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Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons.

Ma YY, Cepeda C, Chatta P, Franklin L, Evans CJ, Levine MS - ASN Neuro (2012)

Bottom Line: MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS.Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount.Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

View Article: PubMed Central - PubMed

Affiliation: Stefan Shirley Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, USA.

ABSTRACT
The striatum can be divided into the DLS (dorsolateral striatum) and the VMS (ventromedial striatum), which includes NAcC (nucleus accumbens core) and NAcS (nucleus accumbens shell). Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons) based on their location, expression of DA (dopamine) D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala(2)-MePhe(4)-Gly(ol)(5)]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS. RMPs (resting membrane potentials) were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials). Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

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Effects of DAMGO on sEPSCs in MSSNs(A) Representative recordings of sEPSCs (holding potential −70 mV) in a D2 receptor-expressing MSSN from NAcS before, during, and after washout of DAMGO (1 μM). (B) Representative time-course of a typical recording from another D2 receptor-expressing MSSN from NAcS before, during and after DAMGO (1 μM). DAMGO decreased the frequency of sEPSCs, which was reversed after DAMGO washout. (C, D) Histograms show the effects of DAMGO on sEPSCs (C) and mEPSCs (D) in D1/D2 cells in the DLS, NAcC and NAcS. In (C, D), data were calculated as changes of average frequencies of EPSCs during versus before DAMGO application, divided by the corresponding values before DAMGO. n = 10–14 (C) or n = 5 (D) in each group. The data were analysed using two-way ANOVAs followed by Bonferroni post hoc tests. *P<0.05, **P<0.01, ***P<0.0001 compared with the DLS. Also, paired t tests were performed between the average frequencies of EPSCs before versus during DAMGO application. #P<0.05, ##P<0.01, ###P<0.001 respectively.
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Figure 5: Effects of DAMGO on sEPSCs in MSSNs(A) Representative recordings of sEPSCs (holding potential −70 mV) in a D2 receptor-expressing MSSN from NAcS before, during, and after washout of DAMGO (1 μM). (B) Representative time-course of a typical recording from another D2 receptor-expressing MSSN from NAcS before, during and after DAMGO (1 μM). DAMGO decreased the frequency of sEPSCs, which was reversed after DAMGO washout. (C, D) Histograms show the effects of DAMGO on sEPSCs (C) and mEPSCs (D) in D1/D2 cells in the DLS, NAcC and NAcS. In (C, D), data were calculated as changes of average frequencies of EPSCs during versus before DAMGO application, divided by the corresponding values before DAMGO. n = 10–14 (C) or n = 5 (D) in each group. The data were analysed using two-way ANOVAs followed by Bonferroni post hoc tests. *P<0.05, **P<0.01, ***P<0.0001 compared with the DLS. Also, paired t tests were performed between the average frequencies of EPSCs before versus during DAMGO application. #P<0.05, ##P<0.01, ###P<0.001 respectively.

Mentions: The effects of the μ-opioid receptor agonist DAMGO (1 μM) on sEPSCs were evaluated 5–8 min after adding it to the ACSF and in the presence of BIC (20 μM). The effects of DAMGO on mEPSCs were determined when Na+ currents were completely blocked by addition of TTX (1 μM). DAMGO produced a marked reduction in the frequency of sEPSCs (Figures 5A and 5B) and mEPSCs in both D1 and D2 cells from the NAcC/NAcS (at least P<0.05, before versus after DAMGO, by paired Student's t tests). The effects in DLS were negligible except for a significant decrease in the frequency of sEPSCs in D2 cells. Furthermore, two-way ANOVA demonstrated a significant sub-regional difference for effects of DAMGO on the average frequency of EPSCs (F2,57 = 7.75, P = 0.0011 in sEPSCs; F2,22 = 21.84, P<0.0001 in mEPSCs). Bonferroni post hoc tests showed significantly larger inhibitory effects of DAMGO on sEPSCs and mEPSCs in D1 cells from the NAcC/NAcS compared with the DLS. In D2 cells, the inhibitory effects of DAMGO on sEPSCs in the DLS disappeared after TTX application, whereas the effects on the NAcC/NAcS still remained (Figures 5C and 5D). The amplitudes of sEPSCs/mEPSCs were not modulated by adding DAMGO (data not shown).


Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons.

