Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use.
TL;DR: Results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.
Abstract: A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.
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TL;DR: The circuit- and cell-level mechanisms of addiction are discussed and interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction.
926 citations
Cites background or result from "Strengthening the accumbal indirect..."
...In contrast to the findings of low striatal D2R in addicted individuals, which in laboratory animals is associated with vulnerability for compulsive cocaine intake, the chemogenetic stimulation of D2R-MSNs (perhaps somewhat akin to lack of DA inhibition through D2R) has been shown to inhibit cocaine intake in mice (Bock et al., 2013)....
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...…D2R in addicted individuals, which in laboratory animals is associated with vulnerability for compulsive cocaine intake, the chemogenetic stimulation of D2R-MSNs (perhaps somewhat akin to lack of DA inhibition through D2R) has been shown to inhibit cocaine intake in mice (Bock et al., 2013)....
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TL;DR: A specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): DREADDs (designer receptors exclusively activated by designer drugs), which is shown to be used ubiquitously to modulate GPCR activity noninvasively in vivo.
Abstract: In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.
532 citations
TL;DR: A review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the Accumbens can inhibit drug seeking in the laboratory setting is provided.
Abstract: The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
408 citations
Cites background from "Strengthening the accumbal indirect..."
...Interestingly, increasing the activity of D2 MSNs normalizes motivated behavior and attenuates drug-seeking behavior (Bock et al., 2013)....
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...Overall, the emerging literature using these D1 and D2 transgenic mice supports a role for D1 MSNs in positively regulating psychostimulant-induced behavioral and cellular responses and D2MSNs in negatively regulating these behaviors (Bertran-Gonzalez et al., 2008; Hikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011; Bock et al., 2013; Farrell et al., 2013; Park et al., 2013)....
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...A number of reports indicate that cocaine-induced behaviors, including seeking and sensitization, are mediated by activation of D1 MSNs (Ferguson et al., 2011; Lobo and Nestler, 2011; Bock et al., 2013; Smith et al., 2013)....
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...In general, most studies show that exposure to cocaine, irrespective of the behavioral model, potentiates excitatory input onto D1 MSNs but not D2 MSNs (Bertran-Gonzalez et al., 2008; Dobi et al., 2011; Pascoli et al., 2012; Bock et al., 2013; MacAskill et al., 2014)....
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...…D1 MSNs in positively regulating psychostimulant-induced behavioral and cellular responses and D2MSNs in negatively regulating these behaviors (Bertran-Gonzalez et al., 2008; Hikida et al., 2010; Lobo et al., 2010; Ferguson et al., 2011; Bock et al., 2013; Farrell et al., 2013; Park et al., 2013)....
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TL;DR: The role of the DA system in drug addiction and food motivation is focused on, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
Abstract: Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
408 citations
Cites background or methods from "Strengthening the accumbal indirect..."
...Recently, Alvarez and co-workers reported that synaptic strengthening onto D2-expressing MSNs in the NAc occurs in mice with a history of intravenous cocaine self-administration (Bock et al., 2013)....
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...Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, while optogenetic activation of D2-MSNs suppressed cocaine self-administration, suggesting that recruitment of D2-MSNs in the NAc functions to restrain cocaine self-administration (Bock et al., 2013)....
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TL;DR: An update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors is provided.
Abstract: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
400 citations
Cites background from "Strengthening the accumbal indirect..."
..., 2013), it has been shown that strengthening the accumbal indirect pathway via D2 receptors promotes resilience to compulsive cocaine use (Bock et al., 2013)....
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...…optogenetic and chemogenetic approaches based on designer receptors exclusively activated by designer drugs (DREADD) technology (Lee et al., 2013), it has been shown that strengthening the accumbal indirect pathway via D2 receptors promotes resilience to compulsive cocaine use (Bock et al., 2013)....
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References
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TL;DR: These findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.
Abstract: Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.
1,614 citations
TL;DR: The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.
Abstract: The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems—so-called direct and indirect pathways—form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D1 and D2 DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.
1,352 citations
TL;DR: This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats to examine psychostimulant and opiate reinforcement.
1,242 citations
TL;DR: This work describes a simple, software-based approach to operating a laser scanning microscope without the need for custom data acquisition hardware and quantifies the effectiveness of the data acquisition and signal conditioning algorithm under a variety of conditions.
Abstract: Background: Laser scanning microscopy is a powerful tool for analyzing the structure and function of biological specimens. Although numerous commercial laser scanning microscopes exist, some of the more interesting and challenging applications demand custom design. A major impediment to custom design is the difficulty of building custom data acquisition hardware and writing the complex software required to run the laser scanning microscope. Results: We describe a simple, software-based approach to operating a laser scanning microscope without the need for custom data acquisition hardware. Data acquisition and control of laser scanning are achieved through standard data acquisition boards. The entire burden of signal integration and image processing is placed on the CPU of the computer. We quantitate the effectiveness of our data acquisition and signal conditioning algorithm under a variety of conditions. We implement our approach in an open source software package (ScanImage) and describe its functionality. Conclusions: We present ScanImage, software to run a flexible laser scanning microscope that allows easy custom design.
1,223 citations
TL;DR: It is reported that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine.
Abstract: Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use (“addiction”) can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.
1,027 citations