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• W2036768211 abstract "Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior. Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior. Addictive drugs mediate their reinforcing properties by targeting the mesocorticolimbic dopamine (DA) system, which we define as including the ventral tegmental area (VTA) and its major targets, the nucleus accumbens (NAc) and prefrontal cortex (PFC). Despite their chemical diversity and individual molecular targets, all addictive drugs have in common that they increase DA concentrations in projection areas of the VTA as well as the VTA itself (Di Chiara and Imperato, 1988Di Chiara G. Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.Proc. Natl. Acad. Sci. USA. 1988; 85: 5274-5278Crossref PubMed Google Scholar, Nestler, 2005Nestler E.J. Is there a common molecular pathway for addiction?.Nat. Neurosci. 2005; 8: 1445-1449Crossref PubMed Scopus (493) Google Scholar). In brief (for a more extensive review on the pharmacology of addictive drugs, see the review by D. Sulzer in the present issue of Neuron and Lüscher and Ungless, 2006Lüscher C. Ungless M.A. The mechanistic classification of addictive drugs.PLoS Med. 2006; 3: e437Crossref PubMed Scopus (60) Google Scholar), nicotine can directly increase firing of DA neurons through α4β2-containing nicotinic receptors that are expressed on DA neurons (Maskos et al., 2005Maskos U. Molles B.E. Pons S. Besson M. Guiard B.P. Guilloux J.P. Evrard A. Cazala P. Cormier A. Mameli-Engvall M. et al.Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.Nature. 2005; 436: 103-107Crossref PubMed Scopus (299) Google Scholar). Opioids (Johnson and North, 1992Johnson S.W. North R.A. Opioids excite dopamine neurons by hyperpolarization of local interneurons.J. Neurosci. 1992; 12: 483-488PubMed Google Scholar), cannabinoids (Szabo et al., 2002Szabo B. Siemes S. Wallmichrath I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids.Eur. J. Neurosci. 2002; 15: 2057-2061Crossref PubMed Scopus (114) Google Scholar), the club drug γ-hydroxybutyrate (GHB) (Cruz et al., 2004Cruz H.G. Ivanova T. Lunn M.L. Stoffel M. Slesinger P.A. Lüscher C. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system.Nat. Neurosci. 2004; 7: 153-159Crossref PubMed Scopus (133) Google Scholar), and benzodiazepines (Tan et al., 2010Tan K.R. Brown M. Labouèbe G. Yvon C. Creton C. Fritschy J.M. Rudolph U. Lüscher C. Neural bases for addictive properties of benzodiazepines.Nature. 2010; 463: 769-774Crossref PubMed Scopus (85) Google Scholar) primarily target GABAergic interneurons in the VTA and decrease their activity, which leads to an indirect increase of DA neuron activity. Such disinhibition can occur because of the cell-type-specific expression of the respective receptors (e.g., μ-opioid receptors are expressed on GABA, but not on DA neurons) or because GABA neurons are more sensitive to the drug than DA neurons. Benzodiazepines, for example, primarily silence interneurons because unitary GABA-A receptor-mediated currents in these cells are larger than in DA neurons. This observation correlates with the interneuron-specific expression of the α1 receptor subunit isoform (Tan et al., 2010Tan K.R. Brown M. Labouèbe G. Yvon C. Creton C. Fritschy J.M. Rudolph U. Lüscher C. Neural bases for addictive properties of benzodiazepines.Nature. 2010; 463: 769-774Crossref PubMed Scopus (85) Google Scholar). Finally, the psychostimulants cocaine, amphetamines, and ecstasy target the DA transporter (DAT), which is normally responsible for the reuptake of DA (Sulzer et al., 2005Sulzer D. Sonders M.S. Poulsen N.W. Galli A. Mechanisms of neurotransmitter release by amphetamines: a review.Prog. Neurobiol. 2005; 75: 406-433Crossref PubMed Scopus (403) Google Scholar). Since midbrain DA neurons also release DA from their dendrites (Cheramy et al., 1981Cheramy A. Leviel V. Glowinski J. Dendritic release of dopamine in the substantia nigra.Nature. 1981; 289: 537-542Crossref PubMed Google Scholar, Beckstead et al., 2004Beckstead M.J. Grandy D.K. Wickman K. Williams J.T. Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons.Neuron. 2004; 42: 939-946Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), DAT inhibition causes an increase of DA in the VTA as well as in the NAc and PFC. Important mechanistic differences exist between the individual members of this class. Cocaine directly inhibits the DAT, while amphetamines are transporter substrates that are taken up into the cell to enhance nonvesicular release of DA. Psychostimulants have in common that they decrease the firing rate of DA neurons through D2 receptor-mediated autoinhibition (Groves et al., 1975Groves P.M. Wilson C.J. Young S.J. Rebec G.V. Self-inhibition by dopaminergic neurons.Science. 