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November 2, 2007
San Diego Convention Center, San Diego, California

Neuronal Adaptations and Counteradaptations

Chair: Susan Volman, Ph.D., National Institute on Drug Abuse

Overview

Long-lasting alterations in neuron excitability and synaptic function observed after exposure to drugs or alcohol may result (1) directly from pharmacological effects, (2) indirectly by engaging brain systems involved in learning, or (3) by compensatory, homeostatic responses. This symposium presents research on cellular mechanisms that regulate neural circuit function and evaluates their relevance to addiction.

Synaptic Plasticity in the Striatum

Robert C. Malenka, M.D., Ph.D.

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. In the dorsal striatum, neural information flows through the basal ganglia in two distinct parallel circuits, termed the direct and indirect pathways. Imbalances in neural activity between these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson’s and Huntington’s diseases. Similar direct and indirect pathways also exist in the core of the nucleus accumbens. Despite their importance, little is known about the cellular and synaptic properties of neurons in these circuits, and current hypotheses suggest that these cells may share similar forms of synaptic plasticity.

Surprisingly, we find major differences between synapses onto direct and indirect pathway striatal medium spiny neurons (MSNs). Excitatory synapses onto indirect pathway MSNs exhibit higher release probability and larger N–methyl–D–asparate (NMDA) receptor currents than direct pathway synapses. Moreover, we find that indirect pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires D2 receptor activation. In a Parkinson’s disease model, indirect pathway eCB-LTD is absent, but is rescued by a D2 receptor agonist or an inhibitor of endocannabinoid degradation. Co-administration of these drugs in vivo reduces Parkinsonian motor deficits, which suggests that the indirect pathway eCB-LTD may play a critical role in the control of movement. We discuss the implication of these findings for the adaptations in neural circuitry that occur during addiction.

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The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines

L. Judson Chandler, Ph.D.

Dendritic spines are morphologically specialized structures that receive the vast majority of central excitatory synaptic inputs. Studies have implicated changes in the size, shape, and number of dendritic spines in activity-dependent plasticity, and have further demonstrated that spine morphology is highly dependent upon the dynamic organizational and scaffolding properties of its postsynaptic density (PSD). In vitro and in vivo models of experience-dependent plasticity have linked changes in the localization of glutamate receptors at the PSD with a molecular reorganization of the PSD and alterations in spine morphology. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence, and addiction. A potential mechanism supporting these adaptive changes that we recently identified is the homeostatic targeting of N–methyl–D–asparate (NMDA) receptors that contains NMDA receptor 2B (NR2B) to the synapse. Prolonged ethanol exposure results in the enchancement of NR2B-containing NMDA receptors selectively at the synapse. This increase is associated with, and dependent upon, a corresponding increase in the localization of the scaffolding protein PSD-95 at the PSD, and with an actin-dependent increase in the size of dendritic spines. These observations led us to propose a molecular model for ethanol-induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the PSD provide an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation, and synaptic plasticity. This model is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a role in the aberrant plasticity of addiction.

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Lorna W. Role, Ph.D.

The heaviest smoking populations in the world include patients with schizophrenia and depressive disorders. Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognomonic deficits of sensorimotor gating. Genetic variations in the alpha7 nicotinic acetylcholine receptor (alpha7*-nAChR) are linked with the sensory-gating deficits associated with schizophrenia. These observations have prompted speculation for comorbidity of nicotine abuse with schizophrenia. Likewise, genetic variants of Neuregulin 1 (Nrg1), which is a key regulator of alpha7*-nAChRs, have recently been associated with heritable forms of schizophrenia. These observations suggest that alpha7 and Nrg1 variants may also predispose to nicotine dependence, and prompt our proposal to test for convergent effects on Nrg1 and alpha7* expression in the comorbidity of nicotine abuse and susceptibility to neuropsychiatric disorders, such as schizophrenia. Initial tests of this hypothesis have yielded intriguing leads as to the mechanisms of nicotinic regulation of corticolimbic circuits related to attention and motivational behaviors in studies of single and compound genetically modified mice.

Behavioral studies reveal deficits in working memory and in attention gating that worsen with age and are ameliorated by nicotine administration in Nrg1tm1Lwr (+/-) mice. Likewise, initial in vivo recordings in both anesthetized and in awake-behaving animals reveal distinct patterns of baseline and nicotine-induced cortico-striatal activity in Nrg1tm1Lwr (+/-) mice compared with wild-type littermates.

