How Adaptation of the Brain to Alcohol Leads to Dependence A Pharmacological Perspective Peter Clapp, Ph.D; Sanjiv V. Bhave, Ph.D; and Paula L. Hoffman, Ph.D The development of alcohol dependence is posited to involve numerous changes in brain chemistry (i.e., neurotransmission) that lead to physiological signs of withdrawal upon abstinence from alcohol as well as promote vulnerability to relapse in dependent people. These neuroadaptive changes often occur in those brain neurotransmission systems that are most sensitive to the acute, initial effects of alcohol and/or contribute to a person’s initial alcohol consumption. Studies of these neuroadaptive changes have been aided by the development of animal models of alcohol dependence, withdrawal, and relapse behavior. These animal models, as well as findings obtained in humans, have shed light on the effects that acute and chronic alcohol exposure have on signaling systems involving the neurotransmitters glutamate, ­aminobutyric acid (GABA), dopamine, and serotonin, as well as on other signaling γ molecules, including endogenous opioids and corticotrophin­releasing factor (CRF). Adaptation to chronic alcohol exposure by these systems has been associated with behavioral effects, such as changes in reinforcement, enhanced anxiety, and increased sensitivity to stress, all of which may contribute to relapse to drinking in abstinent alcoholics. Moreover, some of these systems are targets of currently available therapeutic agents for alcohol dependence. KEY WORDS: Alcohol dependence; alcohol and other drug (AOD) dependence (AODD); addiction; neurobiology; neuroplasticity; neuroadaptation; brain; craving; withdrawal; relapse; neurotransmission; neurotransmitters; glutamate; glutamate receptors; glutamate systems; –aminobutyric acid (GABA); GABA systems; dopamine; serotonin; signaling molecules; endogenous opioids; γ opioid systems; corticotrophin­releasing factor (CRF); animal models; human studies he development of dependence consumption—and that chronic expo­ neurons. This ability allows the brain on alcohol (as well as on other sure to alcohol results in adaptations in to compensate for injury or disease, Tdrugs of abuse) is posited to brain function that eventually lead to to accommodate new experiences, involve changes in brain chemistry that dependence. This model leads to the 1 question: What is the nature of the These behaviors (which can occur in the presence or lead not only to signs of withdrawal absence of physiological dependence) include drinking upon abstention from alcohol (i.e., to neurobiological and functional adapta­ more alcohol than intended, unsuccessful efforts to physical or physiological dependence) tions that result in the state of alcohol reduce alcohol drinking, giving up other activities in favor of drinking alcohol, spending a great deal of time obtain­ (Ritzmann and Tabakoff 1976) but dependence? ing and drinking alcohol, continuing to drink alcohol in In a recent review, Kalivas and also, in humans, to the behaviors that spite of adverse physical and social effects, and the define alcohol dependence, as described O’Brien (2008) discussed the transition development of alcohol tolerance. in the most recent edition of the from “social” drug use to addiction, Diagnostic and Statistical Manual of or dependence, in terms of transient PETER CLAPP, PH.D., is a postdoctoral 1 Mental Disorders (DSM–IV) (American and prolonged neuroplasticity. Neuro­ fellow, SANJIV V. BHAVE, PH.D., is a Psychiatric Association 1994). It gener­ plasticity is defined as the brain’s ability senior instructor, and PAULA L. HOFFMAN, ally is thought that alcohol is consumed to change and reorganize itself through­ PH.D., is a professor in the Department for its positive reinforcing effect— out life by forming new connections of Pharmacology, University of Colorado that is, to repeat the pleasurable experi­ between nerve cells (i.e., neurons) Denver School of Medicine, Aurora, ences associated with initial alcohol and altering the activities of existing Colorado. 310 Alcohol Research & Health Pharmacological Perspective on the Adaptation of the Brain to Alcohol and to adjust to new situations and O’Brien (2008) focused on the initial ual. In either case, dopamine release changes in the environment (e.g., release of the neurotransmitter dopamine in the mesolimbic system (e.g., NAc) exposure to alcohol and other drugs from cells in the brain region called likely is critical for the drive to ingest [AODs]). With respect to AODs this the ventral tegmental area (VTA) that AODs. For example, Kalivas and means that even during the initial is induced by addictive drugs. The O’Brien (2008) postulate that the stages of AOD use, changes in brain VTA is one of the components of a released