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

Alicia Rivera,Jérôme Baufreton,Kirill Shumilov,Diana Suárez-Boomgaard,Belén Gago,Alejandra Valderrama-Carvajal,Anne Taupignon,M Ángeles Real,Cristina Miguelez

doi:10.3390/cells11010031

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.

Highlights

Long-lasting use of drugs of abuse elicits persistent molecular and cellular neuroadaptive changes within discrete brain regions—e.g., ventral tegmental area (VTA), ventral and dorsal striatum, prefrontal cortex, amygdala, or hippocampus—which have been identified as the neural substrate for behavioral abnormalities driving addiction, drug craving, and relapse [1]
Nowadays major attention is being given to the caudate putamen (CPu)—dorsal striatum—since this region play a pivotal role in goal-directed behavior, drug-related habit learning and automaticity of drug consumption [7,8,9]
We found that morphine apparently did not alter the total number of dendrites (Figure 1B), neither the total dendrite length (Figure 1C) nor the number of nodes (Figure 1D)

Summary

Introduction

Long-lasting use of drugs of abuse elicits persistent molecular and cellular neuroadaptive changes within discrete brain regions—e.g., ventral tegmental area (VTA), ventral and dorsal striatum, prefrontal cortex, amygdala, or hippocampus—which have been identified as the neural substrate for behavioral abnormalities driving addiction, drug craving, and relapse [1]. Such drug-mediated alterations affect several neurotransmitters systems—e.g., dopaminergic, GABAergic or glutamatergic systems—signal transduction pathways, neuronal activity, cellular architecture remodeling and synaptic strength [2,3,4,5,6]. It has been hypothesized that the transition from recreational drug use to compulsive drug abuse, and the consolidation of drug-related instrumental behaviors, comprises a transition from the ventral to the dorsal areas of the striatum activity [10]

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