These techniques are harmless and give us insight into the dynamic moment-to-moment changes in electrical activity of the brain. They show when the critical changes are occurring, but their spatial resolution is ambiguous and limited. Recently, a previously unanticipated mechanism was identified linking alcohol metabolism to alcohol-induced epigenetic impairments by way of direct incorporation of alcohol-derived acetate into bath salts drug brain histone acetylation [24]. This was driven by the nuclear translocation of metabolic enzyme acetyl-CoA synthetase 2 (Acss2), inhibition of which prevented alcohol-induced changes of histone acetylation and gene expression, and blocked conditioned place preference to alcohol [24]. This and related epigenetic-metabolic pathways [25] represent a radically novel mechanism of alcohol-induced transcriptional changes.
Furthermore, dysregulation of striatal function can produce pathological drinking behaviors. For instance, manipulations of striatal dopamine D2 receptors (D2Rs), adenosine 2A receptors, or activity of fast-spiking interneurons, among others, alter excessive drinking behaviors [104–106]. Further, disrupted GABAergic transmission in this region is also linked to alcohol-induced cognitive impairments [107]. Together, altered excitability of striatal neurons and upstream cortical regulation of striatal activity influence a diverse range of drinking behaviors, which likely can be attributed to distinct striatal output circuits [108]. A major theme of recent alcohol research has been to leverage animal models and circuit-analysis approaches to link neural circuit activity with specific aspects of AUD [95].
Alcohol and the Brain: An Overview
Acute and chronic use of alcohol affects the activity of multiple neuronal circuits, depicted here schematically in the context of a rodent brain. For example, alcohol activates the mesocorticolimbic brain reward circuit, which encompasses dopaminergic projections from the VTA in the midbrain to several forebrain structures including the striatum and cortex. In addition, CRF neurons projecting from the central amygdala to the BNST were shown to contribute to the escalation of alcohol intake. Prefrontal cortical circuits have been implicated in impaired executive control that underlies excessive drinking, as well as weakened cognitive function in AUD. For example, projections from the mPFC to the dorsal striatum have been linked to habitual alcohol drinking and continued use despite negative consequences. Further, neurons projecting from the mPFC to the dPAG play a critical role in compulsive drinking.
However, research has helped define the various factors that influence a person’s risk for experiencing alcoholism-related brain deficits, as the following sections describe. Transcription factors often form large multimeric protein complexes that bind to target gene promoters or enhancers to regulate the expression of mRNA. Chronic alcohol exposure in rodents upregulates gene expression in neurons, astrocytes, and microglia [26–28], which raises the possibility that transcription factors serve as one of the master regulators of the neuroadaptations induced by alcohol. The mechanisms that drive alcohol-dependent transcriptional alterations are still being unraveled (Figure 1). For example, the transcriptional activity of NF-κB is controlled through the stimulation of the inhibitor κβ kinase (IKKβ). Using pharmacologic and genetic approaches, Ikkβ was shown to contribute to excessive alcohol intake in mice [29], and its action is localized to neurons at least in the NAc and CeA [29].
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Alcoholics may seem emotionally “flat” (i.e., they are less reactive to emotionally charged situations), and may have difficulty with the same kinds of tasks that patients with damage to the right hemisphere have difficulty with. New research has shown that alcoholics are impaired in emotional processing, such as interpreting nonverbal emotional cues and recognizing facial expressions of emotion (Kornreich et al. 2002; Monnot et al. 2002; Oscar-Berman 2000). Impairments in emotional functioning that affect alcoholics may reflect abnormalities in other brain regions which also influence emotional processing, such as the limbic system and the frontal lobes. There is evidence that the frontal lobes are particularly vulnerable to alcoholism-related damage, and the brain changes in these areas are most prominent as alcoholics age (Oscar-Berman 2000; Pfefferbaum et al. 1997; Sullivan 2000) (see figure 2). Alcohol interferes with the brain’s communication pathways and can affect the way the brain looks and works.
Importantly, the neurobiological basis of AUD appears in many cases to manifest in a sex-specific manner. Understanding convergence and divergence between mechanisms in males and females will continue to be critical moving forward [111,112]. Alcohol-induced epigenetic alterations are often mediated by altered expression or activity of epigenetic enzymes, which thus represent a promising new avenue for targeted therapeutic interventions. For example, increased enrichment of DNA methylation in the mPFC was linked to enhanced DNA methyltransferase (Dnmt) activity [23].
The risk of brain damage and related neurobehavioral deficits varies from person to person. This article reviews the many factors that influence this risk, the techniques used to study the effects of alcoholism1 on the brain and behavior, and the implications of this research for treatment. Brain cells (i.e., neurons) communicate using specific chemicals called neurotransmitters. Specialized synaptic receptors on the surface of neurons are sensitive to specific neurotransmitters.
- Posttranslational modifications such as phosphorylation are core molecular signaling events.
