Chromatin regulation in drug addiction and depression

Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatrie disorders, including drug addiction and depression, increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders.     

Opioids, dopamine, stress, and the addictions

The articulated goals of Dialogues in Clinical Neuroscience are to serve as "an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects." My laboratory the Laboratory of the Biology of Addictive Diseases at The Rockefeller University, has for years been focused on "bidirectional translational research," that is, learning by careful observations and study in patient populations with the disorders under study, in this case primarily specific addictive diseases, and then using that knowledge to create improved animal models or other laboratory-based research paradigms, while, at the same time, taking research findings made at the bench into the clinic as promptly as that is appropriate and feasible. In this invited review, therefore, the focus will be on perspectives of our Laboratory of the Biology of Addictive Diseases and related National Institutes of Health/National Institute on Drug Abuse research Center, including laboratory-based molecular neurobiological research, research using several animal models designed to mimic human patterns of drug abuse and addiction, as well as basic clinical research, intertwined with treatment-related research.     

Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity

Although the pharmacology of amphetamine-like psychostimulants at dopamine transporters is well understood, addiction to this class of drugs has proven difficult to deal with. The reason for this disconnection is that while the molecular mechanism of amphetamine action is critical to reinforce drug use, it is only the first step in a sequence of widespread neuroplastic events in brain circuitry. This review outlines the affect of psychostimulants on mesocorticolimbic dopamine projections that mediate their reinforcing effect, and how this action ultimately leads to enduring pathological neuroplasticity in glutamatergic projections from the prefrontal cortex to the nucleus accumbens. Molecular neuroadaptations induced by psychostimulant abuse are described in glutamate neurotransmission, and from this information potential pharmacotherapeutic targets are identified, based upon reversing or countermanding psychostimulant-induced neuroplasticity.     

Alcohol, nicotine, caffeine, and mental disorders

Alcohol, nicotine, and caffeine are the most widely consumed psychotropic drugs worldwide. They are largely consumed by normal individuals, but their use is even more frequent in psychiatric patients, Thus, patients with schizophrenia tend to abuse all three substances. The interrelationships between depression and alcohol are complex. These drugs can all create dependence, as understood in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Alcohol abuse is clearly deleterious to the brain, provoking acute and chronic mental disorders, ranging from intoxication with impairment of cognition, to delirium tremens, halluosis, and dementia. In contrast, the main health consequences of nicotine, notably cancer and cardiovascular disases, lie outside the realm of psychiatry However, the mes of nicotine dependence and motivation to smoke or quit are of concern to psychiatrists.     

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA,ecstasy ), and amphetamines

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies.     

The possible contribution of neuronal nicotinic acetylcholine receptors in depression

Although tobacco use and smoking were introduced long ago, it was only recently that the nicotine contained in the tobacco leaves was recognized as an addictive substance acting on the central nervous system (CNS). However, even prior to this recognition, several studies have reported an association between smoking and psychiatric disorders. One of the many observations was that smoking cessation is accompanied by a marked increase in the probability of major depression. In parallel with the discovery of the neuronal nicotinic acetylcholine receptors and their extensive expression in the CNS, this association sheds new light on the influence of cholinergic transmission in depression. In this article, we examine the various modes of action of nicotine in the CNS and discuss the mechanisms by which this alkaloid can prevent or precipitate mood disorders, and the possibility of discovering new therapeutic avenues for the treatment of depression.     

Historical and cultural aspects of man's relationship with addictive drugs

Our taste for addictive psychoactive substances is attested to in the earliest human records. Historically, psychoactive substances have been used by (i) priests in religious ceremonies (eg, amanita muscaria); (ii) healers for medicinal purposes (eg, opium); or (iii) the general population in a socially approved way (eg, alcohol, nicotine, and caffeine). Our forebears refined more potent compounds and devised faster routes of administration, which contributed to abuse. Pathological use was described as early as classical Antiquity. The issue of loss of control of the substance, heralding today's concept of addiction, was already being discussed in the 17th century. The complex etiology of addiction is reflected in the frequent pendulum swings between opposing attitudes on issues that are still currently being debated, such as: is addiction a sin or a disease; should treatment be moral or medical; is addiction caused by the substance; the individual's vulnerability and psychology, or social factors; should substances be regulated or freely available.     

ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine

The persistence of attention deficit hyperactivity disorder (ADHD) into adolescence and adulthood has now been accepted as a clinical entity. The rate of prevalence among adults is assumed to be from 2% to 4%. With increasing age, a symptom change has to be considered; disturbance of attention becomes more prominent, whereas hyperactivity often diminishes or changes to inactivity. Neuroimaging studies show a high striatal dopamine transporter (DAT) availability in most adults with ADHD; this can be reduced by stimulants. Nicotine seems to have a stimulant-like action on the DAT. In most adults with ADHD, therapy has to be multimodal, combining psychotherapy and medication. Methylphenidate is the first-line drug in adult ADHD; further options are amphetamine and noradrenaline reuptake inhibitors. Nonresponders to methylphenidate seem to have no elevated DAT availability prior to therapy. Combination with other psychiatric disorders occurs frequently in adults with ADHD; in these patients additional pharmacological treatment with special regard to the comorbid disease is recommended.     

Pharmacogenetic aspects of addictive behaviors

Addictions are illnesses of complex causation, including inheritance and a role for gene/environment interactions. Functional alleles influencing pharmacodynamic (tissue response) and pharmacokinetic (absorption, distribution, and metabolism) play a role, but these interact with diverse environmental factors including early life stress, underage drug exposure, availability of addictive agents, and response to clinical interventions including pharmacotherapies. Identification of genetic factors in addiction thus plays an important role in the understanding of processes of addiction and origins of differential vulnerabilities and treatment responses.     

Epigenetic advances in clinical neuroscience

Epigenetics, broadly defined as the regulation of gene expression without alteration of the genome, has become a field of tremendous interest in neuroscience, neurology, and psychiatry. This research has rapidly changed the way researchers think about brain function. Exciting epigenetic discoveries have been found in addiction, early life stress, neurodegeneration, post-traumatic stress disorder, and depression. As researchers more precisely define the epigenetic landscape that regulates disease progression in each of these cases, therapeutics can be designed to specifically target the molecules that mediate these epigenetic processes. Further, epigenetics may lead, to the identification of novel biomarkers for diagnosis and for the monitoring of treatment. Epigenetic profiling is likely to become a routine tool for the diagnosis of neurological and psychiatric disorders in the near future.     

Corticostriatal circuitry in regulating diseases characterized by intrusive thinking

Intrusive thinking triggers clinical symptoms in many neuropsychiatric disorders. Using drug addiction as an exemplar disorder sustained in part by intrusive thinking, we explore studies demonstrating that impairments in corticostriatal circuitry strongly contribute to intrusive thinking. Neuroimaging studies have long implicated this projection in cue-induced craving to use drugs, and preclinical models show that marked changes are produced at corticostriatal synapses in the nucleus accumbens during a relapse episode. We delineate an accumbens microcircuit that mediates cue-induced drug seeking becoming an intrusive event. This microcircuit harbors many potential therapeutic targets. We focus on preclinical and clinical studies, showing that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. We posit that because intrusive thinking is a shared endophenotype in many disorders, N-acetylcysteine has positive effects in clinical trials for a variety of neuropsychiatric disorders, including drug addiction, gambling, trichotillomania, and depression.     

Assessment and treatment of mood disorders in the context of substance abuse

Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.     

Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.     