1975; 190: 522-528Crossref PubMed Google Scholar, Chen and Reith, 1994Chen N.H. Reith M.E. Autoregulation and monoamine interactions in the ventral tegmental area in the absence and presence of cocaine: a microdialysis study in freely moving rats.J. Pharmacol. Exp. Ther. 1994; 271: 1597-1610PubMed Google Scholar). The Gi/o-coupled D2 receptors hyperpolarize DA neurons by activating GIRK/Kir3 channels. Because the block of DA reuptake exceeds the consequences of reducing DA cell firing frequency, there is nevertheless a net increase of ambient DA. Addiction is normally defined as the compulsive use of a drug despite the negative consequences. An addictive drug has the potential to induce the disease, but does so only in a fraction of consumers. Here, we focus on the initial adaptive changes required, but not sufficient, to cause addiction (Redish et al., 2008Redish A.D. Jensen S. Johnson A. A unified framework for addiction: vulnerabilities in the decision process.Behav. Brain Sci. 2008; 31 (discussion 437–487): 415-437Crossref PubMed Scopus (0) Google Scholar). These initial actions of addictive drugs have been extensively studied and remain important targets for possible therapeutic interventions in the treatment of addiction (Figure 1). For example, the drug varenicline, which is used in the treatment of nicotine addiction, targets nicotinic receptors on VTA DA neurons (Coe et al., 2005Coe J.W. Brooks P.R. Vetelino M.G. Wirtz M.C. Arnold E.P. Huang J. Sands S.B. Davis T.I. Lebel L.A. Fox C.B. et al.Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.J. Med. Chem. 2005; 48: 3474-3477Crossref PubMed Scopus (487) Google Scholar). However, the acute actions of drugs of abuse dissipate as the drug leaves the brain and therefore, alone, cannot explain the development of addictive behaviors. To understand addiction, we must elucidate the specific traces the drug experience leaves in the brain and which of these are causally related to the development of addiction. Here, we will focus on some of the key synaptic adaptations that occur after single or repetitive exposures to an addictive drug. This focus is based on the assumption that, like virtually all forms of adaptive experience-dependent plasticity, the neural circuit adaptations that underlie drug-induced behavioral changes will involve drug-induced synaptic changes. Indeed, converging evidence from many studies suggests that addictive drugs modify synaptic transmission in the mesocorticolimbic DA system by hijacking mechanisms normally used for adaptive forms of experience-dependent synaptic plasticity; hence the term “drug-evoked synaptic plasticity.” However, the term should not imply that drug exposure alone is necessarily sufficient to elicit synaptic plasticity. On the contrary, many forms of drug-evoked synaptic plasticity appear to depend on the context in which the drug has been experienced, presumably because the final synaptic adaptation will depend both on the molecular action of the drug and the pattern of neural activity in the brain at the time the drug is experienced. It is also important to note that a single drug experience is certainly not sufficient to induce addiction. However, the synaptic and neural circuit adaptations caused by a drug experience often persist and lay the foundation upon which further drug-induced adaptations occur. Focusing on the mesocorticolimbic DA system makes sense not only because it is well established to be a major site of action of addictive drugs, but also because it has long been considered a structure that is essential for translating motivations into goal-directed actions (Phillips et al., 2003Phillips P.E. Stuber G.D. Heien M.L. Wightman R.M. Carelli R.M. Subsecond dopamine release promotes cocaine seeking.Nature. 2003; 422: 614-618Crossref PubMed Scopus (459) Google Scholar, Zweifel et al., 2009Zweifel L.S. Parker J.G. Lobb C.J. Rainwater A. Wall V.Z. Fadok J.P. Darvas M. Kim M.J. Mizumori S.J. Paladini C.A. et al.Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior.Proc. Natl. Acad. Sci. USA. 2009; 106: 7281-7288Crossref PubMed Scopus (119) Google Scholar). The synaptic adaptations within this system that occur in response to addictive drugs and how these may contribute to addiction-related behaviors in rodent models have been the subject of a number of recent reviews (Kauer and Malenka, 2007Kauer J.A. Malenka R.C. Synaptic plasticity and addiction.Nat. Rev. Neurosci. 