Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide Plays Critical Role in Psychostimulant-Induced Depression

Meng, Qingcai; Kim, Hyoung Chun; Oh, Seikwan; Lee, Yong Moon; Hu, Zhenzhen; Oh, Ki Wan

doi:10.4062/biomolther.2018.141

Cited by 15 publications

(16 citation statements)

References 78 publications

(111 reference statements)

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“…The neurobiological basis for induced depression in CUD does not seem to be primarily mediated by 5-HT dysfunction and other neurotransmitter pathways may be involved. In this regard, research has presented promising results showing alterations in dopamine pathways [ 45 ], the cocaine and amphetamine-regulated transcript (CART) peptide [ 46 ], and neurotrophins [ 47 ]. Cocaine reinforcing effects are directly related to the dopamine concentration in the mesocortical system.…”

Section: Discussionmentioning

confidence: 99%

The Tryptophan System in Cocaine-Induced Depression

Fonseca

Mestre-Pintó

Gómez-Gómez

et al. 2020

JCM

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Major depression disorder (MDD) is the most prevalent psychiatric comorbid condition in cocaine use disorder (CUD). The comorbid MDD might be primary-MDD (CUD-primary-MDD) or cocaine-induced MDD (CUD-induced-MDD), and their accurate diagnoses and treatment is a challenge for improving prognoses. This study aimed to assess the tryptophan/serotonin (Trp/5-HT) system with the acute tryptophan depletion test (ATD), and the kynurenine pathway in subjects with CUD-primary-MDD, CUD-induced-MDD, MDD and healthy controls. The ATD was performed with a randomized, double-blind, crossover, and placebo-controlled design. Markers of enzymatic activity of indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase, kynurenine aminotransferase (KAT) and kynureninase were also established. Following ATD, we observed a decrease in Trp levels in all groups. Comparison between CUD-induced-MDD and MDD revealed significant differences in 5-HT plasma concentrations (512 + 332 ng/mL vs. 107 + 127 ng/mL, p = 0.039) and the Kyn/5-HT ratio (11 + 15 vs. 112 + 136; p = 0.012), whereas there were no differences between CUD-primary-MDD and MDD. Effect size coefficients show a gradient for all targeted markers (d range 0.72–1.67). Results suggest different pathogenesis for CUD-induced-MDD, with lower participation of the tryptophan system, probably more related to other neurotransmitter pathways and accordingly suggesting the need for a different pharmacological treatment approach.

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Section: Discussionmentioning

confidence: 99%

The Tryptophan System in Cocaine-Induced Depression

Fonseca

Mestre-Pintó

Gómez-Gómez

et al. 2020

JCM

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“…This indicates that in addition to MOPs, CART may also be involved in morphine addiction-related signaling [ 54 , 55 ]. The CART peptide is known to play a role in regulating the behavioral sensitization induced by psychostimulants [ 56 ], and the resulting addiction-related anxious and aversive emotions can lead to depression-like behaviors that may ultimately facilitate suicidal actions possibly mediated by GABAergic pathways [ 57 , 58 ]. Therefore, we speculate that the effect of DBS is similar to that of morphine; however, unlike morphine, NAc-DBS does not lead to addiction.…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model

Song

Gao

et al. 2020

Translational Neuroscience

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Deep brain stimulation (DBS) applied to the nucleus accumbens (NAc) alleviates the depressive symptoms of major depressive disorders. We investigated the mechanism of this effect by assessing gene expression and RNA methylation changes in the ventral tegmental area (VTA) following NAc-DBS in a chronic unpredictable mild stress (CUMS) mouse model of depression. Gene expression and N6-methyladenosine (m6A) levels in the VTA were measured in mice subjected to CUMS and then DBS, and transcriptome-wide m6A changes were profiled using immunoprecipitated methylated RNAs with microarrays, prior to gene ontology analysis. The expression levels of genes linked to neurotransmitter receptors, transporters, transcription factors, neuronal activities, synaptic functions, and mitogen-activated protein kinase and dopamine signaling were upregulated in the VTA upon NAc-DBS. Furthermore, m6A modifications included both hypermethylation and hypomethylation, and changes were positively correlated with the upregulation of some genes. Moreover, the effects of CUMS on gene expression and m6A-mRNA modification were reversed by DBS for some genes. Interestingly, while the expression of certain genes was not changed by DBS, long-term stimulation did alter their m6A modifications. NAc-DBS-induced modifications are correlated largely with upregulation but sometimes downregulation of genes in CUMS mice. Our findings improve the current understanding of the molecular mechanisms underlying DBS effects on depression.

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“…Thus, along with these recent positive clinical findings and other major advances in gene editing technology, CART (Cocaine‐and‐Amphetamine‐Regulated Transcription) peptide technology, sphingolipid‐controlled autophagy, represent important targets that are rapidly increasing our understanding of neural circuits in stratifying patient populations based on biological phenotypes. And, in extreme pharmacological responsiveness to psychostimulant‐induced depression may well open up new avenues of research into the underlying pathophysiology of specific depressive disorders …”

Section: The Failure Of Experimental Disease Models Of Depressive Dismentioning

confidence: 99%

Depressive disorders: Treatment failures and poor prognosis over the last 50 years

Blackburn

2019

Pharmacology Res & Perspec

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Depression like many diseases is pleiotropic but unlike cancer and Alzheimer's disease for example, is still largely stigmatized and falls into the dark shadows of human illness. The failure of depression to be in the spotlight for successful treatment options is inherent in the complexity of the disease(s), flawed clinical diagnosis, overgeneralization of the illness, inadequate and biased clinical trial design, restrictive and biased inclusion/exclusion criteria, lack of approved/robust biomarkers, expensive imaging technology along with few advances in neurobiological hypotheses in decades. Clinical trial studies summitted to the regulatory agencies ( FDA / EMA ) for approval, have continually failed to show significant differences between active and placebo. For decades, we have acknowledged this failure, despite vigorous debated by all stakeholders to provide adequate answers to this escalating problem, with only a few new antidepressants approved in the last 20 years with equivocal efficacy, little improvement in side effects or onset of efficacy. It is also clear that funding and initiatives for mental illness lags far behind other life‐treating diseases. Thus, it is no surprise we have not achieved much success in the last 50 years in treating depression, but we are accountable for the many failures and suboptimal treatment. This review will therefore critically address where we have failed and how future advances in medical science offers a glimmer of light for the patient and aid our future understanding of the neurobiology and pathophysiology of the disease, enabling transformative therapies for the treatment of depressive disorders.

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Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide Plays Critical Role in Psychostimulant-Induced Depression

Cited by 15 publications

References 78 publications

The Tryptophan System in Cocaine-Induced Depression

The Tryptophan System in Cocaine-Induced Depression

Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model

Depressive disorders: Treatment failures and poor prognosis over the last 50 years

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