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1.  An Unusual Suspect in Cocaine Addiction 
Neuron  2013;80(4):10.1016/j.neuron.2013.11.001.
Development of drug addiction is extremely complex, but its initiation can be as simple as the flip-flop of glutamatergic receptor subtypes triggered by an “unusual” type of NMDA receptors, as suggested by Yuan and colleagues in this issue of Neuron.
PMCID: PMC3883311  PMID: 24267643
cocaine; NMDA; AMPA; VTA; plasticity; addiction
2.  Cocaine-Induced Membrane Adaptation in the Central Nucleus of Amygdala 
Neuropsychopharmacology  2013;38(11):2240-2248.
Exposure to drugs of abuse lead to both rewarding effects and the subsequent development of negative affects. The progressive dysregulation of both processes is thought to critically contribute to the addictive state. Whereas cocaine-induced maladaptations in reward circuitry have been extensively examined, the cellular substrates underlying negative affect remain poorly understood. This study focuses on the central nucleus of the amygdala (CeA), a brain region that has been implicated in negative affective states upon withdrawal from chronic cocaine use. We observed that the two major types of CeA neurons, low-threshold bursting (LTB) neurons and regular spiking (RS) neurons, exhibited different sensitivity to corticotrophin-releasing factor (CRF), a stress hormone that has been implicated in negative affect during drug withdrawal. Furthermore, LTB and RS neurons developed opposite membrane adaptations following short-term (5 day) cocaine self-administration; the membrane excitability was increased in LTB neurons but decreased in RS neurons. These short-term exposure-induced effects were transient as they were present on withdrawal day 1 but disappeared on withdrawal day 21. However, extended exposure (21 day) led to sustained increase in the membrane excitability of LTB neurons such that it lasted over 21 days into the withdrawal period. These results suggest that CeA neurons can be a cellular target for cocaine to reshape the circuitry mediating negative affects during withdrawal, and that the long-lasting cellular alterations in selective subpopulations of CeA neurons may lead to unbalanced CeA processing, thus contributing to the progressive aggravation of negative affective states during withdrawal from chronic cocaine exposure.
PMCID: PMC3773674  PMID: 23756609
addiction & substance abuse; amygdala; central nucleus; CRF; depression; unipolar / bipolar; low-threshold bursting; membrane excitability; neurophysiology; psychostimulants; regular spiking; amygdala; cocaine; addiction; membrane excitability; low-threshold bursting; regular spiking
3.  Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving 
Nature neuroscience  2013;16(11):10.1038/nn.3533.
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after drug withdrawal. This ‘incubation of cocaine craving’ is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens. However, the circuit-level adaptations mediating this plasticity remain elusive. Here we studied silent synapses—often regarded as immature synapses that express stable NMDA receptors with AMPA receptors either absent or labile—in basolateral amygdala-to-accumbens projection in incubation of cocaine craving. Silent synapses were detected within this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became ‘unsilenced’, a process involving synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased cocaine incubation. Our finding indicates that silent synapse-based reorganization of the amygdala-to-accumbens projection is critical for persistent cocaine craving and relapse after withdrawal.
PMCID: PMC3815713  PMID: 24077564
cocaine; incubation; silent synapse; accumbens; amygdala; NMDA receptor
4.  Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex 
Brain research  2011;1420:1-7.
Despite sleep-loss-induced cognitive deficits, little is known about the cellular adaptations that occur with sleep loss. We used brain slices obtained from mice that were sleep deprived for 8 h to examine the electrophysiological effects of sleep deprivation (SD). We employed a modified pedestal (flowerpot) over water method for SD that eliminated rapid eye movement sleep and greatly reduced non-rapid eye movement sleep. In layer V/VI pyramidal cells of the medial prefrontal cortex, miniature excitatory post synaptic current amplitude was slightly reduced, miniature inhibitory post synaptic currents were unaffected, and intrinsic membrane excitability was increased after SD.
PMCID: PMC3205322  PMID: 21962531
sleep deprivation; prefrontal cortex; membrane excitability; EPSC; IPSC; synaptic; flowerpot
5.  The Density of EAAC1 (EAAT3) Glutamate Transporters Expressed by Neurons in the Mammalian CNS 
The Journal of Neuroscience  2012;32(17):6000-6013.