If genetic epistasis of Nrg1 and alpha7*-nAChR contributes to the high comorbidity of schizophrenia and nicotine dependence, then we predict that compound heterozygotes of Nrg1 and alpha7 would provide a strong model of schizophrenia-related cognitive deficits. To date, both our electrophysiological studies of corticolimbic circuits and our behavioral analyses (open field, PPI, and T-maze) of "single hit" Nrg1/alpha7 mice affirm this idea.

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Jacob P. Waletzky Memorial Lecture

Co-Chairs: Rita P. Liu, Ph.D. and Cathrine Sasek, Ph.D., National Institute on Drug Abuse

Overview

Established in 2003, the Society for Neuroscience Jacob P. Waletzky Memorial Award is given for innovative research in drug addiction and alcoholism. The award is presented to a young scientist within 15 years of obtaining a doctoral degree. The 2007 award recipient is Marina Picciotto, Ph.D.

Studies on the Molecular Basis of Nicotine Addiction and Developmental Responses to Nicotine

Marina Picciotto, Ph.D.

Knockout mice lacking the nicotinic acetylcholine receptor (nAChR) beta2 subunit show greatly attenuated nicotine self-administration, place preference, and locomotor activation. Beta2 subunit-containing nAChRs are present throughout the brain in the regions and circuits that mediate these behaviors. We have generated several lines of transgenic mice with inducible beta2 subunit expression in different brain areas. These mice have been tested in behavioral paradigms to establish where in the brain the beta2-containing receptors may act to mediate the effects of nicotine. Using a line of mice with expression of the beta2 subunit restricted to corticothalamic projections, we have established that normal passive avoidance behavior (a fear-associated learning test) requires expression of the beta2 subunit in this pathway during development. Similarly, nicotine exposure during this critical period results in hypersensitive passive avoidance learning in adulthood. Recent studies using diffusion tensor imaging suggest that corticothalamic dysfunction may be responsible for deficits in auditory learning in human subjects exposed to tobacco smoke during development, because changes in white matter in the internal capsule—the tract including both corticothalamic and thalamocortical axons—correlate with impairments in auditory learning. Thus, the maturation of corticothalamic circuits appears to be sensitive to perturbations of nicotinic receptor function, and altered corticothalamic function may be an important anatomical substrate for the behavioral consequences of developmental smoke exposure.

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Heteromerization of G-Protein-Coupled Receptors: Implications for Central Nervous System Function and Dysfunction

Co-Chairs: Sergi Ferré, M.D., Ph.D. and David Shurtleff, Ph.D., National Institute on Drug Abuse

Overview

During the present decade, evidence has accumulated indicating that heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. This symposium will update the roles of dopamine, opioid, and adenosine receptor heteromers in the central nervous system, and their implications for neuropsychiatric disorders, including drug addiction.

Basic Concepts in G-Protein-Coupled Receptors Homodimerization and Heterodimerization

Rafael Franco, Ph.D.

Until recently, heptahelical G-protein-coupled receptors (GPCRs) were considered to be expressed as monomers on the cell surface of neuronal and non-neuronal cells. It is now becoming evident that this view must be overtly changed, because these receptors can form homodimers, heterodimers, and higher order oligomers on the plasma membrane. We discuss some of the basics and some new concepts of receptor homo- and heteromerization.

Dimers-oligomers modify pharmacology, trafficking, and signaling of receptors. First of all, GPCR homodimers must be considered as the main molecules that are targeted by neurotransmitters or by drugs. Thus, binding data must be fitted to dimer-based models. In these models, it is considered that the conformational changes transmitted within the dimer molecule lead to cooperativity. Cooperativity must be taken into account in the binding of agonist and antagonist drugs, and also in the binding of the so-called allosteric modulators. Cooperativity results from the intramolecular crosstalk in the homodimer. As an intramolecular crosstalk in the heterodimer, the binding of one neurotransmitter to one receptor often affects the binding of the second neurotransmitter to the partner receptor. Coactivation of the two receptors in a heterodimer can completely change the signaling pathway triggered by the neurotransmitter, as well as the trafficking of the receptors. Heterodimer-specific drugs or dual drugs able to simultaneously activate the two receptors in the heterodimer emerge as novel and promising drugs for a variety of central nervous system therapeutic applications.

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Heteromers of Dopamine Receptors

Susan R. George, M.D.

