Biological basis of addiction and alcohol use disorder

ADDICTION

Addiction is a health condition characterized by extreme difficulty to stop or decrease the use of a drug despite known negative consequences to a person’s health and livelihood.¹ A drug of addiction is a substance that has the potential to produce addiction in a minority of vulnerable individuals who use that drug. These drugs include, but are not limited to, alcohol, nicotine, cannabis, stimulants like cocaine and amphetamines, sedatives like benzodiazepines and barbiturates, and opioids like heroin and fentanyl. Furthermore, the route of administration plays an important role in the degree to which a drug can be considered addictive. In general, when drug use is temporally coupled to its rewarding or interoceptive effects, that type of use is more addictive than when the drug’s subjective effects are temporally decoupled from drug administration. This phenomenon is best exemplified by the difference in addiction liability between oral and i.v. administration of methylphenidate.² The biological basis of addiction has been well-studied in humans and animal models, which has resulted in a conceptual framework for which to understand the addiction process. This framework includes 3 stages that are cyclical in nature: binge/intoxication, negative affect/withdrawal, and anticipation/preoccupation. Each stage is associated with underlying brain regions and neural circuitry that contribute to the behaviors and mental phenomena characteristic of that stage.¹ A person can enter the addiction cycle at any stage, not just the binge/intoxication stage. For example, a person with chronic pain may enter the addiction cycle through the negative affect stage and then transition to binge/intoxication. Others may enter the binge/intoxication stage to self-medicate symptoms associated with psychiatric comorbidities.¹ It is a cruel fact that drug use to alleviate these symptoms often exacerbates these symptoms long-term, entrapping a person in the addiction cycle. Therefore, addiction must be treated as a chronic medical disease (eg, diabetes and hypertension) for which long-term treatment is needed for some individuals. While this review will focus on the biological aspects, addiction is biopsychosocial in nature, and the effects of a person’s environment and experiences are extremely important and cannot be decoupled from biology. Finally, addiction is extremely heterogeneous, and individual differences play a key role in addiction research and clinical practice.

While this review focuses on alcohol, at least some of the concepts that characterize addiction to 1 substance generalize to other substances of addiction. Current alcohol use disorder (AUD) is diagnosed using the DSM-5, at least in the United States (see ICD-11 for international diagnostic criteria and definition), upon meeting at least 2 out of 11 criteria regarding one’s symptoms and behaviors related to alcohol use in the past 12-month period. Symptom counts are used to classify mild (2–3), moderate (4–5), and severe (6+) AUD, and alcohol addiction is most associated with moderate to severe AUD. This highlights the important concept of AUD as a spectrum rather than categorical in nature. The neurobiology of addiction is highly distributed and complex, much of which could not be discussed here. For more comprehensive reviews, see.^1,3–5

STAGES OF ADDICTION: FOCUS ON NEUROBIOLOGY OF ALCOHOL AND AUD

Binge/Intoxication

To become addicted, a person usually must use that drug frequently and over a relatively long period of time. Use that transitions to addiction is often binge use, which is heavy intake over a short period of time. For alcohol, binge drinking is defined by the NIAAA as 4 or more drinks for women and 5 or more drinks for men in a 2 h period.⁶ Binge drinking is linked to considerable health risks even for those people who do not transition into addiction.⁷ All drugs of addiction produce acute interoceptive (subjective) effects, which are usually net rewarding, within the organism.⁸ For alcohol, these subjective effects are stimulatory during the ascending limb of the blood alcohol concentration curve and sedative during the descending blood alcohol concentration curve. In general, people with greater sensitivity to the stimulatory effects and attenuated sensitivity to the sedative effects of alcohol are more likely to drink more and develop an AUD.⁹ The stimulatory effects of alcohol are mediated in part by the activation of dopamine and glutamate neurons that project from the ventral tegmental area to the nucleus accumbens (Acb), which is involved in the rewarding effects of nearly all drugs of addiction.¹ This occurs in part from alcohol’s positive allosteric effects on the gamma-aminobutyric acid (GABA-A) receptor (and increased presynaptic GABA release), resulting in disinhibition of these ventral tegmental area→nucleus accumbens glutamate and dopamine neurons.¹ The sedative effects of alcohol are produced in part by alcohol’s ability to decrease N-methyl-D-aspartate (NMDA) receptor activity. Alcohol results in decreased NMDA receptors in the synaptic membrane, resulting in attenuated excitability of the neuron.¹⁰ These effects by alcohol on the GABA-A and NMDA receptors (among many other neurotransmitter systems) produce distributed effects on synaptic plasticity throughout the brain that underlie many of alcohol’s subjective effects and intoxication. The tight association between drug use and the rewarding subjective effects produces a type of learning or conditioning that over time results in greater salience attribution to drug use and its associated cues (termed incentive sensitization). Again, this phenomenon is associated with the activation of the mesocorticolimbic dopamine system coupled temporally to drug use and cues, among other distributed processes.¹