2007; 8: 844-858Crossref PubMed Scopus (449) Google Scholar, Thomas et al., 2008Thomas M.J. Kalivas P.W. Shaham Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.Br. J. Pharmacol. 2008; 154: 327-342Crossref PubMed Scopus (196) Google Scholar, Russo et al., 2010Russo S.J. Dietz D.M. Dumitriu D. Morrison J.H. Malenka R.C. Nestler E.J. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens.Trends Neurosci. 2010; 33: 267-276Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, Kalivas et al., 2009Kalivas P.W. Lalumiere R.T. Knackstedt L. Shen H. Glutamate transmission in addiction.Neuropharmacology. 2009; 56: 169-173Crossref PubMed Scopus (96) Google Scholar, Schmidt and Pierce, 2010Schmidt H.D. Pierce R.C. Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction.Ann. N Y Acad. Sci. 2010; 1187: 35-75Crossref PubMed Scopus (63) Google Scholar, Wolf and Ferrario, 2010Wolf M.E. Ferrario C.R. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine.Neurosci. Biobehav. Rev. 2010; 35: 185-211Crossref PubMed Scopus (79) Google Scholar, Bowers et al., 2010Bowers M.S. Chen B.T. Bonci A. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future.Neuron. 2010; 67: 11-24Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Rather than comprehensively reviewing this same material, we will instead highlight some of the most salient findings with an emphasis on the most recent results that point to important avenues of future research. We will also exhibit the strong bias that changes in synaptic function can best be assayed using electrophysiological techniques. Biochemical and imaging-based measurements certainly provide important information that is critical for understanding the mechanisms underlying the synaptic and circuit adaptations caused by drugs of abuse. However, by definition, changes in synaptic function can be unequivocally provided only by directly measuring function, and this requires recording the postsynaptic responses to afferent stimulation. In the 1990s, based primarily on pharmacological manipulations and biochemical assays, as well as the excitement generated by the elucidation of some of the mechanisms and putative function of hippocampal LTP and LTD, it was proposed that modifications of excitatory synaptic transmission in the mesolimbic DA system are important for the neural circuit adaptations underlying some of the long-lasting behavioral consequences of administration of drugs of abuse, particularly psychostimulants (Overton et al., 1999Overton P.G. Richards C.D. Berry M.S. Clark D. Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons.Neuroreport. 1999; 10: 221-226Crossref PubMed Google Scholar, Wolf, 1998Wolf M.E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants.Prog. Neurobiol. 1998; 54: 679-720Crossref PubMed Scopus (693) Google Scholar, Kalivas, 1995Kalivas P.W. Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants.Drug Alcohol Depend. 1995; 37: 95-100Abstract Full Text PDF PubMed Scopus (152) Google Scholar). A direct test of this hypothesis was subsequently performed and resulted in the first characterization of a form of drug-evoked synaptic plasticity (Ungless et al., 2001Ungless M.A. Whistler J.L. Malenka R.C. Bonci A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.Nature. 2001; 411: 583-587Crossref PubMed Scopus (570) Google Scholar). The experimental approach, now standard, involved preparing acute midbrain slices from an animal that 24 hr earlier had received a single noncontingent injection of cocaine (or saline) and recording from VTA DA neurons. As a surrogate measure of synaptic strength, the authors measured the ratio of the AMPA receptor-mediated ESPC (AMPAR-EPSC) to the NMDA receptor-mediated EPSC (NMDAR-EPSC); the so-called AMPAR/NMDAR ratio. This ratio was significantly increased for approximately a week following the injection of cocaine, and several electrophysiological measures suggested that it was caused, at least in part, by an increase in the AMPAR-EPSCs. A recent study re-examined this question by measuring unitary synaptic responses evoked by a highly localized glutamate source (two-photon photolysis of caged glutamate [Mameli et al., 2011Mameli M. Bellone C. Brown M.T. Lüscher C. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the VTA.Nat. Neurosci. 