A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release - PubMed (original) (raw)
A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release
J Harvey et al. J Neurosci. 1997.
Abstract
The mechanism underlying dopamine D1 receptor-mediated attenuation of glutamatergic synaptic input to nucleus accumbens (NAcc) neurons was investigated in slices of rat forebrain, using whole-cell patch-clamp recording. The depression by dopamine of EPSCs evoked by single-shock cortical stimulation was stimulus-dependent. Synaptic activation of NMDA-type glutamate receptors was critical for this effect, because dopamine-induced EPSC depressions were blocked by the competitive NMDA receptor antagonist D/L-2-amino-5-phosphonopentanoate (AP5). Application of NMDA also depressed the EPSC, and both this effect and the dopamine depressions were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), implicating adenosine release in the EPSC depression. A1 receptor agonists also depressed EPSCs by a presynaptic action, causing increased paired-pulse facilitation, but this was insensitive to AP5. Activation of D1 receptors enhanced both postsynaptic inward currents evoked by NMDA application and the isolated NMDA receptor-mediated component of synaptic transmission. The biochemical processes underlying the dopamine-induced EPSC depression did not involve either protein kinase A or the production of cAMP and its metabolites, because this effect was resistant to the protein kinase inhibitors H89 and H7 and the cAMP-specific phosphodiesterase inhibitor rolipram. We conclude that activation of postsynaptic D1 receptors enhances the synaptic activation of NMDA receptors in nucleus accumbens neurons, thereby promoting a transsynaptic feedback inhibition of glutamatergic synaptic transmission via release of adenosine. Unusually for D1 receptors, this phenomenon occurs independently of adenylyl cyclase stimulation. This process may contribute to the locomotor stimulant action of dopaminergic agents in the NAcc.
Figures
Fig. 1.
The dopamine-induced depression of the EPSC is dependent on synaptic activation of NMDA receptors. A, Single-shock electrical stimulation (to evoke EPSCs) was stopped during the period shown by the hatched bar, during which time dopamine (30 μ
m
, filled bar) was applied. Only once stimulation was resumed did depression of EPSCs commence. Data were pooled from three separate experiments. Each point on the graph is the average of five consecutive records, such as those shown_below_ the graph (taken from a single experiment), and is normalized with respect to the 5 min period immediately before the addition of dopamine. B, Depression of EPSCs by dopamine was reversibly blocked by the NMDA receptor antagonist AP5 (100 μ
m
). The plot (top panel) illustrates data pooled from four individual neurons, and the_x_-axis break, variable between experiments, represents 10–20 min. Bottom panel, Sample records from one experiment, taken at the times indicated.
Fig. 2.
Adenosine A1 receptor activation is required for EPSC depression by both NMDA and dopamine, indicating that adenosine release results from NMDA receptor activation.A, Application of NMDA caused a reversible depression of EPSCs, but this was unaffected by the nitric oxide synthase (NOS) inhibitor
l
-nitroarginine. The plot shows that NMDA (20 μ
m
) depressed EPSCs in a reversible manner. After perfusion of the NOS inhibitor
l
-nitroarginine (100 μ
m
) for 15–20 min, reapplication of NMDA caused a similar depression. Data were pooled from three separate experiments, and sample records of EPSCs from one experiment are displayed_below_ the plot. B, The reversible depression of EPSCs induced by NMDA (20 μ
m
) was reduced considerably by the A1 receptor antagonist DPCPX (200 n
m
), which itself increased EPSC amplitude. The plot shows data pooled from five neurons, and the _x_-axis break corresponds to 3–5 min before the addition of DPCPX. C, DPCPX also blocks depression of EPSCs by dopamine. Dopamine (30 μ
m
) reduced the amplitude of EPSCs, and this effect was blocked in the presence of DPCPX (200 n
m
). DPCPX itself caused a clear facilitation of EPSC amplitude. Data were pooled from five individual neurons; the _x_-axis break corresponds to 3–8 min. D, The EPSC depression caused by the A1 receptor agonist CPA (200 n
m
) is unaffected by the NMDA receptor antagonist AP5 (100 μ
m
). Data were obtained from five experiments; the _x_-axis break corresponds to 10–20 min.
Fig. 3.
