Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Purohit, Kush; Parekh, Puja K.; Kern, Joseph; Logan, Ryan W.; Zheng, Lu; Huang, Yanhua H.; McClung, Colleen A.; Crabbe, John C.; Ozburn, Angela R.

doi:10.1111/acer.13626

Cited by 35 publications

(43 citation statements)

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“…Indeed, several recent studies have demonstrated that electrical activation of NAc via deep brain stimulation (DBS) can attenuate alcohol drinking in animals and reduce alcohol craving in human alcoholics. These data, along with the findings by Purohit and colleagues (), support the notion that sex may be a major factor for effective AUD treatments and should be incorporated as a biological variable into more alcohol drinking studies.…”

supporting

confidence: 71%

“…However, the observation of depressed excitatory signaling in D2 neurons (or enhanced competition by D1 neurons) suggests that increasing activity of the NAc or D2 neurons exclusively may also reduce alcohol drinking behavior. In the May 2018 issue of ACER , Purohit and colleagues () demonstrated that enhancing the activity of NAc neurons with DREADDs reduced binge drinking in female mice. This finding, contrary to the results found in males from Cassataro and colleagues (), strongly suggests sex differences in how the NAc controls binge drinking.…”

mentioning

confidence: 99%

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DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Pomrenze

Giovanetti

2018

Alcoholism Clin & Exp Res

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A LCOHOL USE DISORDERS (AUDs) are a devastating class of addictive disorders that incur a tremendous societal and economic burden. AUDs cost an estimated annual $235 billion in the United States (Rehm et al., 2009) and are very common with a 12-month prevalence of 13.9% and lifetime prevalence of 29.1% (Grant et al., 2015). Current treatment options are limited to psychosocial intervention, 3 FDA-approved medications (disulfiram, acamprosate, and naltrexone), and a handful of other drugs approved for other indications, all with relatively small effect sizes. In addition, most of the knowledge we have on the neurobiology of alcohol drinking in animals comes from male subjects. There is a clear need for a deeper understanding of the neurobiological mechanisms underlying AUDs.The nucleus accumbens (NAc) is a key component of brain reward circuitry important for motivated behaviors related to AUDs and other addictive disorders. The NAc drives motivation with dopamine supplied by the ventral tegmental area and medium spiny neuron (MSN) populations expressing dopamine D1 (G s -coupled) or D2 (G i/o -coupled) receptors, among other neurological markers (e.g., dynorphin, enkephalin, substance P). Extensive work shows that these populations exert opposing actions, such that D1 MSNs drive while D2 MSNs suppress motivated behavior (Bock et al., 2013). Dopamine modulates physiologic responses of MSNs to glutamate released from many cortical and limbic regions. Thus, dopamine likely exerts its drive over motivation through enhancing D1 MSN responses to glutamate while dampening these responses in D2 MSNs (Surmeier et al., 2007). In line with a role in addiction, alcohol self-administration increases extracellular dopamine in the NAc (Weiss et al., 1993) and the reinforcing effects of alcohol are blocked by dopamine antagonists when delivered into the NAc, for example, Rassnick and colleagues (1992). Moreover, alterations in NAc circuit function are thought to underlie certain features of AUDs. Physiologic data demonstrate that alcohol exposure leads to a potentiation of excitatory transmission in D1 MSNs and weakened or unchanged excitatory transmission in D2 MSNs (Beckley et al., 2016;Ji et al., 2017;Renteria et al., 2017Renteria et al., , 2018. These data support a role for D1 MSNs in driving and D2 MSNs in inhibiting motivated behavior and suggest that synaptic modifications within NAc subcircuits might underlie escalated drinking behavior after alcohol exposure. Thus, the NAc plays an essential role in AUDs and may serve as a candidate brain region for therapeutic intervention.A recent study reported reduced binge drinking following inhibition of NAc neurons with genetic tools (Designer Receptors Exclusively Activated by Designer Drugs [DREADDs]) in male mice (Cassataro et al., 2014). These data are consistent with the physiologic results described above, which were collected from male NAc brain slices. Thus, DREADD inhibition of the male NAc most likely reduced alcohol consumption by attenuating enhanced D1 MSN drive ove...

