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.