Both endogenous and exogenous adenosine depressed EPSCs via activation of presynaptic adenosine A1 receptors.A, The ability of adenosine to depress EPSCs is blocked by DPCPX (200 n
m
). The upper graphs are plots of EPSC amplitude (squares, top graph), input conductance (circles,middle graph), and holding current (diamonds, bottom graph) during an experiment on a single neuron, voltage-clamped at −90 mV. The_lower panel_ shows synaptic currents evoked at specific points (1–5) during the same experiment. Neither the reduction in synaptic transmission induced by adenosine nor the enhancement by DPCPX was accompanied by any change in the holding current or input conductance of the neuron. B, Similarly, the selective A1 receptor agonist CPA depressed EPSCs in a DPCPX-sensitive manner. CPA (200 n
m
) depressed EPSCs (squares, top graph) in the absence of any effect on the input conductance (circle,middle graph) or the holding current (diamond, bottom graph). Data were obtained from a single neuron voltage-clamped at −90 mV.C, Paired-pulse facilitation is increased when EPSCs are depressed by the A1 receptor agonist CPA. CPA (200 n
m
) produced a reversible enhancement in the paired-pulse ratio evoked with a 50 msec interstimulus interval. The pairs of EPSCs in the lower panel were obtained in control conditions (1) and in the presence of 200 n
m
CPA (2). In the right trace the first EPSC in_2_ has been scaled to match the size of the first EPSC in_1_. D, Paired-pulse facilitation is decreased when EPSCs are facilitated by the A1 receptor antagonist DPCPX (200 n
m
). Thus the depressant actions of both endogenous and applied adenosine are attributable to a presynaptic mechanism.
Fig. 4.
Dopamine D1 receptor activation enhances postsynaptic NMDA receptor-mediated inward currents independently of synaptic transmission. A, Data pooled from five cells showing that bath application of NMDA (20 μ
m
) induced an inward current. When NMDA was reapplied in the same five cells 5–10 min after application of the D1receptor agonist SKF 38393 (10 μ
m
), NMDA-induced currents were enhanced. Cells were voltage-clamped at −80 to −90 mV with tetrodotoxin (200 n
m
) present throughout. _B,_Continuous record of membrane current from an individual neuron (1 of the 5 in A; voltage-clamped at −90 mV) showing the reversible enhancement of the NMDA-mediated current by SKF 38393 (10 μ
m
).
Fig. 5.
Adenosine A1 receptor blockade prevents dopamine-mediated depression of NMDA receptor-mediated EPSCs (EPSCN) and reveals that dopamine enhances the EPSCN. A, The EPSCN was isolated by application of CNQX (10 μ
m
) to block AMPA receptors and by voltage-clamping at −50 mV. Under these conditions the residual component of the EPSC was blocked completely by the NMDA receptor antagonist AP5 (100 μ
m
). B, Top panel, Dopamine (30 μ
m
) reversibly reduced the EPSCN amplitude. In the presence of the A1receptor antagonist DPCPX (200 n
m
), which itself increased EPSCN amplitude, dopamine caused a clear and reversible facilitation of the EPSCN. The plot shows data pooled from nine cells, and the _x_-axis break corresponds to 3–8 min before the addition of DPCPX. Bottom panel, Sample records from one experiment, taken at the times indicated on the plot.
Fig. 6.
Dopamine depresses EPSCs independently of protein kinase A or metabolism of cAMP. A, Dopamine-induced depressions were unaffected by the protein kinase A inhibitor_H-89_ (1 μ
m
). However, the ability of forskolin (10 μ
m
) to enhance EPSCs was blocked by H-89. The plot consists of data pooled from three cells, and the_x_-axis break corresponds to 3–5 min. B, Rolipram (10 μ
m
), a cAMP-dependent phosphodiesterase inhibitor, failed to affect dopamine-induced depressions. The data in the plot are pooled from three cells, and the_x_-axis break corresponds to 3–6 min.
Fig. 7.
Diagram of a glutamatergic synapse onto a dendritic spine on a medium spiny NAcc output neuron, illustrating the processes operating to permit presynaptic modulation of glutamate release by postsynaptic dopamine D1 receptors. Glutamate released from the cortical afferent (left) activates postsynaptic glutamatergic AMPA and NMDA receptors, resulting in the EPSC. Concurrent activation of D1 receptors amplifies the current caused by the synaptic activation of NMDA receptors, thereby promoting release of adenosine (or a precursor) into the extracellular space. Adenosine in turn acts on presynaptic inhibitory A1receptors to reduce glutamate release. This sequence of events occurs independently of adenylyl cyclase stimulation and production of cyclic AMP.
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