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Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model.

ABSTRACT: We tested the hypothesis that infusion of anisomycin into the medial prefrontal cortex (mPFC) disrupts the reconsolidation of a cocaine-associated memory in the rat cocaine self-administration model. Male Sprague-Dawley rats were trained to lever press for cocaine self-administration (0.5 mg/kg/infusion) along with a cue light presentation on an FR1 followed by an FR3 schedule of reinforcement for 2 h/day. Rats were then given extinction sessions or an equivalent forced abstinence period followed by a 5 min memory reactivation session during which time they received an ip cocaine injection (10 mg/kg, ip) and were allowed to press for contingent cue light presentation. Immediately after reactivation, they were administered an intra-mPFC infusion of vehicle or anisomycin. Two additional control groups received extinction and either no memory reactivation and intra-mPFC infusions as above or intra-mPFC infusions 6 h after memory reactivation. A fourth group received forced abstinence and intra-mPFC infusions immediately after memory reactivation. Combined cocaine + cue-induced reinstatement was given 2-3 days (early) and 8-12 days (late) later. Rats given anisomycin in the Extinction + Reactivation demonstrated decreased reinstatement, while anisomycin treatment did not alter behavior in any of the other three groups. These results suggest that extinction training may recruit the mPFC such that it renders the memory susceptible to disruption by anisomycin. These findings have implications for using extinction training prior to or in conjunction with other therapies, including reconsolidation disruption, to enhance prefrontal control over drug-seeking behavior.

SUBMITTER: Sorg BA

PROVIDER: S-EPMC4346388 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model.

Sorg Barbara A BA Todd Ryan P RP Slaker Megan M Churchill Lynn L

Neuropharmacology 20150107

We tested the hypothesis that infusion of anisomycin into the medial prefrontal cortex (mPFC) disrupts the reconsolidation of a cocaine-associated memory in the rat cocaine self-administration model. Male Sprague-Dawley rats were trained to lever press for cocaine self-administration (0.5 mg/kg/infusion) along with a cue light presentation on an FR1 followed by an FR3 schedule of reinforcement for 2 h/day. Rats were then given extinction sessions or an equivalent forced abstinence period followe ...[more]

PMID: 25576371

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Project description:Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease's chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.

Dataset Information

Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model.

Publications

Anisomycin in the medial prefrontal cortex reduces reconsolidation of cocaine-associated memories in the rat self-administration model.

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