Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor neuroplasticity at the excitatory synapses of these neurons. This effect is also induced by benzodiazepines that are known to act via synaptic gamma2 subunit-containing GABAA receptors (Heikkinen et al., Neuropsychopharmacology 34:290–298, 2009). Here, we have tested a non-benzodiazepine direct GABA- site agonist THIP (also known as gaboxadol). THIP acts preferentially via high-affinity extrasynaptic alpha-beta-delta GABAA receptors, thus, perhaps sharing the receptor subtype target with ethanol. A single sedative doses of THIP (6 mg/kg) and ethanol (2 g/kg) to mice induced glutamate receptor plasticity as evidenced by increased AMPA/NMDA receptor current ratio in excitatory synapses of VTA dopamine neurons ex vivo. The effect of THIP was abolished in GABAA receptor delta-subunit knockout mice, which have a loss of extrasynaptic GABAA receptors. In behavioural experiments on C57BL/6J mice, we found no place preference after conditioning sessions with various doses of THIP but a persistent place aversion in 6-mg/kg THIP-conditioned mice, while ethanol conditioning resulted in place preference. In conclusion, we found that the preferential activation of extrasynaptic delta subunit-containing GABAA receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but this was not associated with rewarding, but aversive responding. Acknowledgements: The study was supported by the Finnish Foundation for Alcohol Studies, the Academy of Finland and the Sigrid Juselius Foundation.