2011; (in press. Published online February 20, 2011)https://doi.org/10.1038/nn.2763Crossref Scopus (52) Google Scholar]). The study concludes that both AMPAR transmission and NMDAR transmission are altered. A population of synapses shows strong rectification of the AMPAR-EPSC along with a decrease of the amplitude of the NMDAR-EPSC. Consistent with this conclusion, the magnitude of LTP at these synapses was reduced and that of LTD increased (Ungless et al., 2001Ungless M.A. Whistler J.L. Malenka R.C. Bonci A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.Nature. 2001; 411: 583-587Crossref PubMed Scopus (570) Google Scholar). This transient enhancement of excitatory synaptic strength in VTA DA cells also occurs following administration of other addictive drugs, including morphine, nicotine, ethanol, and benzodiazepines, but not with nonaddictive psychoactive substances such as fluoxetine or carbamazepine (Saal et al., 2003Saal D. Dong Y. Bonci A. Malenka R.C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.Neuron. 2003; 37: 577-582Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar). (The case, however, seems more complicated for ethanol. When comparing two mouse strains, one injection of ethanol did not affect the AMPAR/NMDAR ratio in C57BL/6 and led to a decrease in DAB mice [Wanat et al., 2009Wanat M.J. Sparta D.R. Hopf F.W. Bowers M.S. Melis M. Bonci A. Strain specific synaptic modifications on ventral tegmental area dopamine neurons after ethanol exposure.Biol. Psychiatry. 2009; 65: 646-653Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. The authors propose that in DAB, a decreased NMDAR signaling is at the origin of this adaptation.) Furthermore, prolonged self-administration of cocaine, unlike passive injections of cocaine or self-administration of food or sucrose, elicits an increase in the AMPAR/NMDAR ratio lasting 3 months (Chen et al., 2008Chen B.T. Bowers M.S. Martin M. Hopf F.W. Guillory A.M. Carelli R.M. Chou J.K. Bonci A. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA.Neuron. 2008; 59: 288-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Cues predicting reward also caused this increase, suggesting that this modification of excitatory synaptic function on VTA DA neurons has important roles in shaping behavioral adaptations (Stuber et al., 2008Stuber G.D. Klanker M. de Ridder B. Bowers M.S. Joosten R.N. Feenstra M.G. Bonci A. Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons.Science. 2008; 321: 1690-1692Crossref PubMed Scopus (92) Google Scholar). Several results suggest that activation of VTA DA neurons alone is sufficient to elicit this form of drug-evoked synaptic plasticity when paired with spontaneous activity. Applying cocaine to isolated midbrain slices caused an increase in the AMPAR/NMDAR ratio in DA cells when measured several hours later (Argilli et al., 2008Argilli E. Sibley D.R. Malenka R.C. England P.M. Bonci A. Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area.J. Neurosci. 2008; 28: 9092-9100Crossref PubMed Scopus (109) Google Scholar). In vivo, driving burst firing in DA cells using light activation of channelrhodopsin (ChR2) also caused synaptic adaptations in DA cells when measured 24 hr later (Brown et al., 2010Brown M.T. Bellone C. Mameli M. Labouèbe G. Bocklisch C. Balland B. Dahan L. Luján R. Deisseroth K. Lüscher C. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.PLoS ONE. 2010; 5: e15870Crossref PubMed Scopus (38) Google Scholar). The synaptic plasticity induced by both of these manipulations was prevented by pharmacological blockade of D1/D5 receptors in the VTA, suggesting that an increase in DA within the VTA is a critical trigger (Schilström et al., 2006Schilström B. Yaka R. Argilli E. Suvarna N. Schumann J. Chen B.T. Carman M. Singh V. Mailliard W.S. Ron D. Bonci A. Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors.J. Neurosci. 2006; 26: 8549-8558Crossref PubMed Scopus (87) Google Scholar). Consistent with this conclusion is the finding that this plasticity is not elicited in mice expressing a mutated DAT that is insensitive to cocaine (Brown et al., 2010Brown M.T. Bellone C. Mameli M. Labouèbe G. Bocklisch C. Balland B. Dahan L. Luján R. Deisseroth K. Lüscher C. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.PLoS ONE. 2010; 5: e15870Crossref PubMed Scopus (38) Google Scholar). An additional induction requirement for this drug-evoked synaptic plasticity is activation of NMDARs on the DA neurons. This conclusion is based on the observations that systemic administration of an NMDAR antagonist blocks the plasticity (Ungless et al., 2001Ungless M.A. Whistler J.L. Malenka R.C. Bonci A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.Nature. 