Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Biochemical Pharmacology (v.75, #1)
Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction by Richard B. Rothman; Michael H. Baumann; Thomas E. Prisinzano; Amy Hauck Newman (pp. 2-16).
The discovery and development of medications to treat addiction and notably, cocaine addiction, have been frustrated by both the complexity of the disorder and the lack of target validation in human subjects. The dopamine transporter has historically been a primary target for cocaine abuse medication development, but addictive liability and other confounds of such inhibitors of dopamine uptake have limited clinical evaluation and validation. Herein we describe efforts to develop analogues of the dopamine uptake inhibitors GBR 12909 and benztropine that show promising profiles in animal models of cocaine abuse that contrast to that of cocaine. Their unique pharmacological profiles have provided important insights into the reinforcing actions of cocaine and we propose that clinical investigation of novel dopamine uptake inhibitors will facilitate the discovery of cocaine-abuse medications.
Keywords: Cocaine; GBR12909; Benztropine; Dopamine transporter; Dopamine uptake inhibitor; Medication discovery
The behavioral pharmacology of hallucinogens by William E. Fantegrossi; Kevin S. Murnane; Chad J. Reissig (pp. 17-33).
Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.
Keywords: Hallucinogens; Serotonin receptors; Drug discrimination; Head twitch behavior; Phenethylamines; Tryptamines
Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings by Bankole A. Johnson (pp. 34-56).
The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.
Keywords: Alcohol dependence; Pharmacotherapy; Naltrexone; Acamprosate; Ondansetron; Topiramate
CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system by George W. Hubert; Douglas C. Jones; Mark C. Moffett; George Rogge; Michael J. Kuhar (pp. 57-62).
Cocaine- and amphetamine-regulated transcript (CART) peptides (CART 55–102 and CART 62–102) are peptidergic neurotransmitters that are widely but specifically distributed throughout the brain, gut and other parts of the body. They are found in many brain regions associated with drug addiction including the nucleus accumbens, ventral tegmental area and ventral pallidum. Injections of CART 55–102 into the nucleus accumbens have no effect on basal locomotor activity. However, an injection of CART just before an i.p. injection of cocaine reduces the locomotor activating effects of cocaine. These and other data suggest that CART in the accumbens blunts the effects of cocaine. A hypothesis is that CART is homeostatic in the accumbens and tends to oppose large increases in dopamine signaling. These actions would therefore be able to regulate the effects of some abused drugs such as the psychostimulants.
Keywords: Abbreviations; CART; cocaine- and amphetamine-regulated transcriptDrug addiction; Cocaine; Amphetamine; Nucleus accumbens; CART
The neurobiology and genetics of impulse control disorders: Relationships to drug addictions by Judson A. Brewer; Marc N. Potenza (pp. 63-75).
Impulse control disorders (ICDs), including pathological gambling, trichotillomania, kleptomania and others, have been conceptualized to lie along an impulsive–compulsive spectrum. Recent data have suggested that these disorders may be considered addictions. Here, we review the genetic and neuropathological bases of the impulse control disorders and consider the disorders within these non-mutually exclusive frameworks.
Keywords: Addiction; Impulse control disorders; Pathological gambling; Brain imaging; Genetics
A role of RGS proteins in drug addiction by Shelley B. Hooks; Kirill Martemyanov; Venetia Zachariou (pp. 76-84).
The diverse family of Regulators of G protein signaling (RGS) proteins are widely distributed proteins with multiple functions, including GAP activity for heterotrimeric G protein alpha subunits. Three members of the RGS family, RGS9-2, RGS4 and RGSz, have been shown to play an essential modulatory role in psychostimulant and opiate drug actions. Interestingly, these proteins show distinct structure, distribution pattern and cellular localization. In addition, each of these proteins is differentially regulated by drugs of abuse in particular brain networks and appears to modulate distinct signal transduction events. The striatal enriched RGS9 plays a prominent role in opiate and psychostimulant drug reward; RGS4 appears to modulate opiate dependence via actions in the locus coeruleus, whereas RGSz modulates analgesia via activation of the PKC pathway.
