Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula.

Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HTRs). Also, 5-HTR activation is known to inhibit M-current in mouse hypothalamic neurons.

Downregulation of M-channels in lateral habenula mediates hyperalgesia during alcohol withdrawal in rats.

Hyperalgesia often occurs in alcoholics, especially during abstinence, yet the underlying mechanisms remain elusive. The lateral habenula (LHb) has been implicated in the pathophysiology of pain and alcohol use disorders. Suppression of m-type potassium channels (M-channels) has been found to contribute to the hyperactivity of LHb neurons of rats withdrawn from chronic alcohol administration.

Elevation of Transient Receptor Potential Vanilloid 1 Function in the Lateral Habenula Mediates Aversive Behaviors in Alcohol-withdrawn Rats.

What We Already Know About This Topic: Chronic alcohol use and withdrawal leads to increased pain perception, anxiety, and depression. These aberrant behaviors are accompanied by increased excitatory glutamatergic transmission to, and activity of, the lateral habenula neurons.Vanilloid type 1, or TRPV1, channels are expressed in the habenula and they facilitate glutamatergic transmission.

Low-dose ethanol excites lateral habenula neurons projecting to VTA, RMTg, and raphe.

It is unclear how social drinking can contribute to the development of addiction in susceptible individuals. However, alcohol's aversive properties are a well-known factor contributing to its abuse. The lateral habenula (LHb) is a key brain structure responding to various aversive stimuli, including those related to alcohol.

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

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.

Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula.

Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs.

Electroacupuncture Attenuates Hyperalgesia in Rats Withdrawn from Chronic Alcohol Drinking via Habenular Mu Opioid Receptors.

Background: Hyperalgesia or increased sensitivity to pain is often found in alcoholics during alcohol withdrawal and may contribute to relapse drinking. Alternative therapies such as acupuncture and electroacupuncture (EA), through mechanisms involving opioid receptors, may reduce pain and substance dependence and withdrawal syndromes. The lateral habenula (LHb), an epithalamic structure rich in mu opioid receptors (MORs), is a critical target for both drugs of abuse and pain.

Pharmacological Manipulation of the Rostromedial Tegmental Nucleus Changes Voluntary and Operant Ethanol Self-Administration in Rats.

Background: The aversive properties of ethanol (EtOH) that limit its intake are poorly understood. There is an increasing interest in the role of the rostromedial tegmental nucleus (RMTg), because it encodes aversion signals and inhibits motivated behaviors. It is also a major source of inhibitory GABAergic inputs to the midbrain dopamine neurons.

Chronic intermittent voluntary alcohol drinking induces hyperalgesia in Sprague-Dawley rats.

The mechanisms of hyperalgesia in alcoholics are not completely clear, and the development of animal models would therefore be necessary in investigating the underlying changes. Several studies including our own have demonstrated that the intermittent access to 20% ethanol two-bottle choice procedure (IA2BC) promotes escalation of drinking, and induces physical dependence in the Sprague-Dawley (SD) rat, one of the strains most commonly used in preclinical alcohol research. In this study, we investigated whether the IA2BC procedure could produce hyperalgesia in SD rats.

Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability.

Individuals exhibiting an anxiety disorder are believed to possess an innate vulnerability that makes them susceptible to the disorder. Anxiety disorders are also associated with abnormalities in the interconnected brain regions of the amygdala and prefrontal cortex (PFC). However, the link between anxiety vulnerability and amygdala-PFC dysfunction is currently unclear.

Serotonin stimulates lateral habenula via activation of the post-synaptic serotonin 2/3 receptors and transient receptor potential channels.

There is growing interest on the role of the lateral habenula (LHb) in depression, because it closely and bilaterally connects with the serotoninergic raphe nuclei. The LHb sends glutamate efferents to the raphe nuclei, while it receives serotoninergic afferents, and expresses a high density of serotonin (5-HT) receptors. Recent studies suggest that 5-HT receptors exist both in the presynaptic and postsynaptic sites of LHb neurons, and activation of these receptors may have different effects on the activity of LHb neurons.