Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine

Mashayekhi, Farideh Jalali; Rasti, Mozhgan; Khoshdel, Zahra; Owji, Ali Akbar

doi:10.1159/000495362

Cited by 13 publications

(6 citation statements)

References 52 publications

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“…Here, spontaneous heroin withdrawal induced an up‐regulation of TH in the VTA. However, two previous studies did not find differences during spontaneous 49 or induced 50 morphine withdrawal, whereas a marked TH up‐regulation was shown in the locus coeruleus. These apparent discrepancies may occur because of differences in the opioid employed (morphine vs. heroin) or the protocol to evaluate spontaneous withdrawal (administration route, opioid treatment duration and time point of withdrawal evaluation).…”

Section: Discussionmentioning

confidence: 63%

CBD‐mediated regulation of heroin withdrawal‐induced behavioural and molecular changes in mice

2022

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Cannabidiol (CBD) may represent a promising therapeutic tool for treating opioid use disorder (OUD). This study was aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous heroin withdrawal. Thirty hours after cessation of 8-day heroin treatment (5, 10, 20 and 40 mgÁkg À1 /12 h; s.c.), spontaneous heroin withdrawal was evaluated in CD1 male mice. The effects of CBD (5, 10 and 20 mgÁkg À1 ; i.p.) on withdrawal-related behaviour were evaluated by measuring anxiety-like behaviour, motor activity and somatic signs. Furthermore, gene expression changes of mu-opioid receptor (Oprm1), proopiomelanocortin (Pomc), cannabinoid CB1 (Cnr1) and CB2 (Cnr2) receptors in the nucleus accumbens (NAcc) and tyrosine hydroxylase (TH) and Pomc in the ventral tegmental area (VTA) were also evaluated by real-time PCR. Anxiety-like behaviour, motor activity and withdrawal-related somatic signs were significantly increased in heroin-treated mice compared to the control group. Interestingly, CBD treatment significantly reduced these behavioural impairments and normalized gene expression of Cnr1 and Pomc in the NAcc and TH in the VTA of mice exposed to spontaneous heroin withdrawal. Also, CBD induced an up-regulation of Cnr2, whereas it did not change the increased gene expression of Oprm1 in the NAcc of abstinent animals.The results suggest that CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for the treatment of heroin withdrawal.

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Section: Discussionmentioning

confidence: 63%

CBD‐mediated regulation of heroin withdrawal‐induced behavioural and molecular changes in mice

2022

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“…We therefore compared galanin and GalR1 mRNA expression in TH+ LC neurons of mice that received saline, chronic morphine, or underwent naloxone‐precipitated withdrawal following chronic morphine (Figure 3). TH mRNA was quantified as a positive control because its expression in LC is consistently enhanced by opioid exposure and withdrawal 6,20,38 . For TH, a one‐way ANOVA indicated a significant effect of treatment on intensity value ( F 2,15 = 6.739, p = 0.0010); intensity was significantly increased after chronic morphine ( p = 0.0177) and withdrawal ( p = 0.0008) compared to saline (Figures 3A–C and 4A).…”

Section: Resultsmentioning

confidence: 96%

Cell‐type specific expression and behavioral impact of galanin and GalR1 in the locus coeruleus during opioid withdrawal

et al. 2021

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The neuropeptide galanin is reported to attenuate opioid withdrawal symptoms, potentially by reducing neuronal hyperactivity in the noradrenergic locus coeruleus (LC) via galanin receptor 1 (GalR1). We evaluated this mechanism by using RNAscope in situ hybridization to characterize GalR1 mRNA distribution in the dorsal pons and to compare galanin and GalR1 mRNA expression in tyrosine hydroxylase‐positive (TH+) LC cells at baseline and following chronic morphine or precipitated withdrawal. We then used genetically altered mouse lines and pharmacology to test whether noradrenergic galanin (NE‐Gal) modulates withdrawal symptoms. RNAscope revealed that, while GalR1 signal was evident in the dorsal pons, 80.7% of the signal was attributable to TH− neurons outside the LC. Galanin and TH mRNA were abundant in LC cells at baseline and were further increased by withdrawal, whereas low basal GalR1 mRNA expression was unaltered by chronic morphine or withdrawal. Naloxone‐precipitated withdrawal symptoms in mice lacking NE‐Gal (GalcKO‐Dbh) were largely similar to WT littermates, indicating that loss of NE‐Gal does not exacerbate withdrawal. Complementary experiments using NE‐Gal overexpressor mice (NE‐Gal OX) and systemic administration of the galanin receptor agonist galnon revealed that increasing galanin signaling also failed to alter behavioral withdrawal, while suppressing noradrenergic transmission with the alpha‐2 adrenergic receptor agonist clonidine attenuated multiple symptoms. These results indicate that galanin does not acutely attenuate precipitated opioid withdrawal via an LC‐specific mechanism, which has important implications for the general role of galanin in regulation of somatic and affective opioid responses and LC activity.

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“…Other proteins, such as metastasis-associated protein 1 and heterogeneous nuclear ribonucleoprotein K, bind to TH gen promoter to stimulate TH transcription in neuronal cells [78,79]. TH expression can also be modulated via complex mechanisms involving aryl hydrocarbon receptor, histone H3 acetylation and DA transporter [80][81][82]. The potential role of LRRK2-PINK1 kinase pair to interact with these TFs, proteins and pathways to modulate TH expression needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

The role of tyrosine hydroxylase–dopamine pathway in Parkinson’s disease pathogenesis

Zhou

Saw

et al. 2022

Cell. Mol. Life Sci.

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Background Parkinson’s disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. Methods We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)–DA pathway. Results We demonstrated that PD-linked LRRK2 mutations were able to modulate TH–DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH–DA pathway. Conclusions Our findings highlight the vital role of the TH–DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH–DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH–DA pathway inhibitors in early or prodromic PD.

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Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine

Cited by 13 publications

References 52 publications

CBD‐mediated regulation of heroin withdrawal‐induced behavioural and molecular changes in mice

CBD‐mediated regulation of heroin withdrawal‐induced behavioural and molecular changes in mice

Cell‐type specific expression and behavioral impact of galanin and GalR1 in the locus coeruleus during opioid withdrawal

The role of tyrosine hydroxylase–dopamine pathway in Parkinson’s disease pathogenesis

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