Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward

Dai, Kathy Z.; Choi, In Bae; Levitt, Ryan; Blegen, Mariah B.; Kaplan, Alanna R.; Matsui, Aya; Shin, Jung Hoon; Bocarsly, Miriam E.; Simpson, Eleanor H.; Kellendonk, Christoph; Alvarez, Veronica A.; Dobbs, Lauren K.

doi:10.1016/j.celrep.2022.111440

Cited by 8 publications

(24 citation statements)

References 81 publications

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“…Our findings suggest that although striatal enkephalin is not necessary for acquisition and expression of conditioned cocaine reward, it maintains cocaine preference, as D2-PenkKO mice show faster extinction of CPP. This is consistent with our previous work, which shows that enhanced met-enkephalin tone in the striatum potentiates acquisition of cocaine place preference 1 . Thus, striatal enkephalin appears to augment cocaine reward, and heightened striatal enkephalin tone may facilitate cocaine-cue associations and prevent extinction learning.…”

Section: Discussionsupporting

confidence: 94%

“…Mice lacking striatal enkephalin extinguished cocaine preference faster and to a greater degree than littermate controls. This is consistent with previous research showing that enhanced striatal enkephalin tone facilitates acquisition of a cocainecontext association 1 . Quite surprisingly, though, naloxone treatment during extinction trials facilitated preference and prevented extinction in mice lacking striatal enkephalin.…”

supporting

confidence: 93%

“…Conversely, repeated treatment with naloxone in an extinction paradigm actually prevents extinction in subjects with low striatal enkephalin. This may be an important consideration for treatment of clinical populations because we previously demonstrated that withdrawal from short-term cocaine downregulates striatal Penk 1 . Thus, significant reduction of striatal enkephalin may occur in human subjects with casual, recreational use of cocaine as well as in subjects with single nucleotide polymorphisms in the Penk loci.…”

Section: Discussionmentioning

confidence: 99%

“…Penk is highly expressed in the striatum and localized to dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs). Evidence suggests that D2-MSNs release enkephalin within the striatum, where it suppresses local GABA transmission onto neighboring MSNs by acting via Gi -coupled MORs 1 . Shifting the balance of striatal output by dysregulating local striatal GABA transmission is associated with greater locomotor sensitization to repeated cocaine and faster acquisition of cocaine place preference 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, MORs expressed in specific ventral striatum subregions appear to mediate distinct aspects of cocaine reward. Blocking MORs in the nucleus accumbens core attenuates acquisition, while blocking MORs in the nucleus accumbens shell attenuates expression of cocaine place preference 1,2 . Data from constitutive Penk knockout mice suggest enkephalin may be the opioid peptide mediating the MOR response, as these mice have decreased cocaine self-administration, motivational breakpoint for cocaine, and cocaine-induced locomotor sensitization 3,4 .…”

Section: Introductionmentioning

confidence: 99%

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Striatal enkephalin supports maintenance of conditioned cocaine reward during extinction

Matsumura

Choi

Asokan

et al. 2023

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Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.

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Section: Discussionsupporting

confidence: 94%

supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%