Aerobic Exercise Attenuates Reinstatement of Cocaine-Seeking Behavior and Associated Neuroadaptations in the Prefrontal Cortex

AbstractCue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30–46 days) withdrawal. Rats were gavage-infused with everolimus (0–1.0 mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24 h. No everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. In addition, everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. everolimus’ “anti-incubation” effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.

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Upregulation ofArc mRNA expression in the prefrontal cortex following cue-induced reinstatement of extinguished cocaine-seeking behavior

Synapse ◽

10.1002/syn.20502 ◽

2008 ◽

Vol 62 (6) ◽

pp. 421-431 ◽

Cited By ~ 39

Author(s):

Arturo R. Zavala ◽

Tracy Osredkar ◽

Jeffrey N. Joyce ◽

Janet L. Neisewander

Keyword(s):

Prefrontal Cortex ◽

Mrna Expression ◽

Cocaine Seeking ◽

Seeking Behavior

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Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

10.1101/533083 ◽

2019 ◽

Author(s):

William C. Buchta ◽

Aubin Moutal ◽

Bethany Hines ◽

Constanza Garcia-Keller ◽

Alexander C.W. Smith ◽

...

Keyword(s):

Prefrontal Cortex ◽

Treatment Options ◽

Health Concern ◽

Self Administration ◽

Drug Seeking ◽

Binding Partner ◽

Cocaine Seeking ◽

Seeking Behavior ◽

Medial Pfc

AbstractCocaine addiction is a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug-seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to Yoked saline controls. By contrast, cued-reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.

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Preclinical evidence to support repurposing Everolimus for craving reduction during protracted drug withdrawal

10.21203/rs.3.rs-147118/v1 ◽

2021 ◽

Author(s):

Alvin S. Chiu ◽

Matthew C. Kang ◽

Laura L. Huerta Sanchez ◽

Anne M. Fabella ◽

Kalysta N. Holder ◽

...

Keyword(s):

Prefrontal Cortex ◽

Metabotropic Glutamate Receptor ◽

Mtor Inhibition ◽

Oral Dosing ◽

Metabotropic Glutamate ◽

Early Withdrawal ◽

Cocaine Seeking ◽

Cocaine Craving ◽

Seeking Behavior ◽

Late Withdrawal

Abstract Cue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with Everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30-46 days) withdrawal. Rats were gavage-infused with Everolimus (0-1.0 mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with Everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24 h. No Everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. Additionally, Everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. Everolimus’ “anti-incubation” effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.

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Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice

10.1101/2020.06.18.158964 ◽

2020 ◽

Author(s):

Judit Cabana-Domínguez ◽

Elena Martín-García ◽

Ana Gallego-Roman ◽

Rafael Maldonado ◽

Noèlia Fernàndez-Castillo ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Short Term Memory ◽

Long Term Potentiation ◽

Cocaine Addiction ◽

Cocaine Exposure ◽

Self Administration ◽

Normal Behavior ◽

Cocaine Seeking ◽

Seeking Behavior

ABSTRACTBackground and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice.Experimental approachWe used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq.Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation.Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

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