The GABAB receptor antagonist, CGP 54626 (2 μM), inhibited the evoked current, confirming the identity of the GABAB sIPSC (Figure 1), similar to previous studies (Johnson and

North, 1992 and Bonci and Williams, 1996). In DA neurons, the GABAB sIPSC did not significantly change 24 hr following METH, compared to saline injection (Figures 1A and 1B). By contrast, the sIPSC was significantly smaller in GABA neurons (Figures 1D and 1E). Moreover, the sIPSC in GABA neurons remained depressed for at least 7 days (Figure 1E). Examination of the paired-pulse ratio for the fast GABAA-mediated IPSC revealed no difference in either DA or GABA neurons (Figures 1C and 1F), suggesting that the depression KRX-0401 cell line of the sIPSC in GABA neurons was not due to the inability of GABA terminals to release GABA. To investigate the effects of METH on synaptic and extrasynaptic GABAB receptors, the GABAB receptor agonist baclofen was applied to the bath. As described previously (Labouèbe et al., 2007), saturating doses of baclofen (300 μM for DA and 100 μM for GABA) elicited large and desensitizing GABABR-activated GIRK currents in DA neurons and small nondesensitizing currents in GABA neurons (Figure 2). All baclofen-activated currents were inhibited with the inwardly rectifying K+ selleck chemical channel inhibitor Ba2+ or the GABAB

receptor antagonist (CGP 54626, not shown). In contrast to the sIPSC recordings, there was an ∼40% decrease in the GABABR-GIRK currents of DA neurons 24 hr following a METH injection (Figures 2A and 2B). However, this decrease in current was not apparent at 7 days following METH injection (Figure 2B). By contrast, the baclofen-activated

GIRK (IBaclofen) currents in GABA neurons were significantly depressed by ∼55% 24 hr following a single METH see more injection and the reduced IBaclofen persisted for 7 days (Figures 2C and 2D). We next examined whether METH altered GABABR-GIRK signaling in other brain regions. There was no significant change in the sIPSC or IBaclofen in CA1 hippocampal pyramidal or GABAergic neurons 24 hr following METH (Figure S1 available online). We also measured the sIPSC and IBaclofen in pyramidal and GABAergic neurons of the prelimbic cortex, a target region of VTA DA cells, and observed no significant changes in GABAB-GIRK currents in METH-injected mice (Figure S1). Thus, a single exposure to METH triggered a profound and long-lasting depression in both the sIPSC and IBaclofen in GABA neurons of the VTA. In addition to postsynaptic GABAB receptors, presynaptic GABAB receptors are also involved in reducing GABA release, typically through inhibition of voltage-gated Ca2+ channels (Padgett and Slesinger, 2010).