Pregnancy, epilepsy, and anticonvulsants

The majority of epileptic disorders are not self-limiting over time, and therefore require a long-lasting and often even lifelong antiepileptic drug (AED) treatment. In women with epilepsy the influence of their disease on the possibility and course of pregnancies, as well as the potential impact of the AED treatment on mother and child, are crucial questions. This review addresses the clinically relevant knowledge concerning the impact of the disease itself and the AED treatment on fertility pregnancy, delivery, the postpartum period, and teratogenicity. Some of the new AEDs appear to have a favorable profile due to a lack of clinically relevant interactions and promising teratogenic profiles. However, the finding of decreases in lamotrigine serum concentrations during hormonal contraception and pregnancy is an instructive example, showing that ongoing studies are urgently needed to further investigate still-unanswered questions. Several prospective multinational surveys are currently being performed, and should add essential information     

Cellular and molecular mechanisms in the long-term action of antidepressants.

The hypotheses on the pathophysiology of depression /mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the “hypothesis of neuroplasticity. ” In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.     

The effectiveness of anticonvulsants in psychiatric disorders

Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.     

Neuroplasticity in addictive disorders

Compulsive drug-taking behavior develops in vulnerable individuals who ingest substances that activate the reward system. This intense activation produces learned associations to cues that predict drug availability. With repetition the reward system becomes reflexively activated by cues alone, leading to a drive toward drug-taking. The central nervous system changes underlying this conditioned behavior are just beginning to be understood. New treatments aimed at this neuroplasticity are being tested in animal models. The clinical significance of these brain changes is that addiction, once established, becomes a chronic illness with relapses and remissions, it therefore requires chronic treatment with medications and behavioral therapies based on an understanding of the fundamental nature of these changes in the brain.     

Characteristics,correlates, and outcomes of childhood and adolescent depressive disorders

Depressive illness beginning early in life can have serious developmental and functional consequences. Therefore, understanding the disorder during this developmental stage is critical for determining its etiology and course, as well as for deveiopinq effective intervention straieqies. This paper summarizes current knoviedqe reqardinq the etiology, phenomenoiogy, correlates, natural course, and consequences of unipolar depression in children and adolescents. Using adult depression as a framevork, the unique aspects of childhood and adolescence are considered in order to better understand depression within a developmental context. The data suggest that the clinical presentation, correlates, and natural course of depression are remarkably similar across the lifespan. There are, however, important developmental differences. Specifically, the familial and psychological context in which depression develops in youngsters is associated with variability in the frequency and nature of depressive symptoms and comorbid conditions among children and adolescents. Maturational differences have also been identified in the neurobiological correlates of depression. These developmental differences may be associated with the observed variability in clinical response to treatment and longitudinal course. Characterization of the developmental differences will be helpful in developing more specific and effective interventions for youngsters, thereby allowing them to reach their full potential as adults.     

Cerebral aging: neuropsychological, neuroradiological, and neurometabolic correlates

The aging process is associated with a progressive cognitive decline, but both the extent of this decline and the profile of age-related cognitive changes remain to be clearly established. Currently, cognitive deficits associated with aging may be diagnosed under the categories of age-associated memory impairment, age-associated cognitive impairment, or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) category of age-related cognitive decline. Age-related decline has been reported for several cognitive domains, such as language (eg, verb naming, verbal fluency), visuospatial abilities (eg, facial discrimination), executive functions (eg, set shifting, problem solving), and memory functions (eg, declarative learning, source memory). There is an age-related decline in brain cortical volume, which primarily involves association cortices and limbic regions. Studies of brain metabolic activity demonstrate an age-related decline in neocortical areas. Activation studies using cognitive tasks demonstrate that older healthy individuals have a different pattern of activation from younger subjects, suggesting thai older subjects may recruit additional brain areas in order to maintain performance.     

Cytokines, neurophysiology, neuropsychology, and psychiatric symptoms

Recent research has overcome the old paradigms of the brain as an immunologically privileged organ, and of the exclusive role of neurotransmitters and neuropeptides as signal transducers in the central nervous system. Growing evidence suggests that the signal proteins of the immune system - the cytokines - are also involved in modulation of behavior and induction of psychiatric symptoms. This article gives an overview on the nature of cytokines and the proposed mechanisms of immune-to-brain interaction. The role of cytokines in psychiatric symptoms, syndromes, and disorders like sickness behavior, major depression, and schizophrenia are discussed together with recent immunogenetic findings.