The extracellular levels of excitatory amino acids are kept low by the action of the glutamate transporters. Glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) are the most abundant subtypes and are essential for the functioning of the mammalian CNS, but the contribution of the EAAC1 subtype in the clearance of synaptic glutamate has remained controversial, because the density of this transporter in different tissues has not been determined. We used purified EAAC1 protein as a standard during immunoblotting to measure the concentration of EAAC1 in different CNS regions. The highest EAAC1 levels were found in the young adult rat hippocampus. Here, the concentration of EAAC1 was ∼0.013 mg/g tissue (∼130 molecules μm−3), 100 times lower than that of GLT-1. Unlike GLT-1 expression, which increases in parallel with circuit formation, only minor changes in the concentration of EAAC1 were observed from E18 to adulthood. In hippocampal slices, photolysis of MNI-d-aspartate (4-methoxy-7-nitroindolinyl-d-aspartate) failed to elicit EAAC1-mediated transporter currents in CA1 pyramidal neurons, and d-aspartate uptake was not detected electron microscopically in spines. Using EAAC1 knock-out mice as negative controls to establish antibody specificity, we show that these relatively small amounts of EAAC1 protein are widely distributed in somata and dendrites of all hippocampal neurons. These findings raise new questions about how so few transporters can influence the activation of NMDA receptors at excitatory synapses.
PMCID: PMC4031369  PMID: 22539860
6.  Searching for Presynaptic NMDA Receptors in the Nucleus Accumbens 
The Journal of Neuroscience  2011;31(50):18453-18463.
The nucleus accumbens shell (NAc) is a key brain region mediating emotional and motivational learning. In rodent models, dynamic alterations have been observed in synaptic N-Methyl-D-aspartic acid receptors (NMDARs) within the NAc following incentive stimuli, and some of these alterations are critical for acquiring new emotional/motivational states. NMDARs are prominent molecular devices for controlling neural plasticity and memory formation. Although synaptic NMDARs are predominately located postsynaptically, recent evidence suggests that they may also exist at presynaptic terminals and reshape excitatory synaptic transmission by regulating presynaptic glutamate release. However, it remains unknown whether presynaptic NMDARs exist in the NAc to contribute to emotional and motivational learning. In an attempt to identify presynaptically-located NMDARs in the NAc, the present study utilizes slice electrophysiological recording combined with pharmacological and genetic tools to examine the physiological role of the putative presynaptic NMDARs in rats. Our results show that application of glycine, the glycine-site agonist of NMDARs, potentiated presynaptic release of glutamate at excitatory synapses on NAc neurons, whereas application of 5,7-dichlorokynurenic acid (DCKA) or 7-chlorokynurenic acid, the glycine-site antagonists of NMDARs, produced the opposite effect. However, these seemingly presynaptic NMDAR-mediated effects could not be prevented by application of D-APV, the glutamate-site NMDAR antagonist, and were still present in the mice in which NMDAR NR1 or NR3 subunits were genetically deleted. Thus, rather than suggesting the existence of presynaptic NMDARs, our results support the idea that an unidentified type of glycine-activated substrate may account for the presynaptic effects appearing to be mediated by NMDARs.
PMCID: PMC3277808  PMID: 22171047
NMDA receptor; presynaptic; NR3; NR1; d-serine; 5,7-dichlorokynurenic acid
7.  A Silent Synapse-based Mechanism for Cocaine-induced Locomotor Sensitization 
The Journal of Neuroscience  2011;31(22):8163-8174.
Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry and electrophysiology in a locomotor sensitization paradigm with repeated, daily noncontingent cocaine (15 mg/kg) injections, we show that dominant negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDAR) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.
PMCID: PMC3286116  PMID: 21632938
cocaine; silent synapse; accumbens; NMDA receptor; CREB; NR2B
8.  Cocaine-induced Homeostatic Regulation and Dysregulation of Nucleus Accumbens Neurons 
Behavioural brain research  2010;216(1):9-18.
