Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats

Guglielmo, Giordano de; Kallupi, Marsida; Pomrenze, Matthew B.; Crawford, Elena; Simpson, Sierra; Schweitzer, Paul; Koob, George F.; Messing, Robert O.; George, Olivier

doi:10.1038/s41467-019-09183-0

Cited by 101 publications

(96 citation statements)

References 44 publications

(61 reference statements)

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“…Studies conducted in animals dependent on, or consuming binge quantities of, ethanol have identified CeA CRF signaling and CRF CeA neurons as a locus of ethanol effects on GABA transmission (Nie et al, 2004;Lowery-Gionta et al, 2012;Pleil et al, 2015;Herman et al, 2016;de Guglielmo et al, 2019). In fact, a recent study from de Guglielmo et al (2019) showed that inhibition of the Crh CeA->BNST projection in ethanol-dependent rats decreased ethanol intake and symptoms of somatic withdrawal, illustrating the potential of these neurons to mediate negative reinforcing aspects of ethanol consumption. Our data and others (Kim et al, 2017;McCullough et al, 2018) indicate that Nts CeA neurons are a subset of Crh CeA and Crh1 CeA neurons, suggesting that other genetically-overlapping CeA projections may also be modulated by a history of ethanol consumption.…”

Section: Cea Neurotensin Neurons In Ethanol Consumptionmentioning

confidence: 99%

“…In addition to Kim et al, other work in CeAPBN projections from genetically-defined subtypes, such as Htr2a (serotonin 2a receptor) and Pnoc (prepronociceptin), have shown that stimulation can support nose-poking behavior (Douglass et al, 2017;Hardaway et al, 2019). Another explanation may be that most of the experiments examining genetically-defined CeA populations have been conducted in mice, whereas studies stimulating the CeA as a whole have largely been performed in rats (however see de Guglielmo et al, 2019).…”

Section: Cea Neurotensin Neurons Promote Positive Valence Behaviorsmentioning

confidence: 99%

“…The central nucleus of the amygdala (CeA) is a heterogeneous structure that plays an important role in the regulation of appetitive, aversive, and ethanol-mediated behaviors (Mahler and Berridge, 2009;Tye et al, 2011;Robinson et al, 2014;McCall et al, 2015;Warlow et al, 2017;Kim et al, 2017;Douglass et al, 2017;Hardaway et al, 2019;Salling et al, 2016). While some data have shed light on neuronal subpopulations influencing fear-and feeding-related behaviors in the CeA (Haubensak et al, 2010;Cai et al, 2014;Douglass et al, 2017), it remains unclear which CeA subpopulations and efferents influence ethanol consumption, particularly during early ethanol seeking (Gilpin et al, 2015;de Guglielmo et al, 2019). A promising CeA subpopulation that may regulate ethanol behaviors are the neurons that express the 13 amino-acid neuropeptide neurotensin (NTS).…”

Section: Introductionmentioning

confidence: 99%

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Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice

Torruella-Suárez

Vandenberg

Cogan

et al. 2018

Preprint

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The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and their projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.

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Section: Cea Neurotensin Neurons In Ethanol Consumptionmentioning

confidence: 99%

Section: Cea Neurotensin Neurons Promote Positive Valence Behaviorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice

Torruella-Suárez

Vandenberg

Cogan

et al. 2018

Preprint

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“…Furthermore, yohimbine‐induced reinstatement of alcohol seeking increased the positive correlation between the CeA and AcbSh (Figure d). The BNST and CeA have strong bi‐directional interconnections implicated in stress and alcohol related behaviours (de Guglielmo, Kallupi, Pomrenze, Crawford & Simpson, ; Erb, Shaham & Stewart, ; Normandeau, Suárez, Sarret, McElligott & Dumont, ).…”

