

Comparison of interval timing behaviour in mice following dorsal or ventral hippocampal lesions with mice having δ -opioid receptor gene deletion

Yin

Meck

2014

Phil. Trans. R. Soc. B

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Mice with cytotoxic lesions of the dorsal hippocampus (DH) underestimated 15 s and 45 s target durations in a bi-peak procedure as evidenced by proportional leftward shifts of the peak functions that emerged during training as a result of decreases in both ‘start’ and ‘stop’ times. In contrast, mice with lesions of the ventral hippocampus (VH) displayed rightward shifts that were immediately present and were largely limited to increases in the ‘stop’ time for the 45 s target duration. Moreover, the effects of the DH lesions were congruent with the scalar property of interval timing in that the 15 s and 45 s functions superimposed when plotted on a relative timescale, whereas the effects of the VH lesions violated the scalar property. Mice with DH lesions also showed enhanced reversal learning in comparison to control and VH lesioned mice. These results are compared with the timing distortions observed in mice lacking δ -opioid receptors (Oprd1 −/− ) which were similar to mice with DH lesions. Taken together, these results suggest a balance between hippocampal–striatal interactions for interval timing and demonstrate possible functional dissociations along the septotemporal axis of the hippocampus in terms of motivation, timed response thresholds and encoding in temporal memory.

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Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Macdonald

Holmes

Beall

et al. 2019

Glia

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A role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated.

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Deletion of the δ Opioid Receptor Gene Impairs Place Conditioning But Preserves Morphine Reinforcement

Abstract: Collectively, the data suggest that δ receptor activity is not involved in morphine reinforcement but facilitates place conditioning. This study reveals a novel aspect of δ opioid receptor function in addiction-related behaviors.

Cited by 71 publications

References 18 publications

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

Comparison of interval timing behaviour in mice following dorsal or ventral hippocampal lesions with mice having δ -opioid receptor gene deletion

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

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