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The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse. 相似文献
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Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction. 相似文献
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Communication between nerve cells in the brain occurs primarily through specialized junctions called synapses. Recently, many details of synaptic transmission have emerged. The identities of specific proteins important for synaptic vesicle release have now been established. We have investigated three synaptic proteins, VAMP (vesicle associated membrane protein; also called synaptobrevin), syntaxin, and SNAP25 (synaptosomal associated protein of 25kDa) as possible targets in the dopamine-mediated modulation of synaptic function in rat striatal slices. These three proteins form a SNARE (soluble N-ethylmalemide-sensitive factor attachment protein receptors) core complex that is known to be essential for synaptic transmission. Although it is envisioned that the SNAREs undergo dynamic and cyclic interactions to elicit synaptic vesicle release, their precise functions in neurotransmission remains unknown. We have examined SNARE complexes in intact rat striatal slices. Cellular proteins were solubilized, separated electrophoretically by SDS-PAGE, and then identified immunologically. Application of dopamine to striatal slices results in SNAREs favoring the SNARE core complex, a complex which forms spontaneously in the absence of crosslinking agents, rather than the monomer form. In addition, rapid crosslinking of dopamine-treated striatal slices demonstrates that the SNARE complex is increased 4 fold in dopamine treated striatal slices compared with control slices. Haloperidol blocked the dopamine-induced change in the core complex. These results suggest that changes in the activities of SNAREs may be involved in the underlying cellular mechanisms(s) of dopamine-regulated synaptic plasticity of the striatum. 相似文献
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Synaptic plasticity in the mesolimbic dopamine system 总被引:6,自引:0,他引:6
Thomas MJ Malenka RC 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2003,358(1432):815-819
Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications. 相似文献
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Hillard CJ 《Life sciences》2005,77(14):1531-1542
Drug abuse continues to take an enormous economic and social toll on the world. Among the costs are reduced productivity, increased need for medical services and stress on families. Treatments that allow affected individuals to reduce compulsive drug use are lacking and novel approaches to their development will likely come from increased understanding of the consequences of chronic exposure to reinforcing drugs. The purpose of this review is to explore the role of lipids in drug abuse and to present a rationale for an increased focus on the interactions between drugs of abuse and lipids in the brain. Small molecular weight lipids function as neuromodulators in the brain and, as such, play a role in the synaptic plasticity that occurs following exposure to drugs of abuse. In addition, the membrane lipid bilayer consists of lipid subdomains and emerging evidence suggests that protein function can be altered by transient associations with these subdomains. Finally, lipidomics is a very new field devoted to the exploration of changes in cellular lipid constituents during phenotypic alterations. Enhanced research in all of these areas will likely provide useful insights into and, perhaps, therapeutic targets for the treatment of drug abuse. 相似文献
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Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems. 相似文献
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Anthony J. Baucum II Abigail M. Brown Roger J. Colbran 《Journal of neurochemistry》2013,124(4):490-501
Distinct physiological stimuli are required for bidirectional synaptic plasticity in striatum and hippocampus, but differences in the underlying signaling mechanisms are poorly understood. We have begun to compare levels and interactions of key excitatory synaptic proteins in whole extracts and subcellular fractions isolated from micro‐dissected striatum and hippocampus. Levels of multiple glutamate receptor subunits, calcium/calmodulin‐dependent protein kinase II (CaMKII), a highly abundant serine/threonine kinase, and spinophilin, a F‐actin and protein phosphatase 1 (PP1) binding protein, were significantly lower in striatal extracts, as well as in synaptic and/or extrasynaptic fractions, compared with similar hippocampal extracts/fractions. However, CaMKII interactions with spinophilin were more robust in striatum compared with hippocampus, and this enhanced association was restricted to the extrasynaptic fraction. NMDAR GluN2B subunits associate with both spinophilin and CaMKII, but spinophilin‐GluN2B complexes were enriched in extrasynaptic fractions whereas CaMKII‐GluN2B complexes were enriched in synaptic fractions. Notably, the association of GluN2B with both CaMKII and spinophilin was more robust in striatal extrasynaptic fractions compared with hippocampal extrasynaptic fractions. Selective differences in the assembly of synaptic and extrasynaptic signaling complexes may contribute to differential physiological regulation of excitatory transmission in striatum and hippocampus. 相似文献
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Behavioral sensitization to psychostimulants such as amphetamine (AMPH) is associated with synaptic modifications that are thought to underlie learning and memory. Because AMPH enhances extracellular dopamine in the striatum where dopamine and glutamate signaling are essential for learning, one might expect that the molecular and morphological changes that occur in the striatum in response to AMPH, including changes in synaptic plasticity, would affect learning. To ascertain whether AMPH sensitization affects learning, we tested wild-type mice and mice lacking NMDA receptor signaling in striatal medium spiny neurons in several different learning tests (motor learning, Pavlovian association, U-maze escape test with strategy shifting) with or without prior sensitization to AMPH. Prior sensitization had minimal effect on learning in any of these paradigms in wild-type mice and failed to restore learning in mutant mice, despite the fact that the mutant mice became sensitized by the AMPH treatment. We conclude that the changes in synaptic plasticity and many other signaling events that occur in response to AMPH sensitization are dissociable from those involved in learning the tasks used in our experiments. 相似文献