2001; 411: 583-587Crossref PubMed Scopus (570) Google Scholar), as does ablation of the critical NMDAR subunit NR1 selectively in DA neurons (Engblom et al., 2008Engblom D. Bilbao A. Sanchis-Segura C. Dahan L. Perreau-Lenz S. Balland B. Parkitna J.R. Luján R. Halbout B. Mameli M. et al.Glutamate receptors on dopamine neurons control the persistence of cocaine seeking.Neuron. 2008; 59: 497-508Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, Zweifel et al., 2008Zweifel L.S. Argilli E. Bonci A. Palmiter R.D. Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors.Neuron. 2008; 59: 486-496Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). A simple model that can explain all of these results is that DA receptor activation on VTA DA neurons leads to an increase in NMDAR EPSCs and that this in turn facilitates the generation of NMDAR-dependent LTP (Schilström et al., 2006Schilström B. Yaka R. Argilli E. Suvarna N. Schumann J. Chen B.T. Carman M. Singh V. Mailliard W.S. Ron D. Bonci A. Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors.J. Neurosci. 2006; 26: 8549-8558Crossref PubMed Scopus (87) Google Scholar). The expression mechanisms of the drug-evoked plasticity at excitatory synapses on VTA DA neurons have also been explored. Because the original report of a cocaine-induced increase in the AMPAR/NMDAR ratio suggested that this was due to an upregulation of AMPARs, it was surprising to find that in mice treated with cocaine, the AMPAR-EPSCs exhibited a partial inward rectification (Bellone and Lüscher, 2006Bellone C. Lüscher C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression.Nat. Neurosci. 2006; 9: 636-641Crossref PubMed Scopus (189) Google Scholar), which is a hallmark of GluA2-lacking AMPARs (Isaac et al., 2007Isaac J.T. Ashby M. McBain C.J. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity.Neuron. 2007; 54: 859-871Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, Liu and Zukin, 2007Liu S.J. Zukin R.S. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death.Trends Neurosci. 2007; 30: 126-134Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). The presence of such AMPARs was confirmed by the sensitivity of the EPSCs to external polyamine toxins such as Joro spider toxin as well as an increased single-channel conductance estimated using nonstationary fluctuation analysis (Mameli et al., 2007Mameli M. Balland B. Luján R. Lüscher C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.Science. 2007; 317: 530-533Crossref PubMed Scopus (114) Google Scholar). While immunohistochemical staining with light microscopic resolution failed to reveal changes in AMPAR subunit expression (Lu et al., 2002Lu W. Monteggia L.M. Wolf M.E. Repeated administration of amphetamine or cocaine does not alter AMPA receptor subunit expression in the rat midbrain.Neuropsychopharmacology. 2002; 26: 1-13Crossref PubMed Scopus (43) Google Scholar), immunogold labeling at the electron microscopy level did show an increase of GluA1 after morphine treatment (Lane et al., 2008Lane D.A. Lessard A.A. Chan J. Colago E.E. Zhou Y. Schlussman S.D. Kreek M.J. Pickel V.M. Region-specific changes in the subcellular distribution of AMPA receptor GluR1 subunit in the rat ventral tegmental area after acute or chronic morphine administration.J. Neurosci. 2008; 28: 9670-9681Crossref PubMed Scopus (28) Google Scholar) and that cocaine treatment causes a decrease of GluA2 content at synapses (Mameli et al., 2007Mameli M. Balland B. Luján R. Lüscher C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.Science. 2007; 317: 530-533Crossref PubMed Scopus (114) Google Scholar, Brown et al., 2010Brown M.T. Bellone C. Mameli M. Labouèbe G. Bocklisch C. Balland B. Dahan L. Luján R. Deisseroth K. Lüscher C. Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.PLoS ONE. 2010; 5: e15870Crossref PubMed Scopus (38) Google Scholar). These results are consistent with a scenario whereby GluA2-containing receptors are exchanged for GluA2-lacking ones and no significant increase in the number of synaptic AMPARs occurs. The insertion of GluA2-lacking AMPARs that are highly conductive at negative potentials but carry minimal current at positive potentials can explain an increase of the AMPAR/NMDAR ratio when calculated at −70 mV/+40 mV, but not when both components are measured at +40 mV. This raises the possibility that cocaine administration may also decrease the number and/or function of synaptic NMDARs, which is supported by the recent observation of a decrease in unitary NMDAR-EPSCs following cocaine treatment (Mameli et al., 2011Mameli M. Bellone C. Brown M.T. Lüscher C. Cocaine inverts rules for synaptic plasticity of glutamate transmission in the VTA.Nat. Neurosci. 