SPNs receive synaptic inputs from both spinal and supraspinal regions. We focused on two monosynaptic GABAergic pathways from local interneurons in the central autonomic area (CAA) (Deuchars et al. 2005) and fibres descending in the lateral funiculus (Lf) from higher autonomic centres. Zolpidem, a GABA_A receptor modulator with subtype selectivity, was used to compare the pharmacological profiles of these two pathways. It displayed high affinity to benzodiazepine (BZ) type I receptors (α1γ2), low affinity to BZ type II receptors (α2/3γ2) and had no effect on α5 subunits (Ali et al. 1998). Wistar rats of either sex (10-15 day) were anaesthetised with urethane (2g/kg i.p.) followed by a cardiac perfusion of 215 mM sucrose aCSF (Deuchars et al. 2005). Transverse thoracic spinal cord slices (300μm) were prepared for whole-cell patch clamp recording. Inhibitory postsynaptic potentials (IPSPs) were evoked by stimulating Lf (Lf-IPSPs) and CAA (CAA-IPSPs) sequentially and isolated in kynurenic acid (2mM). Zolpidem was initially dissolved in ethanol and was bath applied (final concentration of ethanol <1/1000). Amplitudes of IPSPs were measured by averaging 10 consecutive sweeps. At a relatively high concentration of 500nM, zolpidem caused an initial increase in Lf-IPSP amplitude (115.64±10.63%, n=8). A secondary increase in amplitude was also observed in Lf-IPSPs in 6/8 SPNs (130.81±23.24%, mean±SD) after 15 min of drug application. The initial peak response of CAA-IPSPs (142.42±19.86%, mean±SD, n=6) was significantly larger than Lf–IPSPs (P<0.01), whereas a secondary response was less prominent. At a low concentration (100nM), Zolpidem induced a rapid increase in Lf-IPSP amplitude (within 3 min, 119.18% to 166.22%, n=2) whilst CAA-IPSPs either showed no effect or were enhanced but with a time delay (after 15 min). At an even higher concentration (1μM), both IPSPs showed a two phase increase in amplitude with similar time courses (n=2). These data show that different mechanisms of GABAergic modulation are involved in controlling the activities of SPNs. In the descending Lf pathway, it is likely that the receptors are more sensitive to low concentrations of zolpidem than in the CAA pathway. At a concentration which may affect one or both types of receptors, IPSPs elicited by both pathways are enhanced. The secondary enhancements in Lf-IPSP amplitudes may reflect different levels of receptor phosphorylation (Thomson et al. 2000).