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Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area - PubMed

  • ️Tue Jan 01 2008

Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area

Emanuela Argilli et al. J Neurosci. 2008.

Abstract

Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D(5) receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.

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Figures

Figure 1.
Figure 1.

A single cocaine injection induces an increase in AMPAR/NMDAR ratio within 3 h in VTA neurons. A, Representative traces of AMPAR and NMDAR EPSCs from naive animals or animals pretreated 3–5 h earlier with a single injection of cocaine (15 mg/kg, i.p.) or equivalent amount of saline. B, Averaged AMPAR/NMDAR ratios. Cocaine-injected animals (n = 9) show a significantly increased ratio compared with saline-injected (n = 5) or naive (n = 5) animals. **p < 0.01. Error bars represent SEM.

Figure 2.
Figure 2.

Previous exposure to cocaine in vivo reduces the incidence of STD LTP in VTA neurons. A–E, Time course of mean EPSPs before and after the STD LTP induction protocol indicated by the arrow in naive animals (A; n = 9), animals injected 3–5 h earlier with saline (B; n = 8) or cocaine (15 mg/kg, i.p.; C; n = 12), and animals injected 24 h earlier with one injection of cocaine (15 mg/kg, i.p.; D; n = 6) or the last injection of five daily cocaine injections (15 mg/kg, i.p.; E; n = 6). A–C, Representative EPSP traces before and 30 min after the induction protocol are shown above graphs. F, Summary of the magnitude of LTP under various conditions showing a significant reduction of LTP in cocaine-treated animals compared with time-matched saline-treated animals. Coc, Cocaine. **p < 0.01. Error bars represent SEM.

Figure 3.
Figure 3.

Brief exposure to cocaine in vitro induces 3–5 h later an NMDAR-dependent increase in AMPAR/NMDAR ratio and a reduction the incidence of STD LTP in VTA neurons. A, Schematic of the experimental design. B, Averaged AMPAR/NMDAR ratios. Slices treated 3–5 h earlier with cocaine (5 μ

m

, 10 min; n = 9) show a significantly increased ratio compared with vehicle-treated slices (n = 7), control slices (n = 10), and slices treated with APV 5 min before and during cocaine (n = 9). C–E, Time course of mean EPSPs before and after the STD LTP induction protocol in slices treated 3–5 h earlier with vehicle (C; n = 5), cocaine (5 μ

m

, 10 min; D; n = 10), or

d

-APV (50 μ

m

) before and during cocaine (E; n = 7). F, Summary of the magnitude of LTP under various conditions showing a significant reduction of LTP in cocaine-treated slices compared with vehicle-treated slices and slices in which NMDAR was blocked during cocaine. Coc, Cocaine. **p < 0.01. Error bars represent SEM.

Figure 4.
Figure 4.

Cocaine-induced increase in AMPAR/NMDAR ratio in vitro is mediated by D5 receptors and requires protein synthesis during induction. A, B, Averaged AMPAR/NMDAR ratios recorded 3–5 h after bath incubation with different drugs. A, Cocaine-induced LTP was prevented by treatment 5 min before and during cocaine with D1 antagonist SCH-23390 (10 μ

m

; n = 5) but not with D2 antagonist eticlopride (3 μ

m

; n = 5). The D1 agonist SKF-81297 (10 μ

m

; n = 10) alone increases the ratio, but not in the presence of

d

-APV (50 μ

m

; n = 7). B, Cocaine-induced LTP was prevented when the protein synthesis inhibitor anisomycin (40 μ

m

; n = 9) was incubated 20 min before and during cocaine, but not 1 h after (n = 9). Coc, Cocaine; SCH, SCH-23390; Eticlopr, eticlopride; SKF, SKF-81297; Aniso, anisomycin. **p < 0.01. Error bars represent SEM.

Figure 5.
Figure 5.

Brief exposure to cocaine triggers the insertion of GluR2-lacking AMPARs on VTA neurons within 3–5 h. A, Average I–V plots from slices exposed 3–5 h earlier to vehicle (n = 11) or cocaine (n = 7). A, Inset, Representative traces recorded at −70 mV and +40 mV in the presence of

d

-APV (50 μ

m

) and with spermine (100 μ

m

) in the internal solution. B, D, Time course of EPSC amplitudes showing the effect of PhTx-74 (100 μ

m

, 30 min) on VTA neurons exposed 3–5 h earlier with cocaine (n = 8) or vehicle (n = 8) (B) and summary of residual EPSCs measured 20–25 min after drug perfusion (D). The short bar in B indicates the period of high-frequency stimulation (10 Hz, 2 min) that allows binding of the toxin to the open conformation of AMPA channels. C, D, Time course of EPSC amplitudes showing the effect of NASPM (100 μ

m

, 7.5 min) on VTA neurons exposed 3–5 h earlier with cocaine (n = 7) or vehicle (n = 7) (C) and summary of residual EPSCs measured 15–20 min after drug perfusion (D). Norm., Normalized. **p < 0.01. Error bars represent SEM.

Figure 6.
Figure 6.

The expression of STD LTP is mediated by the insertion of GluR2-lacking AMPARs on VTA neurons. A, Time course of mean EPSPs (n = 4) before and after the STD LTP induction protocol indicated by the arrow. The horizontal black bar represents the time of NASPM bath application (100 μ

m

, 15 min). B, Summary of the magnitude of EPSPs in baseline, 25–30 min after LTP induction, and 0–5 min after NASPM exposure. **p < 0.01. Error bars represent SEM.

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