Dataset Information

The PI3-Kinase p110β Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

ABSTRACT:

Background

The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts.

Methods

Here, we inhibited PI3K p110β in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110β confers resilience to cocaine.

Results

Viral-mediated PI3K p110β silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110β inhibition restored this ability. Silencing dopamine D₂ receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110β inhibition restored goal-oriented action. We verified the presence of p110β in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110β in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex.

Conclusions

Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110β provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.

SUBMITTER: Shapiro LP

PROVIDER: S-EPMC8202243 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The PI3-Kinase p110β Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

Shapiro Lauren P LP Pitts Elizabeth G EG Li Dan C DC Barbee Britton R BR Hinton Elizabeth A EA Bassell Gary J GJ Gross Christina C Gourley Shannon L SL

Biological psychiatry 20210127 10

<h4>Background</h4>The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts.<h4>Methods</h4>Here, we inhibited PI3K p110β in the medial prefrontal cortex (mPFC) of cocaine-exp ...[more]

PMID: 33773752

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Project description:MicroRNAs (miRNAs) regulate many basic aspects of cell biology including neuronal plasticity, but little is known of their roles in drug addiction. Extended access to cocaine can trigger the emergence of compulsive drug-seeking behaviors, but molecular mechanisms regulating this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with extended access to cocaine. Striatal overexpression of miR-212 decreases, whereas its inhibition increases cocaine intake in rats with extended but not restricted drug access, suggesting that miR-212 serves as a protective factor against the development of compulsive drug seeking. The transcription factor CREB (cAMP response element-binding protein) is considered a core regulator of cocaine reward. We show that miR-212 controls responsiveness to cocaine by dramatically amplifying striatal CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in vulnerability to addiction, and that noncoding RNAs such as the miRNAs may serve as novel targets for the development of anti-addiction therapeutics. To identify potential targets for miR-212, we transfected cells with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. Human Affymetrix Study: Cells were transfected with a vector to overexpress miR-212 or an empty vector. We then analyzed profiled gene expression using Affymetrix arrays. The complete, unfiltered set of signal intensity data for Samples miR-212 and pMIF, including miR-212/pMIF ratios, are in the supplementary file at the foot of the record. Probes excluded from analysis (pMIF intensity <100) are indicated in the supplementary file by a no in the far-right column, 'Passed data filtering and included in analysis: no/yes'. Probes that were included in the analyses (pMIF intensity >100) are indicated in the supplementary file by a yes in the 'Passed data filtering and included in analysis: no/yes' column. Rat miRNA Study: Rats were permitted access to intravenous cocaine self-administration (0.5 mg/kg/infusion) for 7 consecutive days during restricted (1-h) or extended (6-h) daily sessions. Control rats remained coaine-naïve throughout. 24-h after the last session the dorsal striatum from each rats was removed, and RNA extracted for microarray profiling. There was a total of n=6 rats per access condition. RNA from 2 rats per access condition were pooled on to arrays, for a total of 3 arrays per access condition, and 9 arrays in total.

Dataset Information

The PI3-Kinase p110β Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

Background

Methods

Results

Conclusions

Publications

The PI3-Kinase p110β Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

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