Changhai Cui

Medications development to treat alcohol dependence: a vision for the next decade

More than 76 million people world‐wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholisms (NIAAAs) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long‐range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real‐world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder.

New insights on neurobiological mechanisms underlying alcohol addiction

Alcohol dependence/addiction is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Although recent studies have provided substantial information on the neurobiological mechanisms that drive alcohol drinking behavior, significant challenges remain in understanding how alcohol-induced neuroadaptations occur and how different neurocircuits and pathways cross-talk. This review article highlights recent progress in understanding neural mechanisms of alcohol addiction from the perspectives of the development and maintenance of alcohol dependence. It provides insights on cross talks of different mechanisms and reviews the latest studies on metaplasticity, structural plasticity, interface of reward and stress pathways, and cross-talk of different neural signaling systems involved in binge-like drinking and alcohol dependence.

Neuroimmune mechanisms of alcohol and drug addiction.

Alcohol and other drugs of abuse have significant impacts on the neuroimmune system. Studies have demonstrated that drugs of abuse interact with the neuroimmune system and alter neuroimmune gene expression and signaling, which in turn contribute to various aspects of addiction. As the key component of the CNS immune system, neuroimmune factors mediate neuroinflammation and modulate a wide range of brain function including neuronal activity, endocrine function, and CNS development. These neuromodulatory properties of immune factors, together with their essential role in neuroinflammation, provide a new framework to understand neuroimmune mechanisms mediating brain functional and behavioral changes contributing to addiction. This chapter highlights recent advances in understanding neuroimmune changes associated with exposure to alcohol and other drugs of abuse, including opiates, marijuana, methamphetamine, and cocaine. It provides a brief overview on what we know about neuroimmune signaling and its role in drug action and addiction.

Neurobiology of Alcohol Dependence

In recent years, alcoholism has emerged as one of the major addiction disorders worldwide. Alterations in gene expression together with environmental factors have been shown to play a crucial role in the development of alcoholism. A common thread that links these different phenomena is epigenetics, which may be defined as genetic modifications that occur in the absence of DNA sequence changes. Recent in vitro and in vivo data have shown that different epigenetic modifications can occur in response to both acute and chronic alcohol exposure. These changes can affect gene expression and ultimately brain circuitry that control alcohol tolerance, withdrawal, and dependence. Epigenetic modifications such as DNA methylation, histone acetylation and methylation, and microRNA (miRNA) regulation play a role in alcoholism via mediating effects of alcohol in different tissues or altering alcohol intake. This review focuses on the most current brain research in the rapidly growing field of epigenetics and alcoholism.In recent years, alcoholism has emerged as one of the major addiction disorders worldwide. Alterations in gene expression together with environmental factors have been shown to play a crucial role in the development of alcoholism. A common thread that links these different phenomena is epigenetics, which may be defined as genetic modifications that occur in the absence of DNA sequence changes. Recent in vitro and in vivo data have shown that different epigenetic modifications can occur in response to both acute and chronic alcohol exposure. These changes can affect gene expression and ultimately brain circuitry that control alcohol tolerance, withdrawal, and dependence. Epigenetic modifications such as DNA methylation, histone acetylation and methylation, and microRNA (miRNA) regulation play a role in alcoholism via mediating effects of alcohol in different tissues or altering alcohol intake. This review focuses on the most current brain research in the rapidly growing field of epigenetics and alcoholism.

