A large amount of abstracts related to the neuroscience of addiction

Hey guys.  Here’s the research I have thus far on the background section.  If any of these are useful for your specific pages, feel free to use them.  I haven’t yet critically assessed all of these papers re: scientific validity, but I can knock that out soon.  A lot of these deal with specific pathways and some underlying mechanisms, so once I know what you all intend to put into your pages I can start to work on filling in the gaps and showing the relations among different addictions.

 

• Neuroscience of Addiction
  • George F Koob1, *, Pietro Paolo Sanna1, Floyd E Bloom1
  • Human addictions are chronically relapsing disorders characterized by compulsive drug taking, an inability to limit the intake of drugs, and the emergence of a withdrawal syndrome during cessation of drug taking (dependence). The development of an addiction impacts on several separate neurobiological processes, and these effects are both drug- and drug use–dependent. In animal models of addiction, changes in specific neurotransmitter systems within a highly limited band of structures, including specific parts of the nucleus accumbens and amygdala, may underlie drug reward and the motivational effects associated with dependence. Changes in the signals mediated by several neurotransmitters, including dopamine, opioid peptides, and corticotropin-releasing factor (CRF), and in the regulation of selected transcription factors within the neurons of this reward circuit, may underlie the vulnerability to relapse that characterizes addiction in humans.
• Molecular basis of long-term plasticity underlying addiction
  • Eric J. Nestler
  • Studies of human addicts and behavioural studies in rodent models of addiction indicate that key behavioural abnormalities associated with addiction are extremely long lived. So, chronic drug exposure causes stable changes in the brain at the molecular and cellular levels that underlie these behavioural abnormalities. There has been considerable progress in identifying the mechanisms that contribute to long-lived neural and behavioural plasticity related to addiction, including drug-induced changes in gene transcription, in RNA and protein processing, and in synaptic structure. Although the specific changes identified so far are not sufficiently long lasting to account for the nearly permanent changes in behaviour associated with addiction, recent work has pointed to the types of mechanism that could be involved.
• Neural systems of reinforcement for drug addiction: from actions to habits to compulsion
  • Barry J Everitt1 & Trevor W Robbins1
  • Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use—when a drug is voluntarily taken because it has reinforcing, often hedonic, effects—through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.
• The Neuroscience of Natural Rewards: Relevance to Addictive Drugs
  • Ann E. Kelley and Kent C. Berridge
  • Addictive drugs act on brain reward systems, although the brain evolved to respond not to drugs but to natural rewards, such as food and sex. Appropriate responses to natural rewards were evolutionarily important for survival, reproduction, and fitness. In a quirk of evolutionary fate, humans discovered how to stimulate this system artificially with drugs. Many molecular features of neural systems instantiating reward, and of those systems affected by addictive drugs, are conserved across species fromDrosophilae to rats to humans and include dopamine (DA), G-proteins, protein kinases, amine transporters, and transcription factors such as cAMP response element-binding protein (CREB). A better understanding of natural brain reward systems will therefore enhance understanding of the neural causation of addiction.
• Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction
  • Nora D. Volkow1, Gene-Jack Wang2, Frank Telang1, Joanna S. Fowler3, Jean Logan3, Anna-Rose Childress4, Millard Jayne1, Yeming Ma1, and Christopher Wong3
  • The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.
• Limbic-Striatal Memory Systems and Drug Addiction ☆
  • W Robbinsf2, B.J Everitt
  • Drug addiction can be understood as a pathological subversion of normal brain learning and memory processes strengthened by the motivational impact of drug-associated stimuli, leading to the establishment of compulsive drug-seeking habits. Such habits evolve through a cascade of complex associative processes with Pavlovian and instrumental components that may depend on the integration and coordination of output from several somewhat independent neural systems of learning and memory, each contributing to behavioral performance. Data are reviewed that help to define the influences of conditioned Pavlovian stimuli on goal-directed behavior via sign-tracking, motivational arousal, and conditioned reinforcement. Such influences are mediated via defined corticolimbic-striatal systems converging on the ventral striatum and driving habit-based learning that may depend on the dorsal striatum. These systems include separate and overlapping influences from the amygdala, hippocampus, and cingulate and medial prefrontal cortex on drug-seeking as well as drug-taking behavior, including the propensity to relapse.