- Studies in animal models provide initial hints to possible contributors to these differences.
- A huge risk factor for people who develop alcohol use disorder is early-onset drinking.
- There’s also more of an effect on your brain and its development if you’re younger — one that can have a lasting impact.
Through the translation of these transcripts and others, mTORC1 contributes to mechanisms underlying alcohol seeking and drinking as well as reconsolidation of alcohol reward memories and habit [44–46]. Further, protein translation plays a role in additional alcohol-dependent phenotypes (Figure 1). For example, the activity of mRNA binding protein fragile-X mental retardation protein (Fmrp), which plays an important role in translation [47], is enhanced by alcohol in the hippocampus of mice resulting in alteration in the expression of synaptic proteins [48]. Additionally, Fmrp in the hippocampus plays a role in the acute antidepressant actions of alcohol [49]. Interestingly, rapid antidepressants require coordinated actions of Fmrp and mTORC1 [50], raising the possibility that such coordination may also be relevant in the context of alcohol’s actions. Advances in neuroscience continue to shed light onto regulatory mechanisms relevant for alcohol use.
Inhibition of Dnmt rescued the methylation and transcriptional changes and prevented the escalation of alcohol intake [23]. Decreased binding of Cbp and lysine demethylase Kdm6b was also shown at specific target genes upon adolescent intermittent alcohol exposure, resulting in anxiety-like behaviors in adult rats [22]. Researchers have gained important insights into the anatomical effects of long-term alcohol use from studying the brains of deceased alcoholic patients. These studies have documented alcoholism-related atrophy throughout the brain and particularly in the frontal lobes (Harper 1998). Post mortem studies will continue to help researchers understand the basic mechanisms of alcohol-induced brain damage and regionally specific effects of alcohol at the cellular level. Behavioral neuroscience studies the relationship between the brain and its functions—for example, how the brain controls executive functions and spatial cognition in healthy people, and how diseases like alcoholism can alter the normal course of events.
What Alcohol Can Do to Your Health
Indeed, PET and SPECT studies have confirmed and extended earlier findings that the prefrontal regions are particularly susceptible to decreased metabolism in alcoholic patients (Berglund 1981; Gilman et al. 1990). It is important to keep in mind, however, that frontal brain systems are connected to other regions of the brain, and frontal abnormalities may therefore reflect pathology elsewhere (Moselhy et al. 2001). Continuing to drink despite clear signs of significant impairments can result in an alcohol overdose. An alcohol overdose occurs when there is so much alcohol in the bloodstream that areas of the brain controlling basic life-support functions—such as breathing, heart rate, and temperature control—begin to shut down. Symptoms of alcohol overdose include mental confusion, difficulty remaining conscious, vomiting, seizure, trouble breathing, slow heart rate, clammy skin, dulled responses (such as no gag reflex, which prevents choking), and extremely low body temperature.
Alcohol and the brain: from genes to circuits
CT scans rely on x-ray beams passing through different types of tissue in the body at different angles. Pictures of the “inner structure” of the brain are based on computerized reconstruction of the paths and relative strength of the x-ray beams. CT scans of alcoholics have revealed diffuse atrophy of brain tissue, with the frontal lobes showing the earliest and most extensive shrinkage (Cala and Mastaglia 1981).
Reduced dynorphin activity or blockade of KORs in several brain regions including the CeA [88,89], BNST [90,91], and the striatum, reduce alcohol consumption in mice and rats. KORs have also been shown to modulate the acute actions of alcohol [92], negative affect during withdrawal [93], and the sensitivity of this receptor is augmented after chronic alcohol use [73]. Fast-acting and selective KOR antagonists have been developed and evaluated in preclinical models using rats, yielding promising results that suggest therapeutic potential for treating AUD [94]. Additionally, antidepressants and alcohol interactions receptor tyrosine kinases (RTKs) which are activated by growth factors and cytokines play a role in alcohol consumption [60]. For example, alcohol-dependent activation of the anaplastic lymphoma kinase (Alk) in the hippocampus and PFC activates STAT signaling leading to changes in gene expression, and systemic administration of Alk or Stat3 inhibitors attenuates alcohol intake in mice [61,62]. Surprisingly, a number of growth factors/RTKs such as Bdnf and the glial-derived neurotrophic factor (Gdnf) are endogenous factors that limit alcohol use [60,63].
What effects does alcohol have on mental health?
Just beneath it are the nerve fibers, called the white matter, that connect different cortical regions and link cortical cells with other structures deep inside the brain (subcortical regions). But if you have a response to alcohol that’s noticeably different from other people’s, it may be time to addiction relapse reexamine your relationship with drinking, advised Pagano. «If you can drink other people under the table, or you see your friends leaving alcohol in their glasses and you know you could never do that yourself, those are signals you’ve got a genetic setup for developing an addiction,» said Pagano.