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Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons 总被引:31,自引:0,他引:31
Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction. 相似文献
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Eipper-Mains JE Kiraly DD Palakodeti D Mains RE Eipper BA Graveley BR 《RNA (New York, N.Y.)》2011,17(8):1529-1543
MicroRNAs (miRNAs) are small RNAs that modulate gene expression by binding target mRNAs. The hundreds of miRNAs expressed in the brain are critical for synaptic development and plasticity. Drugs of abuse cause lasting changes in the limbic regions of the brain that process reward, and addiction is viewed as a form of aberrant neuroplasticity. Using next-generation sequencing, we cataloged miRNA expression in the nucleus accumbens and at striatal synapses in control and chronically cocaine-treated mice. We identified cocaine-responsive miRNAs, synaptically enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several predicted synaptic target genes. The miR-8 family, known for its roles in cancer, is highly enriched and cocaine regulated at striatal synapses, where its members may affect expression of cell adhesion molecules. Synaptically enriched cocaine-regulated miRNAs may contribute to long-lasting drug-induced plasticity through fine-tuning regulatory pathways that modulate the actin cytoskeleton, neurotransmitter metabolism, and peptide hormone processing. 相似文献
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Jenner P 《Nature reviews. Neuroscience》2008,9(9):665-677
L-DOPA (L-3,4-dihydroxyphenylalanine) remains the most effective drug for the treatment of Parkinson's disease. However, chronic use causes dyskinesia, a complex motor phenomenon that consists of two components: the execution of involuntary movements in response to drug administration, and the 'priming' phenomenon that underlies these movements' establishment and persistence. A reinterpretation of recent data suggests that priming for dyskinesia results from nigral denervation and the loss of striatal dopamine input, which alters glutamatergic synaptic connectivity in the striatum. The subsequent response of the abnormal basal ganglia to dopaminergic drugs determines the manner and timing of dyskinesia expression. The combination of nigral denervation and drug treatment establishes inappropriate signalling between the motor cortex and the striatum, leading to persistent dyskinesia. 相似文献
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Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis 总被引:1,自引:0,他引:1
Jakawich SK Nasser HB Strong MJ McCartney AJ Perez AS Rakesh N Carruthers CJ Sutton MA 《Neuron》2010,68(6):1143-1158
Homeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (<3 hr) protein synthesis-dependent increases in both presynaptic and postsynaptic function and that the induction of presynaptic, but not postsynaptic, changes requires coincident local activity in presynaptic terminals. This "state-dependent" modulation of presynaptic function requires postsynaptic release of brain-derived neurotrophic factor (BDNF) as a retrograde messenger, which is locally synthesized in dendrites in response to AMPAR blockade. Taken together, our results reveal a local crosstalk between active presynaptic terminals and postsynaptic signaling that dictates the manner by which homeostatic plasticity is implemented at synapses. 相似文献
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Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory 总被引:15,自引:0,他引:15
Morris RG Moser EI Riedel G Martin SJ Sandin J Day M O'Carroll C 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2003,358(1432):773-786
The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity. 相似文献
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High-affinity choline transport sites specifically bind [3H]hemicholinium-3. Hemicholinium-3 binding sites are regulated by in vivo drug treatments in the same manner as these drugs alter acetylcholine release and high-affinity choline transport. The current study examines regulation of binding sites by in vivo drug administration for adult, day 15, and day 5 rats. Drugs or saline were administered intraperitoneally, and striatal and cortical membrane preparations were assayed. Control [3H]hemicholinium-3 binding increases twofold between postnatal days 5 and 15 only in striatum. After day 15, binding increases 2.7-fold in cortex and striatum. Nicotine treatment increases striatal and cortical hemicholinium-3 binding at all three ages, with greater percent increases at day 5. Haloperidol increases binding only in striatum, again with larger effects at day 5. Both striatal and cortical binding are reduced by oxotremorine; however, the magnitude of this effect is unchanged during development. Pentobarbital reduces binding only in striatum, with no developmental change. Atropine and apomorphine do not change binding from control values. In summary, all drug treatments effective in adults were already effective by day 5. Cholinergic terminals present early in development are regulated by similar nicotinic and muscarinic cholinergic, dopaminergic, and sedative-hypnotic mechanisms as the adult. Changes in magnitude may be due to changes in drug metabolism or to developmental differences in regulation. 相似文献
16.
Molecular and cellular cognitive studies of the role of synaptic plasticity in memory 总被引:18,自引:0,他引:18
Silva AJ 《Journal of neurobiology》2003,54(1):224-237
Synaptic plasticity has a central role in nearly all models of learning and memory. Besides experiments documenting changes in synaptic function during learning, most of the evidence supporting a role for synaptic plasticity in memory comes from manipulations that either enhance or lesion synaptic processes. In the last decade, mouse transgenetics (knock outs and transgenics) have provided compelling evidence that the molecular mechanisms responsible for the induction and stability of synaptic changes have a critical role in the acquisition and storage of information. Here, I will review this literature, with a special focus on studies of hippocampal-dependent learning and memory. 相似文献
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Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction. 相似文献
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