Negative affect/withdrawal

Following binge intake of an addictive drug, people often experience withdrawal and negative affect to some degree, which increases in severity over the course of drug binge use and subsequent periods of nonuse.¹ This is a negative emotional state characterized by sadness, anxiety, irritability, malaise, dysphoria, stress, and loss of motivation for natural rewards. The repeated neurochemical effects of alcohol produce adaptations to the nervous system that result in withdrawal during periods of nonuse. These adaptations are homeostatic in nature and reflect the nervous system’s “attempt” to correct the supra-physiological state that alcohol induces in the nervous system, a phenomenon termed “opponent process” in biological systems.¹ The acute effects of alcohol produce a net effect of inhibition (diminished excitability through GABA-A and NMDA receptor modifications) of the nervous system that, in an attempt to return to homeostasis, rebounds to a state of elevated excitability of the nervous system. This is the biological basis for why at least some people with AUD experience alcohol withdrawal after abrupt cessation or significant reduction; of note, alcohol withdrawal may significantly vary across people, with some patients presenting with mild symptoms (eg, anxiety and irritability) while others developing severe withdrawal complicated by seizures or delirium tremens. Neuropeptides like corticotropin-releasing factor, dynorphin, neuropeptide Y, oxytocin, and neurotensin are all involved in this stage, as well as stress response and negative emotionality in general. GABAergic, glutamatergic, and neuropeptide adaptations in the extended amygdala are most linked to this negative affect stage. Other brain regions like the habenula and hypothalamus are involved.¹

Preoccupation/Anticipation

The long-term use of alcohol diminishes cortical control over other parts of the brain, diminishing behavioral flexibility and the ability to choose to use or not to use a drug of addiction, especially under the backdrop of incentive sensitization of drug use and cues and negative affect during nonuse. This stage is also associated with an attentional and motivational bias towards drug procurement and use over other natural rewards. The prefrontal cortex, and its glutamatergic projections are critically involved in this stage, and long-term drug use diminishes the overall activity of the prefrontal cortex. This inability to control drug use behavior is a core component of addiction and is involved in drug relapse following nonuse periods. This stage is also associated with drug craving, which is associated with the insular cortex and many other brain regions.¹

EXTRA-CENTRAL NERVOUS SYSTEM PATHWAYS

While there is empirical evidence that addiction is a brain disease,^1,3 addiction is also a whole-body disease (Figure 1). For example, acute/binge alcohol use upregulates the FGF21 protein in the liver, which results in diminished mesolimbic dopamine activity and decreased alcohol consumption.¹¹ Alcohol also impacts the peripheral and central immune system, which communicates with neurons to impact negative affect during the withdrawal/negative affect stage. Toll-like receptor 4 signaling is closely associated with the inflammatory effects of alcohol and adaptations of microglia in the central nervous system.¹² Alcohol-associated changes in neuroactive steroids like allopregnanolone are also involved in the GABA-A potentiating effects of alcohol and interaction with Toll-like receptors.¹³ Alcohol damages the lining of the gut and disrupts the communication/signaling mechanisms underlying the gut-brain axis, including changes in the gut microbiome/metabolome. Furthermore, changes in gut hormones like ghrelin and glucagon-like peptide 1 (GLP-1) that regulate feeding behavior based on energy needs are also involved in alcohol craving, seeking, and dependence.^14,15 Finally, the vast majority of alcohol is metabolized in the periphery, and these metabolic products impact the nervous system and contribute to the biology of addiction.¹⁶ In conclusion, the biology underlying alcohol addiction is highly distributed and involves multiple systems and organs throughout the body. These interactions and mechanisms are not fully understood and highly complex, even more so given the apparent paradox that peripheral-brain connections seem to play important roles in the mechanisms underlying the development and maintenance of AUD and, at the same time, alcohol is a leading cause of multiple organ damage, including, but not limited to, alcohol-associated liver disease.¹⁷

FIGURE 1.

Addiction as a whole-body disorder. A simplified framework for understanding the key elements of the biological mechanisms underlying AUD and alcohol addiction. This is a conceptual adaptation of the 3-stage addiction cycle proposed in Koob and Volkow.¹ This adaptation specifically focuses on alcohol addiction and emphasizes extra-CNS mechanisms involved. Abbreviations: AUD, alcohol use disorder; CNS, central nervous system; CRF, corticotropin-releasing factor; GABA-A, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; GLP-1, glucagon-like peptide 1; NPY, neuropeptide Y; TLR4, Toll-like receptor 4.