Signaling through each of the five dopamine receptors has been shown to occur primarily via the activation or attenuation of adenylyl cyclase activity through coupling to Gs- and Gi-family G proteins. There have been reports of a Gq-coupled D1-like dopamine receptor in the brain, but the definitive identification of this entity has proven elusive. We have shown that hetero-oligomerization of D1 and D2 receptors generates a novel signaling complex, distinct from D1 or D2 homo-oligomers.

We have identified a novel hetero-oligomeric dopamine-signaling complex in the brain, which consists of D1 and D2 receptors, that couples to Gq/11, generates robust intracellular calcium release when both receptors are coactivated, and increases phosphorylation of calmodulin-dependent protein kinase IIa. This is the first indication that dopamine can directly activate the fast-signaling calcium mechanism in the brain. Hetero-oligomerization has novel implications for signal transduction, such as increasing the repertoire of G-protein-coupled receptors signaling pathways and effector mechanisms available for endogenous ligands. The D1–D2 hetero-oligomer will have considerable significance for understanding the physiology of dopamine systems in the brain, and will also be a novel target for drug discovery once their physiological functions have been fully elucidated.

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Modulation of Function by Opioid Receptor Dimerization

Lakshmi A. Devi, Ph.D.

Opioid receptors belong to the super family of G-protein-coupled receptors characterized by their seven transmembrane domains. The activation of these receptors by narcotic analgesics or by endogenous opioid peptides leads to the activation of inhibitory G-proteins followed by the activation of multiple signal transduction pathways. A number of investigations have suggested that opioid receptor types interact with each other. Previous studies using receptor-selective antagonists, antisense oligonucleotides, or animals lacking opioid receptors have suggested that these interactions modulate receptor activity. We examined opioid receptor interactions (homotypic and heterotypic) using biochemical, biophysical, and pharmacological techniques.

We show that µ and δ opioid receptors physically associate with each other to form heterodimers that exhibit altered agonist affinity, efficacy, and/or potency. Using receptor type-selective antibodies, we immunoisolated interacting complexes from heterologous cells as well as endogenous tissue. Finally, we show that chronic morphine treatment upregulates the levels of µ-δ heterodimers in vivo and leads to the formation of new signaling complexes, which in turn lead to a switch in signaling by µ-δ heterodimers. Taken together, these results suggest that µ-δ heterodimers can be used as unique targets for the development of novel drugs and therapies for the treatment of chronic pain and other pathologies.

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Adenosine Receptor Heteromers and Their Integrative Role in Striatal Function

Sergi Ferré, M.D., Ph.D.

By analyzing the functional role of adenosine receptor heteromers, a series of new concepts was reviewed that should modify our classical views of neurotransmission in the central nervous system. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities, which possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the central nervous system. This is exemplified by changes in binding characteristics that are dependent on co-activation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and post-synaptic neurotransmission. For instance, the adenosine A1–A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the "local module" (the minimal portion of one or more neurons and/or one or more glial cells that operate as independent integrative units), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

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Glial Cells and Addiction

Co-Chairs: Diane Lawrence, Ph.D., David Thomas, Ph.D. and Da-Yu Wu, Ph.D., National Institute on Drug Abuse

Overview

Glial cells play significant roles in neural development, plasticity, neurorepair, and pain modulation, but little is known about how glial cell function is affected by substance abuse. This symposium provides an understanding of the complex nature of astrocyte function and microglial activation; highlights new findings on glial modulation of neuroplasticity, neurotoxicity, and pain; and explores potential ways that substance abuse can affect these processes.

Glia as the “Bad Guys” in Dysregulating Pain & Opioid Actions: Implications for Improving Clinical Pain Control
 

Linda R. Watkins, Ph.D.