Section: Discussionmentioning

confidence: 99%

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

Kastman

Lawrence

2019

Eur J of Neuroscience

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Alcohol use disorders represent an extensive socioeconomic burden, yet effective treatment options are suboptimal. A major hurdle in treating alcohol use disorders is the high rate of relapse. Stress is a major factor that promotes relapse in abstinent drug users; therefore, understanding neural mechanisms that underpin the effects of stress on alcohol seeking is critical. In rodent models of stress‐induced relapse, the α2‐adrenoceptor antagonist, yohimbine, is a widely used chemical stressor to elicit reinstatement of drug/alcohol seeking. However, the exact mechanism how yohimbine precipitates reinstatement of alcohol seeking and the pattern of neural activation associated with yohimbine‐induced reinstatement is poorly understood. Therefore, we counted Fos‐protein positive nuclei across 42 brain regions in alcohol‐experienced alcohol preferring rats that received either yohimbine in the home‐cage (1 mg/kg i.p.) or following yohimbine‐induced reinstatement of alcohol seeking. The number of Fos‐protein positive nuclei was increased in the prefrontal cortex and extended amygdala after home‐cage yohimbine compared to naïve‐ and vehicle‐treated rats. Yohimbine‐induced reinstatement increased the number of Fos‐protein expressing nuclei in multiple other regions including the thalamus, hypothalamus and hippocampus. We then examined inter‐regional correlations in Fos‐protein expression for all 42 brain regions, which showed Fos expression was more strongly positively correlated following yohimbine‐induced reinstatement of alcohol seeking, compared to home‐cage yohimbine. These data suggest low‐dose yohimbine in a non‐drug‐associated context activates stress/impulsivity centres within the brain, whereas yohimbine in the drug‐associated context recruits additional brain regions to drive alcohol seeking.

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“…A second common difference across slice electrophysiology experiments is the recording temperature, with studies performing experiments either at room temperature (e.g., Kirson et al, ; de Guglielmo et al, ), or using an in‐line heater to maintain recording aCSF at a more physiologically relevant temperature (e.g., Herman et al, ; Ji et al, ). Recording temperature affects the excitability of neurons in vitro , with greater activity in cells maintained near physiological temperatures (e.g., Cao and Oertel, ; Lee et al, ; Micheva and Smith, ; Graham et al, ; Baginskas et al, ), and was therefore included as an additional variable in our experiments.…”

Section: Introductionmentioning

confidence: 99%

Synaptic GABAergic transmission in the central amygdala (CeA) of rats depends on slice preparation and recording conditions

2019

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The central nucleus of the amygdala (CeA) is a primarily GABAergic brain region implicated in stress and addictive disorders. Using in vitro slice electrophysiology, many studies measure GABAergic neurotransmission to evaluate the impact of experimental manipulations on inhibitory tone in the CeA, as a measure of alterations in CeA activity and function. In a recent study, we reported spontaneous inhibitory postsynaptic current (sIPSC) frequencies higher than those typically reported in CeA neurons in the literature, despite utilizing similar recording protocols and internal recording solutions. The purpose of this study was to systematically evaluate two common methods of slice preparation, an NMDG‐based aCSF perfusion method and an ice‐cold sucrose solution, as well as the use of an in‐line heater to control recording temperature, on measures of intrinsic excitability and spontaneous inhibitory neurotransmission in CeA neurons. We report that both slice preparation and recording conditions significantly impact spontaneous GABAergic transmission in CeA neurons, and that recording temperature, but not slicing solution, alters measures of intrinsic excitability in CeA neurons. Bath application of corticotropin‐releasing factor (CRF) increased sIPSC frequency under all conditions, but the magnitude of this effect was significantly different across recording conditions that elicited different baseline GABAergic transmission. Furthermore, CRF effects on synaptic transmission differed according to data reporting methods (i.e., raw vs. normalized data), which is important to consider in relation to baseline synaptic transmission values. These studies highlight the impact of experimental conditions and data reporting methods on neuronal excitability and synaptic transmission in the CeA.

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Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats

Cited by 101 publications

References 44 publications

Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice

Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

Synaptic GABAergic transmission in the central amygdala (CeA) of rats depends on slice preparation and recording conditions

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