dopamine promotes neuro­ chemistry occur that affect signaling system of interconnected brain regions plasticity in the mesolimbic system molecules (i.e., neurotransmitters2), called the mesolimbic dopamine sys­ through the activation of certain sig­ the proteins (i.e., receptors) that the tem. In this system, neurons whose naling pathways that ultimately alter neurotransmitters interact with, and cell bodies are located in the VTA, gene expression. Such changes in gene various other molecules. These early extend long “arms” (i.e., axons) to expression may be associated with changes, which are short lived and various other brain regions, most the transition from social drug use based on the initial effects of the prominently the nucleus accumbens to relapsing drug use. particular drug in the brain, already (NAc) and the prefrontal cortex Signaling systems using the neuro­ may lead to signs of withdrawal when (see figure 1). When activated, these transmitter glutamate also may under­ AOD use is stopped. Repeated expo­ neurons release dopamine that acts go adaptive changes that contribute sure to the drug, however, induces on other neurons in the NAc and to AOD dependence. According to longer­lasting changes in neuronal prefrontal cortex. For many years, Kalivas and O’Brien (2008), adaptive function that promote vulnerability researchers thought that this dopamine changes in glutamate­using (i.e., glu­ to relapse behavior, which is related release mediates positive reinforcing tamatergic) systems that transmit to habit formation. At this point, the properties of AODs or other stimuli. signals from various brain regions (e.g., drug­taking behavior is no longer under More recently, it has been proposed the cortex, amygdala, and hippocam­ voluntary control. that the dopamine release, particularly pus) to the striatum are responsible When discussing the neurobiology in the NAc, signals the importance for compulsive drug­seeking behavior that underlies the plastic changes asso­ (i.e., salience) (Iversen and Iversen in dependent people. The investiga­ ciated with AOD use, Kalivas and 2007) of the stimulus to the individ­ tors cite evidence from human and animal studies suggesting that these neurochemical changes, as well as morphological changes, underlie a (mal)adaptive neuroplasticity that enhances the response to the addic­ tive drug, or to cues associated with drug administration, while reducing the response to “normal” biologically rewarding stimuli. Together, these changes in the dopamine and gluta­ mate systems may be the core changes that are the basis for the development of dependence on any drug. In addition, researchers have inves­ tigated the long­lasting plasticity that specifically contributes to alcohol dependence. To this end, investiga­ tors have determined which neuronal systems initially are most sensitive to alcohol’s effects and/or play a role in voluntary alcohol consumption. Subsequently, they examined adapta­ tions in these systems that can be observed after prolonged or chronic intermittent exposure to alcohol. Figure 1 Like other drugs of abuse, alcohol Location of some of the regions in the human brain that are affected by initially increases dopamine release alcohol, including the mesolimbic dopamine system (which includes the in the mesolimbic system. Unlike ventral tegmental area [VTA], nucleus accumbens, and prefrontal cortex), amygdala, striatum, and hippocampus. 2 For a definition of this and other technical terms, see the Glossary, pp. 345–347. Vol. 31, No. 4, 2008 311 most other addictive drugs, however, tamate, opiate, and GABA systems. • Ionotropic glutamate receptors alcohol lacks a specific “receptor” in The CRF system, which is sensitive (iGluRs), which are found on the brain.3 Instead, the effects of bever­ to alcohol’s acute and chronic effects minute protrusions (i.e., spines) age alcohol (i.e., ethanol) on dopamine and is an important mediator of stress on the dendrites of the postsynaptic release may result from direct effects and anxiety, also is discussed. Although cells and produce relatively fast on the firing of dopamine neurons in many more signaling systems are in actions, thereby mediating rapid the VTA and/or be mediated through some way or other affected by alcohol neuronal responses. interactions with other signaling systems, (for information on some of these, such as those using the neurotrans­ see the sidebar “Other Brain Signaling • Metabotropic glutamate receptors mitters glutamate, γ­aminobutyric Systems Involved in Alcohol Depend­ (mGluRs), which are located in the acid (GABA), and serotonin, as well ence”), the discussion emphasizes membrane around the synapse (i.e., as through interactions with the opioid those systems whose function is perisynaptic membranes)