2011; (in press. Published online February 20, 2011)https://doi.org/10.1038/nn.2763Crossref Scopus (52) Google Scholar). This study also examined the functional consequences for further activity-dependent synaptic plasticity. While in slices an induction protocol that depolarizes DA neurons led to LTP, thus obeying a Hebbian induction rule, this protocol was inefficient after cocaine treatment. Conversely, a slight hyperpolarization of the DA neurons during afferent stimulation (i.e., “anti-Hebbian” coincidence) induced a strengthening of AMPAR transmission only in slices from mice that had received cocaine. Thus, cocaine administration not only causes a lasting change in the basal properties of excitatory synapses but may also inverse the rules that govern the induction of activity-dependent synaptic plasticity. As mentioned above, drug-evoked synaptic plasticity at this synapse persists for about a week after a single injection. Beyond this time, the receptor redistribution is reversed and the initial state of the synapse restored (Figure 2). Several lines of evidence implicate metabotropic mGluR1 receptors in this reversal. In fact, pharmacological or synaptic activation of mGluR1 in slices from cocaine-treated mice quickly removes GluA2-lacking AMPARs and replaces them with GluA2-containing ones, leading to an overall depression of synaptic transmission (Bellone and Lüscher, 2005Bellone C. Lüscher C. mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors.Eur. J. Neurosci. 2005; 21: 1280-1288Crossref PubMed Scopus (59) Google Scholar, Bellone and Lüscher, 2006Bellone C. Lüscher C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression.Nat. Neurosci. 2006; 9: 636-641Crossref PubMed Scopus (189) Google Scholar). Such mGluR-LTD relies on mammalian target of rapamycin (mTOR) signaling and rapid synthesis of GluA2 subunits via local translation from prefabricated mRNA present in dendrites of DA neurons (Mameli et al., 2007Mameli M. Balland B. Luján R. Lüscher C. Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.Science. 2007; 317: 530-533Crossref PubMed Scopus (114) Google Scholar). Moreover, interfering with mGluR1 function in vivo by introducing a TAT-conjugated, dominant-negative peptide that disrupts mGluR1-Homer interaction selectively in the VTA significantly prolongs the persistence of cocaine-evoked plasticity (Mameli et al., 2009Mameli M. Halbout B. Creton C. Engblom D. Parkitna J.R. Spanagel R. Lüscher C. Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc.Nat. Neurosci. 2009; 12: 1036-1041Crossref PubMed Scopus (129) Google Scholar). Taken together, these results suggest that mGluR1 triggers an endogenous defense mechanism that ensures the removal of calcium-permeable AMPARs, which were inserted in response to drug exposure. It will be important to determine why such a mechanism does not appear to function following prolonged self-administration of cocaine (Chen et al., 2008Chen B.T. Bowers M.S. Martin M. Hopf F.W. Guillory A.M. Carelli R.M. Chou J.K. Bonci A. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA.Neuron. 2008; 59: 288-297Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). The schematics are drawn from a postembedding EM micrograph of a drug-naive mouse (courtesy of Rafael Lujan, Albacete, Spain). Note that these asymmetrical synapses are made directly onto the shaft of the dendrite (aspiny shaft synapse). In naive animals, NMDARs and AMPARs are present, the latter all containing GluA2. After one dose of cocaine, some GluA2-containing AMPARs are exchanged for GluA2-lacking ones through mechanisms involving endo- and exocytosis. At the same time NMDAR function decreases. After a week of a passive injection (months after self-administration), the baseline composition is restored through mGluR1 activation, mTOR signaling, and de novo synthesis of GluA2 from prefabricated mRNA. Throughout the whole process, the total num" @default.
• W2036768211 created "2016-06-24" @default.
• W2036768211 creator A5041585906 @default.
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• W2036768211 date "2011-02-01" @default.
• W2036768211 modified "2023-10-17" @default.
• W2036768211 title "Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling" @default.
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