• Common Molecular and Cellular Substrates of Addiction and Memory ☆
  • Eric J Nestler
  • Drugs of abuse cause long-lasting changes in the brain that underlie the behavioral abnormalities associated with drug addiction. Similarly, experience can induce memory formation by causing stable changes in the brain. Over the past decade, the molecular and cellular pathways of drug addiction, on the one hand, and of learning and memory, on the other, have converged. Learning and memory and drug addiction are modulated by the same neurotrophic factors, share certain intracellular signaling cascades, and depend on activation of the transcription factor CREB. They are associated with similar adaptations in neuronal morphology, and both are accompanied by alterations in synaptic plasticity (e.g., long-term potentiation, long-term depression) at particular glutamatergic synapses in the brain. There has also been recent convergence in the brain regions now considered important sites for molecular and cellular plasticity underlying addiction and memory. Complex circuits involving the hippocampus, cerebral cortex, ventral and dorsal striatum, and amygdala are implicated both in addiction and in learning and memory. The complexity of the plasticity that occurs in these circuits can be illustrated by CREB, which induces very different behavioral effects in these various brainegions. A better understanding of the molecular and cellular adaptations that occur in these neural circuits may lead to novel interventions to improve memory and combat addiction in humans.
• Is there a common molecular pathway for addiction?
  • Eric J Nestler
  • Drugs of abuse have very different acute mechanisms of action but converge on the brain’s reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.
• Affective Neuroscience and the Treatment of Sexual Addiction
  • Alexandra Katehakisa
  • Affective neuroscience illuminates the neuropsychobiological impact of traumatic early childhood attachment patterns on the affective, cognitive, and behavioral development of sexual addicts and their partners. It also guides therapists to access patients’ blunted right hemisphere through awareness of their bodily states and, thereby, to remediate patients’ hobbled capacities for establishing genuine relationships, achieving insight, and regulating emotions independently. By enriching the current cognitive-behavioral, task-oriented treatment with attention to the neurobiological causes, and costs, of sexual addiction, we create a recovery protocol that helps patients progress beyond sexual sobriety to achieve previously unattainable interpersonal connection, self-reflection, and internally regulated affective states.
• Book: Addiction Neuroethics: The Ethics of Addiction Research and Treatment by Adrian Carter, Wayne Hall, and Judy Illes
• Memory and Addiction: Shared Neural Circuitry and Molecular Mechanisms
  • Ann E. Kelley,
  • An important conceptual advance in the past decade has been the understanding that the process of drug addiction shares striking commonalities with neural plasticity associated with natural reward learning and memory. Basic mechanisms involving dopamine, glutamate, and their intracellular and genomic targets have been the focus of attention in this research area. These two neurotransmitter systems, widely distributed in many regions of cortex, limbic system, and basal ganglia, appear to play a key integrative role in motivation, learning, and memory, thus modulating adaptive behavior. However, many drugs of abuse exert their primary effects precisely on these pathways and are able to induce enduring cellular alterations in motivational networks, thus leading to maladaptive behaviors. Current theories and research on this topic are reviewed from an integrative systems perspective, with special emphasis on cellular, molecular, and behavioral aspects of dopamine D-1 and glutamate NMDA signaling, instrumental learning, and drug cue conditioning.
• Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: Implications for understanding the neurobiology of addiction
  • Liu1, M.J. Bubar, M.F. Lanfranco, G.R. Hillman, K.A. Cunningham,
  • Serotonin (5-HT) action via the 5-HT2C receptor (5-HT2CR) provides an important modulatory influence over neurons of the prefrontal cortex (PFC), which is critically involved in disorders of executive function including substance use disorders. In the present study, we investigated the distribution of the 5-HT2CR in the rat prelimbic prefrontal cortex (PrL), a subregion of the medial prefrontal cortex (mPFC), using a polyclonal antibody raised against the 5-HT2CR. The expression of 5-HT2CR immunoreactivity (IR) was highest in the deep layers (layers V/VI) of the mPFC. The 5-HT2CR-IR was typically most intense at the periphery of cell bodies and the initial segment of cell processes. Approximately 50% of the 5-HT2CR-IR detected was found in glutamate decarboxylase, isoform 67 (GAD 67)-positive neurons. Of the subtypes of GABA interneurons identified by expression of several calcium-binding proteins, a significantly higher percentage of neurons expressing IR for parvalbumin also expressed 5-HT2CR-IR than did the percentage of neurons expressing calbindin-IR or calretinin-IR that also expressed 5-HT2CR-IR. Since parvalbumin is located in basket and chandelier GABA interneurons which project to cell body and initial axon segments of pyramidal cells, respectively, these results raise the possibility that the 5-HT2CR in the mPFC acts via the parvalbumin-positive GABAergic interneurons to regulate the output of pyramidal cells in the rat mPFC.
• Amphetamine Depresses Excitatory Synaptic Transmission via Serotonin Receptors in the Ventral Tegmental Area
  • Susan Jones and Julie A. Kauer
  • The ventral tegmental area (VTA) is the origination zone for dopaminergic neurons involved in reward and addictive properties of a variety of abused substances. A major excitatory projection to VTA neurons originates in the medial prefrontal cortex, and several lines of evidence suggest that glutamatergic synapses on VTA neurons are activated and modified during exposure to psychostimulant drugs. Here, we report for the first time that amphetamine depresses excitatory glutamatergic synaptic transmission onto VTA neurons in the midbrain slice preparation. Unexpectedly, this depression is mediated not by activation of dopamine receptors, but instead by activation of serotonin receptors. Our findings suggest that an acute effect of amphetamine exposure is the release of serotonin in the VTA, which in turn modulates excitation of VTA neurons. This process may be an important early component of permanent changes occurring in the reward pathway that contribute to drug addiction.
• Dual Serotonin (5-HT) Projections to the Nucleus Accumbens Core and Shell: Relation of the 5-HT Transporter to Amphetamine-Induced Neurotoxicity
  • Pierre Brown1 and Mark E. Molliver1,2
  • Dopamine release in the nucleus accumbens (NAc) has been implicated as mediating the rewarding effects of stimulant drugs; however, recent studies suggest that 5-HT release may also contribute. In an effort to assess the role of 5-HT in drug-mediated reward, this study analyzed the serotonergic innervation of NAc using immunocytochemistry for 5-HT and the 5-HT transporter (SERT). We report that in control rats the NAc receives two distinct types of 5-HT axons that differ in regional distribution, morphology, and SERT expression. Most regions of the NAc are innervated by thin 5-HT axons that express SERT, but in the caudal NAc shell nearly all 5-HT axons lack SERT and have large spherical varicosities. Two weeks after methamphetamine orp-chloroamphetamine (PCA) treatment, most 5-HT axons in dorsal striatum and NAc have degenerated; however, the varicose axons in the shell appear intact. These drug-resistant 5-HT axons that lack SERT densely innervate the caudal one-third of the accumbens shell, the same location where dopamine axons are spared after methamphetamine. Moreover, 4 hr after PCA, the varicose axons in the caudal shell retain prominent stores of 5-HT, whereas 5-HT axons in the rest of the NAc are depleted of neurotransmitter. The results demonstrate that two functionally different 5-HT projections innervate separate regions of the NAc and that selective vulnerability to amphetamines may result from differential expression of SERT. We postulate that action potentials conducted from the raphe nuclei can release 5-HT throughout the NAc, whereas transporter-mediated release induced by stimulant drugs is more restricted and unlikely to occur in the caudal NAc shell.
• Dual dopamine/serotonin releasers: Potential treatment agents for stimulant addiction.
  • Rothman, Richard B.; Blough, Bruce E.; Baumann, Michael H.
  • “Agonist therapy” for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the “antistimulant” role of 5-HT2C receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
• Dual dopamine/serotonin releasers: Potential treatment agents for stimulant addiction.
  • Rothman, Richard B.; Blough, Bruce E.; Baumann, Michael H.
  • “Agonist therapy” for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the “antistimulant” role of 5-HT2C receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression. (PsycINFO Database Record (c) 2012 APA, all rights reserved)