Homeostatic response is an endowed self-correcting/maintaining property for living units, ranging from subcellular domains, single cells, and organs to the whole organism. Homeostatic responses maintain stable function through the ever-changing internal and external environments. In central neurons, several forms of homeostatic regulation have been identified, all of which tend to stabilize the functional output of neurons toward their prior “set-point.” Medium spiny neurons (MSNs) within the forebrain region of the nucleus accumbens (NAc) play a central role in gating/regulating emotional and motivational behaviors including craving and seeking drugs of abuse. Exposure to highly salient stimuli such as cocaine administration not only acutely activates a certain population of NAc MSNs, but also induces long-lasting changes in these neurons. It is these long-lasting cellular alterations that are speculated to mediate the increasingly strong cocaine-craving and cocaine-seeking behaviors. Why do the potentially powerful homeostatic mechanisms fail to correct or compensate for these drug-induced maladaptations in neurons? Based on recent experimental results, this review proposes a hypothesis of homeostatic dysregulation induced by exposure to cocaine. Specifically, we hypothesize that exposure to cocaine generates false molecular signals which mislead the homeostatic regulation process, resulting in maladaptive changes in NAc MSNs. Thus, many molecular and cellular alterations observed in the addicted brain may indeed result from homeostatic dysregulation. This review is among the first to introduce the concept of homeostatic neuroplasticity to understanding the molecular and cellular maladaptations following exposure to drugs of abuse.
PMCID: PMC2975799  PMID: 20708038
9.  Zones of Enhanced Glutamate Release from Climbing Fibers in the Mammalian Cerebellum 
Purkinje cells in the mammalian cerebellum are remarkably homogeneous in shape and orientation, yet they exhibit regional differences in gene expression. Purkinje cells that express high levels of zebrin II (aldolase C) and the glutamate transporter EAAT4, cluster in parasagittal zones that receive input from distinct groups of climbing fibers (CFs); however, the physiological properties of CFs that target these molecularly distinct Purkinje cells have not been determined. Here we report that CFs that innervate Purkinje cells in zebrin II immunoreactive (Z+) zones release more glutamate per action potential than CFs in Z− zones. CF terminals in Z+ zones had larger pools of release-ready vesicles, exhibited enhanced multivesicular release, and produced larger glutamate transients. As a result, CF-mediated excitatory postsynaptic currents (EPSCs) in Purkinje cells decayed more slowly in Z+ zones, which triggered longer duration complex spikes containing a greater number of spikelets. The differences in the duration of CF EPSCs between Z+ and Z− zones persisted in EAAT4 knockout mice, indicating that EAAT4 is not required for maintaining this aspect of CF function. These results indicate that the organization of the cerebellum into discrete longitudinal zones is defined not only by molecular phenotype of Purkinje cells within zones, but also by the physiological properties of CFs that project to these distinct regions. The enhanced release of glutamate from CFs in Z+ zones may alter the threshold for synaptic plasticity and prolong inhibition of cerebellar output neurons in deep cerebellar nuclei.
PMCID: PMC2894469  PMID: 20505095
10.  In vivo Cocaine Experience Generates Silent Synapses 
Neuron  2009;63(1):40-47.
Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated post-developmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B–containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.
PMCID: PMC2721479  PMID: 19607791
silent synapse; NMDA receptor; NR2B; cocaine; accumbens
11.  CREB Modulates the Functional Output of Nucleus Accumbens Neurons: A CRITICAL ROLE OF N-METHYL-D-ASPARTATE GLUTAMATE RECEPTOR (NMDAR) RECEPTORS* 
The Journal of biological chemistry  2007;283(5):2751-2760.
Nucleusaccumbens(NAc)mediumspinyneuronscyclebetween two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element-binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-D-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with the CREB enhancement of NAc membrane excitability (Dong, Y., Green, T., Saal, D., Marie, H., Neve, R., Nestler, E.J., and Malenka, R.C.(2006)Nat. Neurosci.9,475–477), may counteract drug-induced maladaptations in the NAc and thus ameliorate the addictive state.
PMCID: PMC2535571  PMID: 18055458

Results 1-11 (11)