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Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors

  1. Brooks G Robinson  Is a corresponding author
  2. Alec F Condon
  3. Daniela Radl
  4. Emiliana Borrelli
  5. John T Williams
  6. Kim A Neve
  1. Oregon Health & Science University, United States
  2. University of California, Irvine, United States
  3. VA Portland Health Care System, United States
Research Advance
Cite this article as: eLife 2017;6:e31924 doi: 10.7554/eLife.31924
3 figures and 1 additional file

Figures

Cocaine-induced adaptation in D2 receptor desensitization.

Shown on the left are representative traces from naïve and cocaine-treated groups in all genotypes of quinpirole (quin., 10 µM)-induced D2 receptor-GIRK currents (I-quinpirole) reversed by sulpiride (sulp., 600 nM) recorded from dopamine neurons in the SNc using EGTA internal solution. For further comparison, scaled and peak aligned current declines are also shown (horizontal scale bars = 90 s, vertical scale bars = 100 pA). (A) In wild type animals there were significant overall effects of internal solution (F(1, 30)=23.57, p<0.001) and cocaine treatment (20 mg/kg, F(1, 30)=4.259, p=0.048) on the decline of I-quinpirole. Post-hoc analyses indicate that in both treatment conditions the decline using BAPTA (B) internal was less than that using EGTA (E, p<0.001 for naïve and coc-treated). Additionally, with EGTA internal there was significantly reduced decline following cocaine treatment (p=0.049, n = 7–9 neurons from 5 to 8 mice). (B) In mice in which the long isoform of the D2 receptor has been knocked out (D2L-KO), there was an overall effect of internal solution (F(1, 32)=37.09, p<0.001), but not of cocaine treatment (F (1, 32)=2.917, p=0.097). In post hoc analyses, there was significantly more decline when using EGTA internal than BAPTA internal in both treatment conditions (p<0.001 for naïve, p=0.002 for cocaine-treated), and the decline was significantly reduced following drug exposure when EGTA internal was used (p=0.021, n = 8–12 neurons from 4 to 7 mice). (C) In animals with the short isoform of the D2 receptor knocked out (D2S-KO), there was an overall effect of internal solution (F(1, 28)=21.24, p<0.001) with EGTA currents declining significantly more that those of BAPTA in both treatment conditions (p=0.001 for naïve, p=0.007 for coc-treated, n = 7–9 neurons from 4 to 7 mice). Cocaine treatment caused no change in desensitization of the D2-GIRK current in this genotype. Comparisons were done using two-way ANOVAs followed by Fisher’s LSD when p<0.05. *p<0.05, **p<0.01, ***p<0.001.

https://doi.org/10.7554/eLife.31924.002
Amplitude of D2-GIRK currents.

(A) In wild type mice, there was an overall significant effect of internal solution on D2-GIRK current density (pA/pF, F(1, 30)=76.32, p<0.001). The current density was greater when using the strong calcium buffering BAPTA (B) internal solution compared with the weak buffering EGTA (E) internal solution (p<0.001 for naïve and coc-treated, n = 7–11 neurons from 5 to 7 mice). There was no difference between naïve and cocaine-treated groups. (B) From D2L-KO mice, there was an overall significant effect of internal solution (F(1, 32)=12.85, p=0.001). The current density of the BAPTA group was significantly larger than that of EGTA in both naïve and coc-treated conditions (p=0.016 for naïve, p=0.016 for coc-treated, n = 7–12 neurons from 4 to 7 mice), however there was no difference between treatment conditions. (C) In D2S-KO mice, there was no significant effect of internal solution or drug treatment (n = 7–9 neurons from 5 to 7 mice). Analyses were done by two-way ANOVAs followed by Fisher’s LSD when p<0.05. *p<0.05, **p<0.01, ***p<0.001.

https://doi.org/10.7554/eLife.31924.004
No change in GABAB desensitization following cocaine exposure.

GABAB receptor decline/desensitization was measured by bath application of baclofen (30 µM) for ~5 min. There were no significant effects of EGTA (E, 0.01 mM) versus BAPTA (B, 10 mM) internal solution or treatment condition (naïve versus coc-treated) on the decline in GABAB-GIRK currents (I-baclofen) from (A) wild type mice, (B) D2L-KO mice, or (C) D2S-KO mice (p<0.05, n = 5–9 neurons from 3 to 6 mice). Analyses were done using two-way ANOVAs.

https://doi.org/10.7554/eLife.31924.006

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