Work during the past 15 years has challenged classical views of pain and opioid actions. Glia (microglia and astrocytes) in the central nervous system are now recognized as key players in pain amplification, including pathological pain such as neuropathic pain; compromising the ability of opioids, such as morphine, for suppressing pain; causing chronic morphine to lose effect, contributing to opioid tolerance; driving morphine dependence/withdrawal; and driving morphine reward, linked to drug craving and drug abuse. These opioid effects on glia are caused by the activation of a non-classical, non-stereoselective opioid receptor that is distinct from the receptor expressed by neurons that suppresses pain. This implies that the effects of opioids on glia and neurons should be pharmacologically separable. Our studies have revealed that opioid administration leads to an opposing process: glial release of proinflammatory cytokines that oppose the analgesic actions of opioids. The glial opposition of analgesia occurs in response to a broad range of opioids, including, but not restricted to, morphine and methadone. Upon opioid administration, both pain suppression and proinflammatory cytokine-induced pain enhancement simultaneously occur as opponent processes. Blocking proinflammatory cytokine actions markedly enhances the magnitude and duration of opioid analgesia. Indeed, morphine dose-response functions performed in the absence versus presence of cytokine inhibitors reveal a marked leftward shift in the dose-response function when proinflammatory cytokine actions are blocked, demonstrating that these endogenous proinflammatory mediators naturally compromise the analgesic efficacy of both intrathecally and systemically delivered opioid analgesics. Glial proinflammatory cytokines upregulate in response to chronic opioids, contributing to the development of opioid tolerance, opioid dependence/withdrawal, and opioid reward, measured both neurochemically (via in vivo microdialysis) and behaviorally (via conditioned place preference). Of fundamental importance is our discovery that opioids activate glia via a non-stereoselective receptor separate from the classical opioid receptor: toll-like receptor 4 (TLR4). Given that neuronally inactive (+)-naloxone blocks this glial receptor, but not neuronal opioid receptors, this finding predicts that (+)-opioids such as (+)-naloxone should potentiate opioid analgesia by not blocking morphine effects on neurons, yet removing glial activation that opposes analgesia. This is true.

On the basis of our data, we predict that suppressing glial activation will suppress the pathological pain of various etiologies, improve opioid analgesia, suppress opioid tolerance, suppress opioid dependence, and suppress opioid reward linked to drug craving/drug seeking.

Further, our data lead us to conclude that opioid activation of glia is fundamentally different than for neurons: glial receptors are not stereoselective, opioid effects on glia must be via different receptors (TLR4) than for neurons, effects of glia and neurons should be separable, and to increase the efficacy of opioids, one should either modify opioids so they do not bind glia and/or create long-lasting, orally available versions of [+]-naloxone.

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Astrocytic Modulation of Neuronal Excitability in the Nucleus Accumbens

Philip G. Haydon, M.D.

For the past decade, we have begun to appreciate that astrocytes can play active signaling roles in the nervous system. These glial cells express a plethora of neurotransmitter receptors that can mobilize intracellular Ca2+. In response to Ca2+ elevations, astrocytes release chemical transmitters, including glutamate, adenosine triphosphate, and D-serine, that act on neighboring neurons to modulate synaptic transmission and neuronal excitability. Because astrocytes are known to express mGluR5, a receptor that is critical for cocaine-induced drug-seeking behaviors, we have asked whether this receptor modulates neuron function through a glial intermediate. Studies in the nucleus accumbens demonstrate that activation of mGluR5 stimulates astrocytic Ca2+ oscillations, and that as a consequence, astrocytes excite medium spiny neurons (MSNs) through the glial release of glutamate. Furthermore, brief stimulation of glutamatergic afferents induces prolonged excitation of astrocytes, which in turn are able to continuously excite MSNs. We summarize these results and discuss the diversity of actions of glial-induced transmission and how it can impact synaptic transmission and neural network function.

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Fine-Tuning Microglial Activation Toward Neuroprotection or Cytodestruction: The Role of Microglial Heterogeneity and Novel Receptor Families

Monica J. Carson, Ph.D.

Microglia are the tissue macrophages of the central nervous system (CNS), and their activation is a frequent and early response in nearly all CNS neuropathologies. Similar to other macrophage populations, microglia are highly plastic in their phenotype and are capable of performing a wide variety of cytoprotective (“wound healing”) versus cytodestructive (pathogen-defense) functions.

To date, there is substantial debate as to which specific microglial responses that occur during neurodegenerative disease are beneficial versus maladaptive for CNS function. In part, this debate is limited by the incomplete knowledge of how the CNS environment elicits and directs microglia activation. Using flow cytometry and in situ hybridization analysis of murine models of immune- and non-immune-mediated neurodegeneration, we contrast microglial expression of Golli-myelin basic protein and two related receptor families: triggering receptors expressed on myeloid cells (TREMs) and TREM-like transcripts (TLTs). Because of the presence of immunoreceptor tyrosine-based inhibitory motif domain, TLTs are postulated to trigger inhibitory intracellular signaling pathways, whereas TREMs are postulated to trigger immunoreceptor tyrosine-based activation motif-mediated activating intracellular signaling pathways. The heterogeneous basal and induced expression of these molecules suggests that microglia function is heterogeneous in the CNS and highly context-dependent.