Neuroimmune mechanisms of brain function and alcohol related disorders

Studies using human alcoholic brains, gene knockout mice, and gene expression profiling have revealed a clear link between alcohol exposure and altered expression of neuroimmune factors. However, it is essentially unknown how neuroimmune factors contribute to changes in brain function and behavior associated with alcohol drinking. Neuroimmune factors, such as cytokines, chemokines, oxidases, proteases, extracellular matrix proteins as well as certain trophic factors, are key components of the innate neuroimmune system and play essential roles in neuroinflammatory responses. Recent research has further established that actions of neuroimmune factors extend beyond their role in neuroinflammation. They are expressed in neurons and glia and regulate neurodevelopment, neuronal function and plasticity. These features of neuroimmune molecules, together with their roles in neurodegenerative diseases and psychiatric disorders, provide a new perspective for examining neuroimmune mechanisms in alcohol-related disorders. A high priority of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is to stimulate research on alcohol’s actions on the neuroimmune system. To achieve this goal, NIAAA has employed multiple venues to promote research studies in this area. Specifically, under the American Recovery and Reinvestment Act (ARRA) initiative, NIAAA developed a challenge grant research topic on ‘‘Functional Roles of Neuroimmune Factors in Mediating Behavior,’’ which was selected as a high priority challenge topic for NIH. This effort led to the funding of several ongoing studies under this topic. To enhance this research area, NIAAA developed a program announcement entitled ‘‘Neuroimmune Mechanisms of Alcohol Related Disorders (PA-11-064 and PA-11-065).’’ This Funding Opportunity Announcement (FOA) seeks research proposals to address the role of neuroimmune factors in the response and the neuroadaptation to acute and chronic alcohol exposure. Studies supported by this announcement will provide fundamental insights into neuroimmune mechanisms underlying changes induced by alcohol on brain function and behavior. To further stimulate this research area, NIAAA organized a satellite symposium on ‘‘Neuroimmune Mechanisms of Brain Function and Alcohol Related Disorders’’ at the 40th Annual Meeting of the Society for Neuroscience (SFN) that was held on November 12, 2010. The purpose of this satellite symposium was to provide fundamental insights on the roles of neuroimmune factors in neurodevelopment,

Neural-Immune Interactions in Brain Function and Alcohol Related Disorders

Rapid advances in understanding neural-immune interactions have far reaching impact on research in many areas of neuroscience. It is becoming increasingly clear that neuroimmune factors modulate a wide range of brain functions and play an important role in development, normal brain function, and CNS dysfunctions, including neurodegenerative diseases, neuropsychiatric disorders and addiction. Neural Immune Interaction in Brain Function and Alcohol Related Disorders integrates emerging knowledge on neural-immune interactions with related key discoveries in alcohol research to provide a comprehensive overview of neuroimmune system in brain function and behavior associated with alcohol use disorders. Readers will benefit from cutting edge insights provided by outstanding, active researchers in the fields of neuroimmune research and alcohol use disorders

Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol

Limited attention has been given to our understanding of how the brain responds to low-dose alcohol (ethanol) and what molecular and cellular targets mediate these effects. Even at concentrations lower than 10mM (0.046 g% blood alcohol concentration, BAC), below the legal driving limit in the USA (BAC 0.08 g%), alcohol impacts brain function and behavior. Understanding what molecular and cellular targets mediate the initial effects of alcohol and subsequent neuroplasticity could provide a better understanding of vulnerability or resilience to developing alcohol use disorders. We review here what is known about the neurobiology of low-dose alcohol, provide insights into potential molecular targets, and discuss future directions and challenges in further defining targets of low-dose alcohol at the molecular, cellular, and circuitry levels.

Alcohol and the Neuroimmune Response: Current Status and Future Directions

The recent progress in the understanding of the immune response within the CNS and the novel findings that neuroimmune factors such as the cytokines have a role beyond immune response including developmental changes and modulation of behavior add new perspective to interpreting brain function. These advances also invite reexamination of mechanisms involved in brain dysfunction and diseases. This book attempts to bring forth the most recent advances in the neuroimmune field and to summarize the recent findings implicating neuroimmune factors in the response to alcohol and in the modulation of drinking behaviors. This chapter tries to integrate these recent observations linking neuroimmune response and neuroimmune modulators to the mechanisms producing alcoholism and the neuroadaptations responsible for alcohol dependence. Since this area of alcohol research is at its beginning, opportunities for advances are highly likely. The recent findings in neuroimmune research may identify new processes through which alcohol impacts health. Several of the novel neuroimmune findings with potential relevance for future alcohol research are noted here.