scholarly journals Preclinical evidence to support repurposing everolimus for craving reduction during protracted drug withdrawal

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

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.

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

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.

scholarly journals Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

2010 ◽  
Vol 108 (1) ◽  
pp. 385-390 ◽  
Author(s):  
Khaled Moussawi ◽  
Wenhua Zhou ◽  
Haowei Shen ◽  
Carmela M. Reichel ◽  
Ronald E. See ◽  
...  
Keyword(s):  
Animal Model ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Synaptic Potentiation ◽  
Metabotropic Glutamate ◽  
Excitatory Transmission ◽  
Motivated Behavior ◽  
Cocaine Seeking ◽  
Glutamate Homeostasis ◽  
Induced Changes

Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.

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