mTOR signaling in the nucleus accumbens mediates behavioral sensitization to methamphetamine

Huang, Shin-Han; Wu, Wanrong; Li, Liming; Huang, Peng; Chen, Jin-Chung

doi:10.1016/j.pnpbp.2018.03.017

Cited by 30 publications

(36 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, deficits and mutations in eIF2 and eIF4 pathways have been associated with neurological disorders and aging [96,97]. The fact that these pathways are deeply affected by Meth, and their recovery in the presence of Tat, suggests the potential involvement of upstream mTOR [98][99][100][101][102] as a critical element in Tat along with Meth sensitization, and as a response to mitochondrial oxidative stress [103,104]. In the presence of Tat, mitochondrial dysfunction and oxidative phosphorylation pathways were also maintained at control levels.…”

Section: Discussionmentioning

confidence: 99%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

View full text Add to dashboard Cite

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

show abstract

Section: Discussionmentioning

confidence: 99%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

View full text Add to dashboard Cite

show abstract

“…Interestingly, they all converge on mTOR signaling (see Section 6, Table 1). In fact, mTOR-induced autophagy inhibition exacerbates the ultrastructural effects of METH [126,134,135,136], while rapamycin administration reverts both behavioral and morphological alterations induced by METH [137]. Such an issue will be further dealt with in the next paragraph.…”

Section: Beyond Classic Neurodegenerationmentioning

confidence: 99%

“…The abnormal activity of DA receptors is an additional commonality between METH and schizophrenia, which is likely to represent the molecular mechanism underlying behavioral alterations [130,131,132]. Remarkably, mTOR over-activation was recently linked to METH-induced behavioral sensitization, while rapamycin prevents such an effect [137]. Likewise, rapamycin was found to be beneficial for ameliorating psychotic symptoms [109,112,114,153,154].…”

Section: Bridging Neurodegeneration and Psychiatric Disorders: Thementioning

confidence: 99%

“…Therefore, disruption of DISC1 activity, due to genetic rearrangements (i.e., balanced (1;11) (q42;q14) chromosomal translocation) or missense mutations, produces schizophrenic-like behavior, which is bound to enhanced Akt activity, over-activation of mTOR signaling, and depressed autophagy [213,214,215]. Likewise, administration of either D1R agonists or METH enhances Akt activity and over-activates mTOR signaling [133,137,216]. Remarkably, inhibition of mTOR with rapamycin reverses the effects occurring in both DISC1-shRNA and METH-treated mice, while ameliorating behavioral alterations [137,153,212].…”

Section: Mtor Modulation Of Dopamine Transmission In Methamphetamimentioning

confidence: 99%

“…Likewise, administration of either D1R agonists or METH enhances Akt activity and over-activates mTOR signaling [133,137,216]. Remarkably, inhibition of mTOR with rapamycin reverses the effects occurring in both DISC1-shRNA and METH-treated mice, while ameliorating behavioral alterations [137,153,212]. Again, an impaired Akt signaling, achieved by neuronal deletion of rictor, a key regulatory subunit of mTORC2, contributes to schizophrenia-like phenotypes in rictor-null (KO) mice [217].…”

Section: Mtor Modulation Of Dopamine Transmission In Methamphetamimentioning

confidence: 99%

See 2 more Smart Citations

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

show abstract

mTOR Expression in Hippocampus and Prefrontal Cortex Is Downregulated in a Rat Model of Schizophrenia Induced by Chronic Administration of Ketamine

Xie

et al. 2020

J Mol Neurosci

View full text Add to dashboard Cite

mTOR signaling in the nucleus accumbens mediates behavioral sensitization to methamphetamine

Cited by 30 publications

References 39 publications

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

mTOR Expression in Hippocampus and Prefrontal Cortex Is Downregulated in a Rat Model of Schizophrenia Induced by Chronic Administration of Ketamine

Contact Info

Product

Resources

About