Keywords: G protein coupled receptors; Signal transduction; Scaffolding protein; Receptor desensitization; Opiate receptors; Dopamine receptors
Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse by Jean-Pol Tassin (pp. 85-97).
A challenge in drug dependence is to delineate long-term behavioral and neurochemical modifications induced by drugs of abuse. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. Although addictive properties of drugs of abuse are generally considered to be mediated by an increased release of dopamine in the ventral striatum, recent pharmacological and genetic experiments indicate an implication of α1b-adrenergic receptors in behavioral and rewarding responses to psychostimulants and opiates. Later on, it was shown that not only noradrenergic but also serotonergic systems, through 5-HT2A receptors, were controlling behavioral effects of drugs of abuse. More recently, experiments performed in animals knockout for α1b-adrenergic or 5-HT2A receptors indicated that noradrenergic and serotonergic neurons, besides their activating effects, inhibit each other by means of the stimulation of α1b-adrenergic and 5-HT2A receptors and that this mutual inhibition vanishes in wild type mice with repeated injections of psychostimulants, opiates or alcohol. Uncoupling induced by repeated treatments with drugs of abuse installs a stable sensitization of noradrenergic and serotonergic neurons, thus explaining an increased reactivity of dopaminergic neurons and behavioral sensitization. We propose that noradrenergic/serotonergic uncoupling is a common stable neurochemical consequence of repeated drugs of abuse which may also occur during chronic stressful situations and facilitate the onset of mental illness. Drug consumption would facilitate an artificial re-coupling of these neurons, thus bringing a temporary relief.
Keywords: Amphetamine; Cocaine; Morphine; Alcohol; Antidepressants; Alpha1b-adrenergic receptors; 5-HT; 2A; receptors
“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice by George R. Uhl; Tomas Drgon; Catherine Johnson; Oluwatosin O. Fatusin; Qing-Rong Liu; Carlo Contoreggi; Chuan-Yun Li; Kari Buck; John Crabbe (pp. 98-111).
Family, adoption and twin data each support substantial heritability for addictions. Most of this heritable influence is not substance-specific. The overlapping genetic vulnerability for developing dependence on a variety of addictive substances suggests large roles for “higher order” pharamacogenomics in addiction molecular genetics. We and others have now completed genome-wide association (GWA) studies of DNAs from individuals with dependence on a variety of addictive substances versus appropriate controls. Recently reported replicated GWA observations identify a number of genes based on comparisons between controls and European-American and African-American polysubstance abusers. Here we review the convergence between these results and data that compares control samples and (a) alcohol-dependent European-Americans, (b) methamphetamine-dependent Asians and (c) nicotine dependent samples from European backgrounds. We also compare these human data to quantitative trait locus (QTL) results from studies of addiction-related phenotypes in mice that focus on alcohol, methamphetamine and barbiturates. These comparisons support a genetic architecture built from largely polygenic contributions of common allelic variants to dependence on a variety of legal and illegal substances. Many of the gene variants identified in this way are likely to alter specification and maintenance of neuronal connections.
Keywords: Association genome scanning; Substance dependence; Microarray; Pooled; Neuronal connections
Homers regulate drug-induced neuroplasticity: Implications for addiction by Karen K. Szumlinski; Alexis W. Ary; Kevin D. Lominac (pp. 112-133).
Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.
Keywords: Abbreviations; AAV; adeno associated viral vector; CCHomer; coiled coil Homer; IEG; immediate early gene; KO; knock-out; mGluR; metabotropic glutamate receptor; NAC; nucleus accumbens; NMDA; N; -methyl-; d; -aspartate; PFC; prefrontal cortex; PSD; postsynpatic density; VTA; ventral tegmental area; WT; wild typeHomer proteins; Addiction; Glutamate; Nucleus accumbens; Prefronal cortex; Prenatal stress
Rats selectively-bred for behavior related to affective disorders: Proclivity for intake of alcohol and drugs of abuse, and measures of brain monoamines by J.M. Weiss; C.H.K. West; M.S. Emery; R.W. Bonsall; J.P. Moore; K.A. Boss-Williams (pp. 134-159).
