Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum

To better understand the effect of the dopamine D4 receptor (DRD4) on glutamate (Glu) neurotransmission in the brain, we utilized transgenic mice with partial or complete removal of functional DRD4 plasma membrane expression (DRD4+/- and DRD4-/-, respectively). We measured resting extracellular Glu levels, Glu clearance kinetics, and KCl-evoked release of Glu in the striatum and nucleus accumbens core of these mice using in vivo amperometry coupled to a novel microelectrode array configured for sub-second detection of Glu. Recordings from DRD4-/- and DRD4+/- mice were compared with their wild-type littermates (DRD4+/+). Resting extracellular levels of Glu were increased in the striatum of DRD4-/- mice (p<0.01). Glu clearance kinetics were significantly decreased in the dorsal striatum of DRD4-/- mice (p<0.05). KCl-evoked overflow of Glu was reliably measured but unchanged in the striatum of the three groups. By contrast, no changes in resting Glu, Glu uptake kinetics, or KCl-evoked release of Glu were observed in the nucleus accumbens core among the three genotypes. These data indicate that the DRD4 receptor is involved in modulation of Glu neurotransmission, primarily in the striatum. A better understanding of Glu control by the DRD4 may improve our understanding of the physiological role of the DRD4 in disorders such as attention-deficit/ hyperactivity disorder and schizophrenia.