Using overexpression and knock-down strategies, we demonstrated the broad array of microglial functions regulated by these receptor families. We further found that despite being defined as “activating” receptors, TREMs may help to trigger neuroprotective and anti-inflammatory responses within the CNS.

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Glial Cell Induction and Suppression of Neuronal Synapses

Ben A. Barres, M.D., Ph.D.

We previously identified thrombospondin (TSP) as a 450-kD astrocyte-secreted protein that is sufficient to induce structural central nervous system (CNS) synapses, and is necessary for astrocyte-enhanced synaptogenesis in vitro. In order to better understand the molecular and cellular mechanisms by which TSP promotes the formation of structural synapses, we investigated the identity of the responsible TSP receptor(s). We found that all five TSP isoforms have strong synapse-inducing activity as a result of sharing a common epidermal growth factor-like domain. Using this domain, we have identified that TSP induces synapse formation through a novel interaction with a widely expressed transmembrane neuronal cell surface molecule, which has not been previously linked to synapse formation. The identification of the mechanism by which TSP induces synapse formation will hopefully shed light on CNS synapse formation and the role of astrocytes in CNS development, addiction, and disease.

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Henri Begleiter Memorial Symposium

Co-Chairs: Nora D. Volkow, M.D., Director, National Institute on Drug Abuse and T.K. Li, Ph.D., National Institute on Alcohol Abuse and Alcoholism

Overview

Endophenotypes are proximal to gene function, and hence provide a powerful approach to uncovering genes and genetic risk factors that contribute to complex behavioral phenotypes, such as alcohol dependence and drug abuse. This symposium addresses how some genetically influenced differences in susceptibility are unique to alcoholism (e.g., metabolic differences), whereas others (such as impulsivity) influence a range of related outcomes, including externalizing, mood disorders, and substance abuse.

Genetic Epidemiological Perspectives on Alcohol Use and Dependence
 

Kenneth S. Kendler, M.D. 

Both twin and adoption studies have consistently shown that the levels of alcohol consumption and liability to alcohol abuse and dependence (AAD) are substantially influenced by genetic factors. I will address three issues being examined in the genetic epidemiology of alcohol use and AAD.

The first issue is that of specificity. Are genes that influence risk to AAD largely specific to this condition, or are they shared with other substance use disorders and/or externalizing disorders? Two studies that address this question are reviewed; both were performed in male and female twin pairs from the Virginia Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD). AAD shares substantial genetic risk factors with other externalizing disorders, as well as with the abuse or dependence of nicotine, cannabis, and cocaine. However, both studies also found substantial sources of genetic effects on AAD that are not shared with other syndromes. Thus, genetic risk factors for AAD are partly nonspecific and partly specific.

The second issue to be explored is the developmental influences of genetic and shared environment factors on alcohol intake. A sample of male–male twin pairs from VATSPSUD shows rather striking developmental effects. Twin resemblance for the quantity of alcohol consumed in early adolescence is entirely environmental in origin. Genetic factors become progressively more important as individuals move into late adolescence and then early adulthood.

The third issue concerns genetic control of exposure to the environment. Genes likely contribute to the etiologic pathway to AAD, in part through impacting on exposure to deviant environments, including drug availability. A developmental twin study of peer deviance in the VATSPSUD shows increasing genetic effects on this key aspect of social environment as individuals move from childhood to adolescence to young adulthood. The same study also shows that genetic influences on self-reported alcohol availability become stronger when individuals leave home and begin young adulthood. Finally, genetic epidemiological methods are applied to parsing causal pathways between deviance in the individual (as operationalized by the criteria for conduct disorder) and deviance in the peer group.

These results, which can hopefully be applied directly to the study of AAD, show genetic causal paths from individual to peer deviance, and shared environmental causal pathways in the reverse direction, from peer deviance to individual deviance. Genetic epidemiologic methods are now moving beyond simple models of heritability to explore critical questions about the dynamic contribution of genetic and environmental risk factors to individual differences in alcohol consumption and the risk for AAD.

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Bernice Porjesz, Ph.D. 

Biological endophenotypes are more proximal to gene function than psychiatric diagnosis, and provide a powerful strategy when searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, and thus, provide a more direct connection with underlying biological vulnerability.