Several lines of rats potentially useful for studying affective disorders have been developed in our laboratory though selective breeding for behavioral characteristics. The propensity of these lines to consume alcohol and other drugs of abuse (amphetamine and cocaine) was examined. Also, measurement of the concentration of brain monoamines – norepinephrine, dopamine, and serotonin – as well as estimation of their metabolism by measurement of the major extracellular metabolites of these monoamines was carried out to examine possible relationships of brain chemistry to the behavioral characteristics shown by these lines, as well as to their propensity for drug usage. The lines of rats are: Swim Low-active (SwLo) and Swim High-active (SwHi), which show either very low (SwLo) or very high (SwHi) amounts of motor activity in a swim test; Swim-test Susceptible (Susceptible or SUS) and Swim-test Resistant (Resistant or RES), which are highly susceptible (SUS) or highly resistant (RES) to having their swim-test activity depressed by being exposed to a stressful condition prior to the swim test; and Hyperactive (HYPER), which show spontaneous nocturnal hyperactivity compared to non-selectively bred (i.e., normal) rats as well as both extreme hyperactivity and behavioral depression after being exposed to a stressful condition. Regarding alcohol and drug usage, SUS rats readily consume alcohol while all other lines including non-selected, normal rats do not, and SwLo rats show a strong tendency to consume amphetamine and cocaine. Marked differences in brain monoamines were found between the various lines and normal rats, with salient differences seen in norepinephrine, particularly in the hippocampus, and in dopamine in forebrain regions (striatum and nucleus accumbens).
Keywords: Selectively-bred rats; Drug intake; Neurochemistry
Approach to the genetics of alcoholism: A review based on pathophysiology by Michael D. Köhnke (pp. 160-177).
Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.
Keywords: Review; Genetic; Candidate gene; Alcohol; Addiction; Association
Genetics of nicotine dependence and pharmacotherapy by Christina N. Lessov-Schlaggar; Michele L. Pergadia; Taline V. Khroyan; Gary E. Swan (pp. 178-195).
Nicotine dependence is substantially heritable. Several regions across the genome have been implicated in containing genes that confer liability to nicotine dependence and variation in individual genes has been associated with nicotine dependence. Smoking cessation measures are also heritable, and measured genetic variation is associated with nicotine dependence treatment efficacy. Despite significant strides in the understanding of the relative contribution of genetic and environmental factors to nicotine dependence and treatment, emergent challenges necessitate interdisciplinary coordinated effort for effective problem solving. These challenges include refinement of the nicotine dependence phenotype, better understanding of the dynamic interplay between genes and environment in nicotine dependence etiology, application and development of molecular and statistical methodology that can adequately address vast amounts of data, and continuous translational cross-talk.
Keywords: Phenotype refinement; Genes; Environment; Comorbidity; Pharmacogenetics; Transdisciplinary
Monoamine transporters and psychostimulant addiction by Leonard L. Howell; Heather L. Kimmel (pp. 196-217).
Psychostimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, the dopamine transporter plays a primary role in the reinforcing and behavioral-stimulant effects of psychostimulants in animals and humans. Moreover, both serotonin and norepinephrine systems can reliably modulate the neurochemical and behavioral effects of psychostimulants. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid γ-aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates, including monoamines, and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. In particular, functional agonist treatments may be used effectively to stabilize monoamine neurochemistry, influence behavior and lead to long-term abstinence. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.
Keywords: Abbreviations; GABA; γ-aminobutyric acid; NIDA; National Institute on Drug Abuse; CEWG; Community Epidemiology Work Group; ADHD; attention deficit hyperactivity disorder; SLC; solute carrier; MDMA; 3,4-methylenedioxymethamphetamine; SNP; single nucleotide polymorphism; VTA; ventral tegmental area; LC; locus coeruleus; VMAT; vesicular monoamine transporter; ERK1/2; extracellular signal-related kinases 1 and 2; RTI-336; 3β-(4-chlorophenyl)tropane-2β-[3-(4-methylphenyl)isoxazol-5-yl] hydrochloride; mGluR; metabotropic glutamate receptor; NAC; N; -acetylcysteine; NMDA; N; -methyl-; d; -aspartate; PET; positron emission tomography; FDG; 2-fluoro-2-deoxy-; d; -glucose; AMPA; α-amino-3-hydroxy-5-methylisoxazole-4-propionic acidMonoamine transporters; Psychostimulants; Dopamine; Serotonin; Norepinephrine; Addiction
Glutamatergic substrates of drug addiction and alcoholism by Justin T. Gass; M. Foster Olive (pp. 218-265).
