34 ± 0.23, n = 7). We also examined the weighted decay time constant (τW) of the NMDAR EPSCs recorded at +40 mV and found that it was larger in nigrostriatal neurons when compared to the other neuronal subpopulations although this difference reached statistical significance only when compared to the decay time constant of neurons projecting to mPFC (Figure S2A, mesolimbic lateral shell neurons:

75.0 ± 19.4 ms, DAPT in vivo n = 10; nigrostriatal neurons: 138.5 ± 16.5 ms, n = 9; mesocortical neurons: 52.5 ± 10.0 ms, n = 10; mesolimbic medial shell neurons: 88.5 ± 17.2 ms, n = 8). Finally, we measured paired-pulse ratios at 50 ms and 100 ms interstimulus intervals (Figure S2B) but found no differences between the subpopulations of neurons in this estimate of the average

probability of transmitter release. The larger AMPAR/NMDAR ratios in mesocortical and mesolimbic medial selleck chemicals shell neurons are consistent with our suggestion that these neurons have not previously been studied and suggest that the basal properties of their excitatory synapses are different from synapses on mesolimbic lateral shell neurons and nigrostriatal neurons. Given that some of the basic properties of DA neurons differ depending on the brain regions to which they project, a critical question is whether these neuronal subpopulations are all modulated in the same manner by a “rewarding” experience. To address this issue, we took advantage of the well-established modification of excitatory synapses on VTA DA neurons caused by in vivo administration of drugs of abuse, an increase in the AMPAR/NMDAR ratio (Ungless et al., 2001, Saal et al., 2003, Borgland et al., 2004, Dong et al., 2004, Faleiro et al., 2004, Liu et al., 2005, Bellone

and Lüscher, 2006, Argilli et al., 2008, Chen et al., 2008, Engblom et al., 2008 and Heikkinen et al., 2009). Twenty-four hours prior to slice preparation, cocaine (15 mg/kg, ip) or, in most experiments, saline (0.9%, ip, volume matched for experimental injections) was administered to animals mafosfamide that 1–3 weeks previously had been injected with Retrobeads. Consistent with previous results, neurons projecting to NAc lateral shell and which express a large Ih exhibited a clear increase in their AMPAR/NMDAR ratios after cocaine administration (Figure 3A: saline, 0.33 ± 0.06, n = 7; cocaine, 0.61 ± 0.05, n = 13; p = 0.003). Surprisingly, however, cocaine did not significantly increase AMPAR/NMDAR ratios in either nigrostriatal cells (Figure 3B, saline: 0.34 ± 0.02, n = 6; cocaine: 0.48 ± 0.06, n = 14; p = 0.169) or in VTA cells projecting to mPFC (Figure 3C, control: 0.61 ± 0.04, n = 10; cocaine: 0.59 ± 0.07, n = 6; p = 0.765). In contrast, even though the basal AMPAR/NMDAR ratios were high, a large increase occurred in VTA DA neurons projecting to NAc medial shell (Figure 3D, saline: 0.60 ± 0.07, n = 5; cocaine: 1.1 ± 0.08, n = 9; p = 0.002). Cocaine administration did not affect the paired-pulse ratios in any DA neuron subpopulations (data not shown).