Lesions of the Lateral Habenula Increase Voluntary Ethanol Consumption and Operant Self-Administration, Block Yohimbine-Induced Reinstatement of Ethanol Seeking, and Attenuate Ethanol-Induced Conditioned Taste Aversion

Haack, Andrew K.; Sheth, Chandni; Schwager, A; Sinclair, Michael S.; Tandon, Shashank; Taha, Sharif A.

doi:10.1371/journal.pone.0092701

Cited by 62 publications

(67 citation statements)

References 41 publications

(57 reference statements)

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“…Interestingly, a previous study found that lesions of the LHb increase voluntary ethanol drinking and operant-self administration in rats (Haack et al, 2014), in contrast to the reduced drinking after DBS observed in our current study. The mechanisms underlying the disparity are unclear.…”

Section: Discussioncontrasting

confidence: 99%

High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats

Zuo

et al. 2016

IJNPPY

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Background:Development of new strategies that can effectively prevent and/or treat alcohol use disorders is of paramount importance, because the currently available treatments are inadequate. Increasing evidence indicates that the lateral habenula (LHb) plays an important role in aversion, drug abuse, and depression. In light of the success of high-frequency stimulation (HFS) of the LHb in improving helplessness behavior in rodents, we assessed the effects of LHb HFS on ethanol-drinking behavior in rats.Methods:We trained rats to drink ethanol under an intermittent access two-bottle choice procedure. We used c-Fos immunohistochemistry and electrophysiological approaches to examine LHb activity. We applied a HFS protocol that has proven effective for reducing helplessness behavior in rats via a bipolar electrode implanted into the LHb.Results:c-Fos protein expression and the frequency of both spontaneous action potential firings and spontaneous excitatory postsynaptic currents were higher in LHb neurons of ethanol-withdrawn rats compared to their ethanol-naïve counterparts. HFS to the LHb produced long-term reduction of intake and preference for ethanol, without altering locomotor activity. Conversely, low-frequency electrical stimulation to the LHb or HFS applied to the nearby nucleus did not affect drinking behavior.Conclusions:Our results suggest that withdrawal from chronic ethanol exposure increases glutamate release and the activity of LHb neurons, and that functional inhibition of the LHb via HFS reduces ethanol consumption. Thus, LHb HFS could be a potential new therapeutic option for alcoholics.

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Section: Discussioncontrasting

confidence: 99%

High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats

Zuo

et al. 2016

IJNPPY

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“…For instance, studies found that rats drink more alcohol if the LHb was lesioned before the start of drinking (Haack et al, 2014; Tandon et al, 2017), indicating that the LHb plays a brake-like role during the acquisition phase. Conversely, we found that temporal inhibition of the LHb by DNQX or chemogenetic tool reduced drinking in rats that have been drinking ethanol for two months, when the animals may have already become ethanol dependent (Li et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats

Kang

et al. 2017

Neuropharmacology

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Depression is a well-known risk factor for developing relapse drinking, but the neuronal mechanisms underlying the interactions between depression and alcohol use disorders remain elusive. Accumulating evidence has associated depression with hyperactivity of the lateral habenula (LHb), an epithalamic structure in the brain that encodes aversive signals. Glutamate receptors contribute substantially to the excitability of LHb neurons. Glutamatergic synapses in LHb neurons largely express GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that can be modulated by Ca2+/calmodulin-dependent protein II (CaMKII). In the current study, we tested the hypothesis that withdrawal from repeated cycles of ethanol drinking triggers an increase in LHb AMPAR and CaMKII activity concomitant with depression-like symptoms, and their inhibitions bring a reduction in depressive-like behaviors and alcohol consumption. Western blotting revealed a higher level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (GluA1-Ser831) in the LHb of ethanol-withdrawn rats than that of age-matched naïve counterparts. In ethanol-withdrawn rats, pharmacological inhibition of LHb AMPAR activity significantly mitigated the depressive-like behavior and ethanol drinking and seeking behaviors, but affected neither sucrose intake nor locomotor activity; and inhibition of LHb CaMKII activity, or chemogenetic inhibition of LHb activity produced similar effects. Conversely, activation of LHb AMPARs induced depressive-like behaviors in ethanol-naïve rats. These results demonstrate that CaMKII-AMPAR signaling in the LHb exemplifies a molecular basis for depressive-like symptoms during ethanol withdrawal and that inhibition of this signaling pathway may offer a new therapeutic approach to address the comorbidity of alcohol abuse and depression.

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“…Conversely, direct excitation of VTA-GABA neurons disrupts reward-related behaviors (van Zessen et al, 2012), and stimulation of VTA-GABA neurons or inhibition of VTA-dopamine neurons promotes aversion (Tan et al, 2012). Interestingly, Taha and colleagues showed that lesions of the LHb increases ethanol consumption (Haack et al, 2014); which may be due to the reduction of RMTg activity, since RMTg receives a major excitatory input from LHb.…”

Section: Discussionmentioning

confidence: 99%

Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

Chen

Zuo

et al. 2016

Neuropharmacology

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There has been increasing interest in the rostromedial tegmental nucleus (RMTg), given its potential regulatory role in many aversion-related behaviors. The RMTg contains mostly GABAergic neurons, sends a dense inhibitory projection to dopamine neurons in the midbrain, and is rich with μ-opioid receptors (MOR). Like most addictive drugs, ethanol has both aversive and rewarding properties. However, the cellular mechanisms underlying the effects of ethanol, particularly the aversive effect that limits its intake are not well understood. Recent studies have linked aversion with synaptic inhibition of dopamine neurons in the ventral tegmental area. To determine a potential role that the RMTg plays in the effect of ethanol, in this study, we employed a neurotoxin, dermorphin-saporin (DS), to lesion RMTg neurons prior to assessing ethanol-related behaviors. Rats were infused with DS bilaterally into the RMTg. This manipulation substantially increased the intake and preference for ethanol but not sucrose. It also reduced the number of neurons with MOR and glutamic acid decarboxylase 67 immunoreactivity within the RMTg. These changes did not occur after intra-RMTg infusion of blank saporin or vehicle. Importantly, intra-RMTg DS infusion significantly enhanced expression of conditioned place preference induced by ethanol (2g/kg, i.p.), and slowed the extinction process. These results suggest that MOR-expressing GABAergic neurons in the RMTg contribute significantly to the regulation of ethanol consumption and related behaviors.

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Lesions of the Lateral Habenula Increase Voluntary Ethanol Consumption and Operant Self-Administration, Block Yohimbine-Induced Reinstatement of Ethanol Seeking, and Attenuate Ethanol-Induced Conditioned Taste Aversion

Cited by 62 publications

References 41 publications

High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats

High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats

Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats

Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

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