The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism.
Keywords: Abbreviations; 5-HT; 5-hydroxytryptamine (serotonin); AC; adenylyl cyclase; AMPA; α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; Amyg; amygdaloid complex; ATP; adenosine triphosphate; BLA; basolateral amygdala; cAMP; cyclic adenosine monophosphate; CB; cannabinoid; CPP; conditioned place preference; CPu; caudate-putamen; DARPP-32; dopamine and cAMP-regulated phosphoprotein-32; kDa; EAAT; excitatory amino acid transporter; EPSC; excitatory postsynaptic current; ERK; extracellular signal-related kinase; FC; frontal cortex; GABA; gamma-aminobutyric acid; GPCR; G-protein coupled receptor; Hipp; hippocampus; ICSS; intracranial self-stimulation; iGluR; ionotropic glutamate receptor; IP; 3; inositol triphosphate; IVSA; intravenous self-administration; KA; kainic acid; MAPK; mitogen-activated protein kinase; LTD; long-term depression; LTP; long-term potentiation; MDMA; methylenedioxymethamphetamine; mGluR; metabotropic glutamate receptor; MSN; medium spiny neuron; NAcc; nucleus accumbens; nAChR; nicotinic acetylcholine receptor; NMDA; N; -methyl-; d; -aspartate; PKA; protein kinase A; PKC; protein kinase C; PPT; pedunculopontine tegmentum; SNP; single nucleotide polymorphism; Thal; thalamus; THC; Δ9-tetrahydrocannabinol; VGCC; voltage-gated calcium channel; vGluT; vesicular glutamate transporter; VTA; ventral tegmental area; x; c; cystine-glutamate exchangerDrug addiction; Alcoholism; Glutamate; Synaptic plasticity; Pharmacotherapeutics; Relapse
Neurobiology of addiction by Aviel Goodman (pp. 266-322).
Evidence that psychoactive substance use disorders, bulimia nervosa, pathological gambling, and sexual addiction share an underlying biopsychological process is summarized. Definitions are offered for addiction and addictive process, the latter being the proposed designation for the underlying biopsychological process that addictive disorders are hypothesized to share. The addictive process is introduced as an interaction of impairments in three functional systems: motivation-reward, affect regulation, and behavioral inhibition. An integrative review of the literature that addresses the neurobiology of addiction is then presented, organized according to the three functional systems that constitute the addictive process. The review is directed toward identifying candidate neurochemical substrates for the impairments in motivation-reward, affect regulation, and behavioral inhibition that could contribute to an addictive process.
Keywords: Addiction; Neurobiology; Neuroscience; Substance abuse; Bulimia; Gambling
Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction by Yann S. Mineur; Marina R. Picciotto (pp. 323-333).
Human twin studies have suggested that there is a substantial genetic component underlying nicotine dependence, ongoing smoking and ability to quit. Similarly, animal studies have identified a number of genes and gene products that are critical for behaviors related to nicotine addiction. Classical genetic approaches, gene association studies and genetic engineering techniques have been used to identify the gene products involved in nicotine dependence. One class of genes involved in nicotine-related behavior is the family of nicotinic acetylcholine receptors (nAChRs). These receptors are the primary targets for nicotine in the brain. Genetic engineering studies in mice have identified a number of subunits that are critical for the ability of nicotine to activate the reward system in the brain, consisting of the dopaminergic cell bodies in the ventral tegmental area and their terminals in the nucleus accumbens and other portions of the mesolimbic system. In this review we will discuss the various lines of evidence suggesting that nAChRs may be involved in smoking behavior, and will review the human and animal studies that have been performed to date examining the genetic basis for nicotine dependence and smoking.
Keywords: Nicotine; Nicotinic; Addiction; Genetics; Mouse; Human