The Collaborative Study on the Genetics of Alcoholism has used heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We found significant linkage and association between brain oscillations and genes involved with inhibitory neural networks (e.g., GABRA2 [gamma-aminobutyric acid A receptor, alpha2], CHRM2 [cholinergic receptor, muscarinic 2]), including frontal networks that are deficient in individuals with alcohol dependence, impulsivity, and related disinhibitory disorders. We reported significant linkage and linkage disequilibrium for the beta frequency of the electroencephalograph and GABRA2 (a GABAA receptor gene on chromosome 4), which we found is also associated with diagnosis of alcohol dependence and related disorders. We also reported significant linkage and linkage disequilibrium between the theta and delta event-related oscillations underlying P3 generation to target stimuli and CHRM2, a cholinergic muscarinic receptor gene on chromosome 7, that we found is also associated with diagnosis of alcohol dependence and related disorders. Thus, the identification of genes important for the expression of the endophenotypes (brain oscillations) helps to identify genes that increase the susceptibility for risk of alcohol dependence and related disorders. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of complex disorders. We present our recent genetic findings related to brain oscillations and central nervous system disinhibition.

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Functional Alleles and Intermediate Phenotypes in Alcoholism and Dyscontrol Disorders

David Goldman, M.D. 

Dr. Henri Begleiter’s 1984 paper in Science, “Event-Related Brain Potentials in Boys at Risk for Alcoholism,” opened a paradigm shift in genetic studies of addiction. Working with a team of investigators that included Dr. Bernice Porjesz, Dr. Begleiter discovered that alcohol-naïve, at-risk boys already had a neurobiological indicator of attentional deficits, which directly pointed to the action of genes or early life experience. Addiction studies with intermediate phenotypes and endophenotypes (heritable and disease-associated intermediate phenotypes) now encompass stress/anxiety responses, behavioral control, reward, and obsessionality, as well as pharmacokinetic and pharmacodynamic responses to the drugs themselves. An important aspect of the intermediate phenotype approach was the ability to predict effects of functional alleles critical to the neurobiology being accessed. For frontal cognition, which Dr. Begleiter had primarily studied with electrophysiological techniques, a functional catecholamine methyl transferase (COMT) Val158Met polymorphism was replicably linked to working memory and task switching, with the Met158 allele that leads to higher dopamine levels coherently associated to better performance and greater cortical efficiency as assessed by cognitive functional magnetic resonance imaging. In recent years, we reported a series of linkages of functional alleles to another major neurobiology of addictions: variation in resiliency and vulnerability to stress/anxiety responses. Such variation is a key to drug-induced disruptions of the homeostatic maintenance of mood, and addicted patients who have suffered such disruptions remain vulnerable to stress-induced relapse.

For example, a chromosome 4 signal to alcoholism (reported by the Collaborative Study on the Genetics of Alcoholism [COGA] and us) and beta electroencephalograph (reported by COGA) were isolated to the GABAA alpha 2 subunit gene region by Dr. Howard Edenberg and collaborators at COGA. Isolation of the chromosome 4 linkage signal region sets the stage for locus identification and for a gene for alcoholism, and associated electrophysiological variation represents one culmination of a multicenter collaborative study that Dr. Begleiter originated and co-led with his late colleague Dr. Ted Reich. We and others replicated the GABAA finding at the haplotype and allele level, and we found that the linkage is anxiety-mediated. For the serotonin transporter (HTT) and COMT, common functional alleles lead to increased stress and emotional responses, and do so by actions on amygdala function as well as alterations to the modulatory effects of other brain regions, including the frontal cortex.

At the behavioral level, COMT and HTT modulate variation in anxiety, obsessionality, suicidality, and cognitive performance. Pursuing the intermediate phenotype trail blazed by Dr. Begleiter, we recently discovered a functional haplotype of neuropeptide Y (NPY), an anxiolytic neuropeptide that counteracts corticotropin-releasing hormone activations that are important in addicted individuals. The NPY haplotype predicts lower in vivo mRNA and NPY levels and is functional in cells transfected in vitro. The primary sequence alteration was identified in the promoter region. The NPY haplotype predicts trait anxiety, measured as harm avoidance. Coherently, the low-expression haplotype predicts enhanced amygdala fMRI metabolic response to emotional challenge, and poorer ability to respond to a pain/stress challenge by releasing endogenous opioids and displacing the exogenous ligand, [11C]carfentanil.

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