2008
DOI: 10.1016/j.neuron.2008.07.010
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Glutamate Receptors on Dopamine Neurons Control the Persistence of Cocaine Seeking

Abstract: Cocaine strengthens excitatory synapses onto midbrain dopamine neurons through the synaptic delivery of GluR1-containing AMPA receptors. This cocaine-evoked plasticity depends on NMDA receptor activation, but its behavioral significance in the context of addiction remains elusive. Here, we generated mice lacking the GluR1, GluR2, or NR1 receptor subunits selectively in dopamine neurons. We report that in midbrain slices of cocaine-treated mice, synaptic transmission was no longer strengthened when GluR1 or NR1… Show more

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Cited by 222 publications
(289 citation statements)
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“…A unifying interpretation of these results is that bursts of DA neuron activity in response to important events provide generalized salience signals that facilitate learning associations of environmental cues with these events, whereas increased tonic DA, such as those measured by microdialysis, is independent of burst firing, and provides sufficient DA to engage most behaviors. Lack of NMDARs in DA neurons not only impairs burst firing, but also precludes LTP of synaptic AMPARs (21,22). AMPAR currents are transiently potentiated in DA neurons after exposure to cocaine, stress, or during learning paradigms (21,22,(45)(46)(47).…”
Section: Discussionmentioning
confidence: 99%
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“…A unifying interpretation of these results is that bursts of DA neuron activity in response to important events provide generalized salience signals that facilitate learning associations of environmental cues with these events, whereas increased tonic DA, such as those measured by microdialysis, is independent of burst firing, and provides sufficient DA to engage most behaviors. Lack of NMDARs in DA neurons not only impairs burst firing, but also precludes LTP of synaptic AMPARs (21,22). AMPAR currents are transiently potentiated in DA neurons after exposure to cocaine, stress, or during learning paradigms (21,22,(45)(46)(47).…”
Section: Discussionmentioning
confidence: 99%
“…Genetic inactivation of the essential NR1 subunit (Grin1) of the NMDAR selectively in neurons expressing the dopamine transporter gene (Slc6a3) is sufficient to inactivate NMDAR currents in these cells (21,22). To determine whether burst firing depends on functional NMDAR signaling, we monitored DA neuron activity in freely moving control (Slc6a3 ϩ/Cre ;Grin1 ϩ/lox ) and knockout (KO, Slc6a3 ϩ/Cre ;Grin1 ⌬/lox ) mice, chronically implanted with recording electrodes in the ventral tegmental area/substantia nigra pars compacta.…”
Section: Genetic Inactivation Of Nmdar In Da Neurons Impairs Burst Fimentioning
confidence: 99%
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“…Alternatively, it may be that developmental adaptive mechanisms tend to offset the effects of a GLUA1 loss in 5-HT neurons. To decipher the contribution of specific neuronal populations to the Gria1-knockout phenotype, other investigators have also turned to the CreERT2/loxP-system to achieve inducible and tissuespecific Gria1-deletions in adult mice (Engblom et al, 2008;Inta et al, 2013;Vogt et al, 2014). Interestingly, the selective deletion of Gria1 in neither dopaminergic neurons nor in Gria1 fl/fl mice and 33 neurons from 6 Gria1 5-HT À / À mice)) and (e) the excitatory responses to AMPA (1 and 3 mM) was enhanced in Gria1 5-HT À / À mice (concentration: F 1,115 ¼ 54.1, po0.001; genotype: F 1,115 ¼ 9.9, p ¼ 0.002; two-way ANOVA on ranks (n ¼ 32 and 30 neurons from 6 Gria1 fl/fl mice (1 mM and 3 mM) and 32 and 25 neurons from 6 Gria1 5-HT À / À mice (1 mM and 3 mM))).…”
Section: Behavioral Phenotypementioning
confidence: 99%
“…Surgical procedures, sampling of microdialysates, and quantification of extracellular 5-HT was performed as previously described (Engblom et al, 2008) (see Supplementary section for details).…”
Section: Microdialysismentioning
confidence: 99%