Cocaine-induced neuroadaptations in the dorsal striatum: Glutamate dynamics and behavioral sensitization

Parikh, Vinay; Naughton, Sean X.; Shi, Xiaoming; Kelley, Leslie K.; Yegla, Brittney; Tallarida, Christopher S.; Unterwald, Ellen M.

doi:10.1016/j.neuint.2014.05.016

Cited by 39 publications

(30 citation statements)

References 85 publications

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“…Mice were injected with CA (1, 10 mg/kg ip) or saline (ip) for 7 days for analysis of GLT-1 expression in the nucleus accumbens using previously described methods (Rasmussen et al 2011; Parikh et al 2014). Twenty-four h after the last injection, mice were anesthetized with isoflurane and decapitated.…”

Section: Methodsmentioning

confidence: 99%

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

et al. 2015

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The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine’s reinforcing efficacy at 100-fold lower doses than CTX.

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Section: Methodsmentioning

confidence: 99%

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

et al. 2015

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“…Recently, the use of genetic cellular tagging has enabled researchers to identify the clusters of neurons within the PFC that trigger excitatory signals into NAc with exposure to cocaine cues (Cruz et al, 2014). Though not as extensively investigated as the NAc, the dorsal striatum also undergoes neuroplastic changes with repeated cocaine exposure; these are implicated in habit learning and in the automatic cocaine consumption triggered by repeated cocaine exposures (Everitt et al, 2008;Hearing et al, 2011;Lavaur et al, 2009;Parikh et al, 2014).…”

Section: Box 3 Synaptic Plasticity In Da Circuitsmentioning

confidence: 99%

The Brain on Drugs: From Reward to Addiction

Volkow

Morales

2015

Cell

1,025

777

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Advances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain's reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction.

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“…An example of these in observed for our prefrontal iGluR and SAPAP studies. In sensitized animals, normal function can be restored to the glutamatergically-overactive dorsal striatum by the introduction of AMPA antagonist [204]. This would fit our findings for the SAPAP studies, as the NMDA/AMPA receptor ratio is vital to proper synaptic functioning [205].…”

Section: Chapter 5 Conclusionsupporting

confidence: 78%

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

Summers¹

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DEDICATIONTo my mother Andrea, who through her example taught me that the values of hard work, integrity, and good manners never go out of style To Karen, who taught me the true meaning of courage under the threat of certain death, and that those no longer with us physically continue to live in our thoughts iv ACKNOWLEDGEMENTS All information and data in this text was only possible due to the generous support and inexhaustible patience of my advisor Jeff Steketee and my graduate committee (which included Drs. John Boughter, Michael McDonald, Kazuko Sakata, and Wen Lin Sun). Also, instrumental to the completion of this project were the helping hands of Dr. Steve Tavalin. This project also could have never been completed without financial support from the University of Tennessee Health Science Center Neuroscience Institute and the National Institute on Drug Abuse (NIDA).v ABSTRACT Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or cocaine sensitization would alter iGluRs levels in the mPFC, and SAPAP levels in multiple sites of the mesocorticolimbic system. To test these hypotheses, we investigated the effects of psychostimulant sensitization on various parameters of self-administration by infusing a low-dose cocaine reward proven to not induce sensitization during self-administration (reported here as 0.3 mg/kg/infusion). Although drug exposure did not significantly alter self-administration behavior, we did find that more drug exposed subjects acquired selfadministration behavior when compared to drug naïve controls. We also investigated the effects of acute cocaine exposure and/or cocaine sensitization on iGluRs in the mPFC and SAPAPs in the entire mesocorticolimbic circuit thru western blotting, immunolabeling of proteins of interest, and comparing protein levels to those found in cocaine naïve controls. A limited self-administration protocol also tested if SAPAP levels were altered by self-administration of a low-dose cocaine reward. For these experiments, we found that SAPAP protein levels are altered in multiple regions of the mesocorticolimbic system in response to contingent and non-contingent cocaine exposure, and that iGluR receptor subunits are altered in the prefrontal cortex in response to non-contingent cocaine exposure. vi PREFACEThe Incans that first cultivated the coca plant for medicinal use five millennia ago reserved this "Elix...

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Cocaine-induced neuroadaptations in the dorsal striatum: Glutamate dynamics and behavioral sensitization

Cited by 39 publications

References 85 publications

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

The Brain on Drugs: From Reward to Addiction

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

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