Dataset Information

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum.

ABSTRACT: Long-term exposition to morphine elicits structural and synaptic plasticity in reward-related regions of the brain, playing a critical role in addiction. However, morphine-induced neuroadaptations in the dorsal striatum have been poorly studied despite its key function in drug-related habit learning. Here, we show that prolonged treatment with morphine triggered the retraction of the dendritic arbor and the loss of dendritic spines in the dorsal striatal projection neurons (MSNs). In an attempt to extend previous findings, we also explored whether the dopamine D4 receptor (D4R) could modulate striatal morphine-induced plasticity. The combined treatment of morphine with the D4R agonist PD168,077 produced an expansion of the MSNs dendritic arbors and restored dendritic spine density. At the electrophysiological level, PD168,077 in combination with morphine altered the electrical properties of the MSNs and decreased their excitability. Finally, results from the sustantia nigra showed that PD168,077 counteracted morphine-induced upregulation of μ opioid receptors (MOR) in striatonigral projections and downregulation of G protein-gated inward rectifier K+ channels (GIRK1 and GIRK2) in dopaminergic cells. The present results highlight the key function of D4R modulating morphine-induced plasticity in the dorsal striatum. Thus, D4R could represent a valuable pharmacological target for the safety use of morphine in pain management.

SUBMITTER: Rivera A

PROVIDER: S-EPMC8750869 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Dopamine D<sub>4</sub> Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum.

Rivera Alicia A Suárez-Boomgaard Diana D Miguelez Cristina C Valderrama-Carvajal Alejandra A Baufreton Jérôme J Shumilov Kirill K Taupignon Anne A Gago Belén B Real M Ángeles MÁ

Cells 20211223 1

Long-term exposition to morphine elicits structural and synaptic plasticity in reward-related regions of the brain, playing a critical role in addiction. However, morphine-induced neuroadaptations in the dorsal striatum have been poorly studied despite its key function in drug-related habit learning. Here, we show that prolonged treatment with morphine triggered the retraction of the dendritic arbor and the loss of dendritic spines in the dorsal striatal projection neurons (MSNs). In an attempt ...[more]

PMID: 35011592

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Project description:Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked DA release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum (DS) of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein, we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The DS, therefore, exhibits a total of at least five distinct evoked responses (four fast types and one slow type). All five response types conform to kinetic models based entirely on first-order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the DS terminal field. We report also that functionally distinct subregions of the DS express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct subregions of this key DA terminal field. The dorsal striatum is composed of five significantly different dopamine domains (types 1-4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion model of evoked dopamine overflow. We also report that functionally distinct subregions of the dorsal striatum express selective dopamine kinetic diversity.

Project description:Stressful experiences form stronger memories due to enhanced neural plasticity mechanisms linked to glucocorticoid hormones (cortisol in humans, corticosterone in rats). Among other neural structures, the dorsal striatum plays a role in the corticosterone-induced consolidation of stressful memories, particularly in the cued water maze task. Neural plasticity is related to mitochondrial activity due to the relevance of energy production and signaling mechanisms for functional and morphological neuronal adaptations. Corticosterone has been shown to enhance brain mitochondrial activity by activating glucocorticoid receptors. In this context, striatum functions are susceptible to change in relation to mitochondrial responses. Based on this evidence, we hypothesized that training in the cued water maze would induce an increase in corticosterone levels and mitochondrial activity (mitochondrial membrane potential and calcium content) in the dorsal striatum, and that these adaptations might be related to memory consolidation of the task. We used an ELISA assay to evaluate plasma and striatal corticosterone levels; mitochondrial activity was determined with the florescent probes MitoTracker Red (mitochondrial membrane potential) and Rhod-2 (calcium content) in brain slices containing the dorsal striatum of rats trained in the cued water maze and euthanized at different times after training (0.5, 1.5, or 6.0 h). We also analyzed the effect of post-training inhibition of striatal mitochondrial activity by OXPHOS complex 1 inhibitor rotenone, on the consolidation of the cued water maze task. We found that cued water maze training induced an increase in corticosterone levels and a time-dependent elevation of mitochondrial membrane potential and mitochondrial calcium content in the dorsal striatum. Unexpectedly, rotenone administration facilitated the retention test. Altogether, our results suggest that enhanced mitochondrial activity in the dorsal striatum is relevant for cued water maze consolidation. The increase in mitochondrial activity was contextually associated with an elevation of corticosterone in plasma and the dorsal striatum. Additionally, our swimming groups also showed an increase in mitochondrial activity in the dorsal striatum, but with a different pattern, which could suggest a differential functional adaptation in this structure.

Dataset Information

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum.

Publications

Dopamine D<sub>4</sub> Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum.

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