Ma YY, Cepeda C, Chatta P, Franklin L, Evans CJ, Levine MS - ASN Neuro (2012)

Effects of DAMGO on sEPSCs in MSSNs(A) Representative recordings of sEPSCs (holding potential −70 mV) in a D2 receptor-expressing MSSN from NAcS before, during, and after washout of DAMGO (1 μM). (B) Representative time-course of a typical recording from another D2 receptor-expressing MSSN from NAcS before, during and after DAMGO (1 μM). DAMGO decreased the frequency of sEPSCs, which was reversed after DAMGO washout. (C, D) Histograms show the effects of DAMGO on sEPSCs (C) and mEPSCs (D) in D1/D2 cells in the DLS, NAcC and NAcS. In (C, D), data were calculated as changes of average frequencies of EPSCs during versus before DAMGO application, divided by the corresponding values before DAMGO. n = 10–14 (C) or n = 5 (D) in each group. The data were analysed using two-way ANOVAs followed by Bonferroni post hoc tests. *P<0.05, **P<0.01, ***P<0.0001 compared with the DLS. Also, paired t tests were performed between the average frequencies of EPSCs before versus during DAMGO application. #P<0.05, ##P<0.01, ###P<0.001 respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3297119&req=5

Figure 5: Effects of DAMGO on sEPSCs in MSSNs(A) Representative recordings of sEPSCs (holding potential −70 mV) in a D2 receptor-expressing MSSN from NAcS before, during, and after washout of DAMGO (1 μM). (B) Representative time-course of a typical recording from another D2 receptor-expressing MSSN from NAcS before, during and after DAMGO (1 μM). DAMGO decreased the frequency of sEPSCs, which was reversed after DAMGO washout. (C, D) Histograms show the effects of DAMGO on sEPSCs (C) and mEPSCs (D) in D1/D2 cells in the DLS, NAcC and NAcS. In (C, D), data were calculated as changes of average frequencies of EPSCs during versus before DAMGO application, divided by the corresponding values before DAMGO. n = 10–14 (C) or n = 5 (D) in each group. The data were analysed using two-way ANOVAs followed by Bonferroni post hoc tests. *P<0.05, **P<0.01, ***P<0.0001 compared with the DLS. Also, paired t tests were performed between the average frequencies of EPSCs before versus during DAMGO application. #P<0.05, ##P<0.01, ###P<0.001 respectively.
Mentions: The effects of the μ-opioid receptor agonist DAMGO (1 μM) on sEPSCs were evaluated 5–8 min after adding it to the ACSF and in the presence of BIC (20 μM). The effects of DAMGO on mEPSCs were determined when Na+ currents were completely blocked by addition of TTX (1 μM). DAMGO produced a marked reduction in the frequency of sEPSCs (Figures 5A and 5B) and mEPSCs in both D1 and D2 cells from the NAcC/NAcS (at least P<0.05, before versus after DAMGO, by paired Student's t tests). The effects in DLS were negligible except for a significant decrease in the frequency of sEPSCs in D2 cells. Furthermore, two-way ANOVA demonstrated a significant sub-regional difference for effects of DAMGO on the average frequency of EPSCs (F2,57 = 7.75, P = 0.0011 in sEPSCs; F2,22 = 21.84, P<0.0001 in mEPSCs). Bonferroni post hoc tests showed significantly larger inhibitory effects of DAMGO on sEPSCs and mEPSCs in D1 cells from the NAcC/NAcS compared with the DLS. In D2 cells, the inhibitory effects of DAMGO on sEPSCs in the DLS disappeared after TTX application, whereas the effects on the NAcC/NAcS still remained (Figures 5C and 5D). The amplitudes of sEPSCs/mEPSCs were not modulated by adding DAMGO (data not shown).

Bottom Line: MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS.Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount.Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

View Article: PubMed Central - PubMed

Affiliation: Stefan Shirley Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, USA.

ABSTRACT
The striatum can be divided into the DLS (dorsolateral striatum) and the VMS (ventromedial striatum), which includes NAcC (nucleus accumbens core) and NAcS (nucleus accumbens shell). Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons) based on their location, expression of DA (dopamine) D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala(2)-MePhe(4)-Gly(ol)(5)]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS. RMPs (resting membrane potentials) were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials). Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

Show MeSH
Related in: MedlinePlus