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.

RETRACTED ARTICLE: Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies

“…Reportedly, therapy with morphine for at least three days results in substantial levels of morphine dependence [ 4 ]. Chronic morphine use promotes neurobiological adaptations, including synaptic and structural plasticity in specific brain regions, that ultimately lead to the development of addiction [ 5 , 6 ]. However, there is currently incomplete knowledge of the molecular mechanisms behind the transcriptional regulation of morphine addiction in the striatum, despite the tight association between this region and the establishment of drug-related habits and the consolidation of addiction [ 7 – 10 ].…”

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain

“…Experimental studies have shown that drugs of abuse elicit glutamatergic synaptic plasticity that contributes to the reorganization of neural circuits, and putatively, the establishment of addictive behaviors ( van Huijstee and Mansvelder, 2014 ; Christian et al, 2021 ; Pascoli et al, 2022 ). Dopamine, which is released in response to nicotine exposure, is a prerequisite for drug-induced plasticity ( Belin et al, 2009 ; Lee et al, 2020 ; Rivera et al, 2021 ), and a key regulator of structural and synaptic plasticity ( Urakubo et al, 2020 ; Speranza et al, 2021 ). In addition, nicotine activates nicotinic acetylcholine receptors (nAChRs), which also has been demonstrated to be important for synaptic plasticity at both inhibitory and excitatory synapses ( Dani et al, 2001 ; Partridge et al, 2002 ; Adermark, 2011 ).…”

Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice

“…Each slice was transferred to a recording chamber that was perfused continuously with oxygenated ACSF at 32–34 °C following our standard protocol [ 45 , 46 ]. LC neurons were visualized using infrared gradient contrast video microscopy (Eclipse workstation, Nikon) and with a 60X water-immersion objective (Fluor 60X/1.00 W, Nikon).…”