The neurobiological control of locomotor activity, either spontaneous or that initiated by the drugs of abuse, has previously been suggested to arise, at least partly, from the mesolimbic dopamine system [42]. The GluA1−/− mice show a robust endophenotype of novelty-induced hyperactivity in the present data and in [16], [43], an observation that could be due to the modified glutamate receptor activation in the VTA DA neurons. Thus, either the baseline elevation in AMPA/NMDA ratio or the inability to adapt to exogenous stimuli due to the static AMPA/NMDA ratio of GluA1−/− mice might contribute to the hyperactive phenotype. However, the VTA DA cells are unlikely causes for the hyperactive phenotype, since (i) GluA1−/− mice show no difference in activation of the VTA DA cells in response to novelty in the similar experimental setting as used here [44], (ii) no change in locomotor activity was observed despite the sustained elevation of AMPA/NMDA ratio in wild-type mice pretreated one day earlier with drugs of abuse [17], [45], and (iii) a mouse line lacking GluA1 in the VTA DA cells shows both unchanged baseline locomotor activity and AMPA/NMDA ratio [36].
