Cocaine Enhances NMDA Receptor-Mediated Currents in Ventral Tegmental Area Cells via Dopamine D₅Receptor-Dependent Redistribution of NMDA Receptors

Abstract

Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D 1 /D 5 receptor agonist. The effect of cocaine was blocked by a DA D 1 /D 5 receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2B and their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D 5 -like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors.

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

“…This effect was prevented in rats exposed to cocaine and MK-801 (Scheggi et al, 2002). Cocaine-induced changes in the expression of NMDA receptor subunits may be mediated by extracellular dopamine, via stimulation of dopamine receptors (Schilstrom et al, 2006). Interactions between NR2B subunits of the NMDA receptor and the D2 dopamine receptor were observed in the neostriatum of cocaine-exposed rats and may contribute to the stimulant effect of cocaine.…”

“…Changes in the expression of NMDA receptor subunits were observed in the brains of cocaine-exposed rats (Huber et al, 2001;Schilstrom et al, 2006;Yamaguchi et al, 2002;Scheggi et al, 2002). In VTA neurons, cocaine induced an increase in NR1 and NR2B subunit expression and their redistribution to synaptic membranes (Schilstrom et al, 2006). NR2B expression was also shown to be increased in the NAc and in the hippocampus of cocaine-exposed rats.…”

“…Furthermore, plasticity of glutamatergic synaptic transmission in the VTA is one of the brain adaptations induced by cocaine, and contributes to the development of addictive behaviours (Schilstrom et al, 2006;Wolf, 1998). Changes in the expression of NMDA receptor subunits were observed in the brains of cocaine-exposed rats (Huber et al, 2001;Schilstrom et al, 2006;Yamaguchi et al, 2002;Scheggi et al, 2002). In VTA neurons, cocaine induced an increase in NR1 and NR2B subunit expression and their redistribution to synaptic membranes (Schilstrom et al, 2006).…”

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…We first tested the ability of ex vivo cocaine bath application to induce depotentiation of synaptic strength in the NAc shell and core. For ex vivo psychostimulant challenge studies, a dose of 10 μM was used as this concentration has been shown to promote plasticity in acute slice preparations without causing local anesthetic effects (Brodie and Dunwiddie, 1990;Schilstrom et al, 2006;Yasuda et al, 1984). Similar to in vivo psychostimulant drug exposure, incubation of acute slices for 10 min in cocaine (10 μM) reversed in vivo cocaine-induced increases in synaptic strength in the NAc shell (Figure 4b; Sal (0.70 ± 0.02), Coc (1.15 ± 0.07), Coc-Coc (0.81 ± 0.03); F (2,16) = 17.15, po0.001) and NAc core (Figure 4d; S (0.85 ± 0.03), C (1.23 ± 0.13), C-C (0.70 ± 0.06); F (2,13) = 7.81, p = 0.009).…”

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

“…In addition, no changes were detected in either mean value of the decay time constant (being 5.03±0.08 and 4.87 ± 0.05 ms in the absence and presence of cocaine, respectively) or the holding current (being the change of À0.76±4.15 pA) or input resistance (from 0.39±0.05 to 0.48 ± 0.1 GO). This lack of effect could be ascribed to the specificity of acute effect of cocaine on DA neurons, which appears to be merely on NMDA-mediated EPSCs (Schilstrom et al, 2006). WIN55212-2.…”