PMC

A critical level of GABAergic inhibition regulates LTP induction in dopamine neurons. a, The effects of partial blocking of GABA_A receptor with bicuculline (BMI, 0.3 and 1 μM) on LTP induction in 5-7 d saline-treated rats. Scales: 5 mV, 50 ms. b, The effects of enhancing GABA_A receptor activation with diazepam (DIA, 0.1 and 1 μM) on LTP induction in 5-7 d cocaine-treated rats. Scales: 5 mV, 50 ms. c, Summary graph showing concentration-dependent effects of bicuculline and diazepam on LTP induction in saline- and cocaine-treated rats. Error bars, s.e.m.

Repeated cocaine exposure facilitates LTP induction in VTA dopamine neurons. a, Left, the protocol for LTP induction consists of 20 bursts of EPSP-spike pairs. Right, a typical postsynaptic response during one burst of paired stimuli. Scales: 30 mV, 100 ms. b,c, examples (top) and summary (below) of normalized EPSP amplitude before and after the pairing stimulation for 5-7 d saline- and cocaine-treated rats. Arrow, induction. Scales: 5 mV, 50 ms. d,e, The effect of the pairing stimulation on the EPSP amplitude for 1 d saline- or cocaine-treated rats. Error bars indicate s.e.m.

Comparison of LTP induced by two different protocols and cocaine-induced changes in the AMPAR/NMDAR ratio. a, Effects of spike-timing and steady-depolarization pairing protocols on the amplitude of EPSPs (spike-timing, same data of but averaged at 5 min interval) and EPSCs (steady depolarization) for 1 d saline-treated rats (n = 7). c, Examples of total, AMPAR and NMDAR-mediated EPSCs in slices from 1 d saline- and cocaine-injected rats. Scales: 50 pA, 15 ms. c, Summary of mean AMPAR/NMDAR ratios obtained by the experimenters who were either “blind” or “nonblind” to the treatment history of the rats. * p < 0.05, t-test. Error bars, s.e.m.

The effect of blocking GABAergic inhibition on LTP induction in dopamine neurons. a-d, In the presence of bicuculline (BMI, 20 μM) or picrotoxin (PTX, 100 μM), the pairing stimulation induced LTP for all saline- or cocaine-treated rats. Data are presented in the same manner as those in . Scales: 5 mV, 50 ms. e, Summary of LTP induction under various conditions. “Con”, without any blockers. “+AP5”, BMI and AP5. The total number of neurons examined is shown in the parenthesis. Data significantly different from the baseline value of the same experiment are marked by the asterisk (p < 0.01; paired Student's t-test). Error bars, s.e.m.

Effects of cocaine exposure on GABAergic inhibition of VTA neurons. a, Repeated cocaine treatment reduced the amplitude of maximal IPSCs in dopamine neurons. Top, Sample IPSCs in response to stimuli of incremental intensities (20 to 140 μA). Scales: 100 pA, 15 ms. Bottom, the mean amplitude of maximal IPSCs after 1-7 d saline or cocaine treatment, and 12 d withdrawal from 7 d cocaine treatment (19 d, n = 17-25 for each bar). b, Mean maximal IPSC amplitudes in non-dopamine neurons (n = 15-19). Scales: 150 pA, 15 ms. c, Samples (top) and average amplitudes (below) of currents induced by puffing muscimol (20 μM, arrow) at the soma of dopamine neurons. (* p < 0.01, t-test). Scales: 500 pA, 3s. d, Repeated cocaine treatment (5-7 d) had no effect on the mean mIPSC frequency but decreased the mean mIPSC amplitude (*p < 0.01, t-test) and significantly shifted the mIPSC amplitude distribution (bin size 2 pA) towards smaller values (p < 0.001, Kolmogorov-Smirnov test). Sample traces of mIPSCs are shown at the top. Scales: 80 pA, 250 ms. e, Effect of repeated cocaine exposure on the probability for spike initiation in dopamine neurons. Top, Examples of APs induced by 80 μA stimulation for 5 d saline-treated rat before (left) and after (right) BMI (20 μM). Scales: 30 pA, 10 ms. Bottom, Input-output curves (fit with the Boltzmann function) of probability of APs induced by graded stimuli for 5-7 d saline- and cocaine-treated rats. Error bars, s.e.m (n = 8-10).