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confidence: 71%

mentioning

confidence: 99%

DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Pomrenze

Giovanetti

2018

Alcoholism Clin & Exp Res

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“…That is, in vivo chemogenetic manipulation of dMSN or iMSN via hM3Dq or hM4Di, mimicking glutamatergic or GABAergic enhancement, respectively, affected alcohol consumption with hM3Dq activation in dMSNs or hM4Di activation in iMSNs promoting alcohol consumption, and oppositely reducing consumption through hM3Dq activation in iMSNs or hM4Di in dMSNs (Cheng et al, 2017). Anatomically distinct functions of the NAc core and shell in alcohol consumption were revealed in a limited access mouse model where alcohol consumption was reduced or increased following hM3Dq or hM4Di stimulation, respectively, of the NAc core but not accumbal shell (Purohit et al, 2018). It has also been observed that activation of KORD in neurons projecting to the NAc from the ventral subiculum decreased context-induced relapse of alcohol self-administration (Marchant et al, 2016a).…”

Section: Addictionmentioning

confidence: 98%

Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

et al. 2019

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“…Mice were serially treated with vehicle prior to DID during week 1 to establish baseline drinking, then vehicle or CNO during weeks 2-5 to measure the effects of chronic treatment, and then mice were treated with vehicle again during week 6 to determine whether there were any lasting effects of chronic CNO treatment. Ethanol intake was measured as described in Purohit at al., 2018 [29]. For neuronal morphology analysis, female HDID-1 mice (S34.G36; n = 4-5/fluid type/treatment) were deeply anesthetized 22 h after the last DID and transcardially perfused with 0.01 M PBS and 4% w/v paraformaldehyde (PFA).…”

Section: Methodsmentioning

confidence: 99%

“…Purina brand food (5LOD, PMI Nutrition International, Brentwood, MO, USA) was suspended in a wire-top, and food and water were available ad libitum. Female mice were used in experiments 1 and 2 to facilitate comparison with data our group had previously published in C57BL/6J mice [29]. Male and female mice were used in experiment 3.…”

Section: Introductionmentioning

confidence: 99%

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

et al. 2020

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Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting effects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs.Brain Sci. 2020, 10, 109 2 of 22 (DID) paradigm, mice are offered an ethanol solution early into the active period of their circadian cycle and can achieve BALs >80 mg%, suggesting they drink to intoxication [1]. C57BL/6J mice are typically reported as high drinking and can achieve BALs >80mg% in the DID paradigm; however, significant inbred strain differences have been observed suggesting there exists a genetic contribution to this phenotype [2,3]. The DID assay was used to independently create two lines of mice, HDID-1 and HDID-2, that were selectively bred (from genetically heterogeneous HS/Npt progenitors) for high BALs after DID [4,5]. HDID and HS/Npt mice have been extensively characterized and HDID mice represent a unique genetic animal model of risk for drinking to intoxication [6][7][8][9][10][11][12][13][14]. FDA approved compounds for treatment of AUD, as well as several investigational compounds, have been tested for efficacy in reducing binge-like drinking using the DID paradigm in C57BL/6J and HDID mice, as well as other genotypes, with mixed results [15][16][17][18][19][20]. Together, the results of these studies suggest that testing potential therapies in more than one inbred strain may represent a more beneficial strategy for clinical translation.Koob and Volkow (2010) reviewed decades of clinical and pre-clinical studies to address the neural circuitry associated with the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation [21]. The nucleus accumbens (NAc) is identified as an important region for each of these three stages. There is also extensive evidence that altering activity in the NAc reduces alcohol drinking, craving, and relapse. To achiev...

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Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Cited by 35 publications

References 43 publications

DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

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