The study of the mechanisms of neuronal adaptation in response to drugs of abuse has recently advanced remarkably as many research groups have observed LTP-like processes in relevant neuronal populations after exposure to stimulant and sedative drugs of abuse. Most interestingly, a single dose of various drugs of abuse can induce a persistent glutamate receptor change in the ventral tegmental area (VTA) dopamine neurons ex vivo one to several days after exposure. This can be determined electrophysiologically as increased peak current ratio of AMPA/NMDA receptor-mediated currents in dopamine neurons of midbrain slices. We have also found that benzodiazepines can induce similar glutamate receptor activations, presumably through disinhibition of GABAergic interneurons in VTA. This process seems to be dependent on synaptic g2 subunit-containing GABA-A receptors. To test this mechanism, we used another GABA-A ligand, gaboxadol, which activates the GABA site and which prefers non-g2 subunit-containing receptor subtypes. One single dose of gaboxadol also persistently increased AMPA/NMDA ratio in DA neurons, and this change was dependent on increased targeting of calcium permeable AMPA receptor subunits, such as GluA1. Thus, also extrasynaptic d subunit-containing receptors might mediate the adaptation to GABAergic drugs. But how do the mice with benzodiazepine-induced persistently altered glutamate mechanisms in DA neurons respond to additional challenge by other drugs of abuse? We have observed that 24 h after the benzodiazepine pre-treatment, the mice exhibited blunted psychomotor responses to acute morphine and amphetamine, suggesting that the potential for neuroplasticity should be intact for the drugs of abuse to induce strong behavioral actions. Supported by the Academy of Finland and the Sigrid Juselius Foundation