Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization

Koya, Eisuke; Golden, Sam A.; Harvey, Brandon K.; Guez-Barber, Danielle; Berkow, Alexander; Simmons, Danielle E.; Bossert, Jennifer M.; Nair, Sunila G; Uejima, Jamie L.; Marin, Marcelo Tadeu; Mitchell, Timothy B.; Farquhar, David; Ghosh, Sukhen C.; Mattson, Brandi J.; Hope, Bruce T.

doi:10.1038/nn.2364

Cited by 240 publications

(362 citation statements)

References 41 publications

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“…Finally, targeted delivery of a pharmacological agent allowed control of the cell cycle with cellular specificity. This general approach can be extended to other small organic compounds bearing appropriate maskable functionality to control disparate cellular behaviors such as neural activity, gene transcription, and protein synthesis with genetic specificity and high spatiotemporal precision (38).…”

Section: Resultsmentioning

confidence: 99%

Selective esterase–ester pair for targeting small molecules with cellular specificity

Tian

Yang

Wysocki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

163

212

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Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations. cellular imaging | microscopy | enzyme substrates | fluorophores | pharmacological agents C hemical probes are essential tools in biology for measuring and manipulating cellular properties. Optimization of the structural and electronic features of small molecules allows the fine-tuning of molecular recognition specificity for a particular cellular target. Even with high molecular specificity, however, the application of small molecules in complex biological environments is frequently limited by poor cellular specificity. The inability to target small molecules, such as imaging or pharmacological agents, to defined cellular populations can confound the evaluation and control of discrete subsets of cells within a multicellular environment. A general and efficient strategy for cell-specific targeting, combining the molecular specificity of small molecules with the cellular specificity of genetics, would allow intracellular pathways in defined cell types to be selectively probed in complex tissues.An attractive approach for general cell-specific delivery of small molecules employs selective enzyme-substrate pairs. In this strategy, compounds are masked by attachment of a standard, disposable blocking group that is stable to native cellular enzymes, but labile to a specific exogenous enzyme. Expression of such a protein in a genetically defined cell population permits unmasking of the small molecule with cellular specificity. To be useful across experimental paradigms, such a system should utilize an enzyme that unmasks molecules with high efficiency, expresses in different cell types, and exhibits low cellular toxicity. The cognate masking group must be modular, synthetically efficient, and allow molecules to diffuse passively across the cellular membrane, while also exhibiting favorable solubility and stability in aqueous solution.To date only a few enzyme-substrate pairs have been used as targeted delivery systems for small molecules, and none meet all the criteria outlined above. Strategies employing enzymes encoded by common reporter genes (1) have found some success in targeting small molecules (2-4), ...

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Section: Resultsmentioning

confidence: 99%

Selective esterase–ester pair for targeting small molecules with cellular specificity

Tian

Yang

Wysocki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

163

212

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“…One possible mechanism is the more robust DA release (39,40) and neuronal firing seen from drug-vs. nondrug-rewarded contexts. Distinct populations of NAc neurons differentially process information about goal-directed behaviors for cocaine versus natural reward (41,42). Further, cocaine administration has been suggested to more rapidly accelerate the development of habits than that of a food reinforcer (13).…”

Section: Discussionmentioning

confidence: 99%

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Liu

Chefer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experienceinduced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S−) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S− was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S−). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.context cues | neuroplasticity | drug addiction P reventing or reducing the incidence of relapse remains the major challenge for the treatment of addiction, as recidivism rates can range as high as 90%. Both preclinical (1) and human addiction studies (2) have demonstrated that following repeated pairings with drug administration, various contextual and environmental stimuli when subsequently presented alone can elicit drug-seeking and drug-taking behaviors. Further, dysregulation within specific brain circuits regulating cognitive control and/or emotional regulation (3) can amplify the perceived salience of environmental contexts and cues that provoke craving (4) and thereby enhance susceptibility to relapse (2). These observations speak to the important role of reward learning in addictive processes (5). As such, it is critical to better understand the neural mechanisms and circuitry underlying the retrieval of cue-induced memories as an important intermediary in developing more efficacious interventions to decrease recidivism.The amygdala, nucleus accumbens (NAc), and various prefrontal cortical regions respond to drug-associated cues in human cocaine addicts (6, 7). Supporting their critical roles in the neural circuitry of drug-seeking behavior, these regions have also been identified using preclinical reinstatement models (8, 9). For example, NAc neurons exhibit conditioned responses to drugassociated env...

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“…The acquisition of sensitization is facilitated by associative learning that links a specific context to drug exposure (Badiani et al, 1995). Specific alterations in immediate early gene expression and neuronal morphology are observed following such contextspecific sensitization (Robinson and Kolb, 1997;Mattson et al, 2008;Koya et al, 2009;Singer et al, 2009). Increased dendritic branching and spine density of medium spiny neurons in the nucleus accumbens (NAc) occur only with context-dependent sensitization but not following a context-independent paradigm (Singer et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

Benneyworth

Coyle

2012

Neuropsychopharmacol

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Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SRÀ/À) and glycine transporter 1 heterozygous mutant (GlyT1À/ + ). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SRÀ/À) or increased (GlyT1À/ + ) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SRÀ/À mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SRÀ/À mice. GlyT1 À/ + mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SRÀ/À data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia.

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Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization

Cited by 240 publications

References 41 publications

Selective esterase–ester pair for targeting small molecules with cellular specificity

Selective esterase–ester pair for targeting small molecules with cellular specificity

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

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