Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum

Abstract

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 + /À and DRD4À/À, 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 DRD4À/À and DRD4 + /À mice were compared with their wild-type littermates (DRD4 + / + ). Resting extracellular levels of Glu were increased in the striatum of DRD4À/À mice (po0.01). Glu clearance kinetics were significantly decreased in the dorsal striatum of DRD4À/À mice (po0.05). 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.

Contributions by a Novel Edge Effect to the Permselectivity of an Electrosynthesized Polymer for Microbiosensor Applications

“…Further investigations will include microband arrays to determine whether similar edge effects are observed at this class of electrode, 103 a format finding increasing use in the design of implantable biosensors. 104,105 …”

Disruptions in the Regulation of Extracellular Glutamate by Neurons and Glia in the Rat Striatum Two Days after Diffuse Brain Injury

“…Because the amplitude of the glutamate signals was similar between sham (30.4 -1.6 lM) and TBI (32.4 -1.9 lM) (t 14 = 0.8139, p = 0.429) (Fig. 4B), we compared specific parameters of glutamate clearance Thomas et al, 2009Thomas et al, , 2011. After local application of glutamate, glutamate levels spiked and rapidly returned to baseline concentrations as glutamate diffused from the local area, and through uptake of glutamate from the extracellular space.…”

“…(Friedemann and Gerhardt, 1992) In vivo anesthetized recordings of extracellular glutamate Two days after midline FPI, rats were anesthetized with urethane (1.25 g/kg i.p.) (Sigma-Aldrich) and prepared for in vivo electrochemical recordings as previously described (Day et al, 2006;Hascup et al, 2007;Hinzman et al, 2010;Stephens et al, 2009;Thomas et al, 2009Thomas et al, , 2011. Briefly, animals were placed in a stereotaxic frame and body temperature was maintained at *37°C with a water pad connected to a recirculating water bath.…”

“…), the slope of the linear regression of the natural log transformation of the decay over time (Hinzman et al, 2010;Nickell et al, 2007;Thomas et al, 2009). …”

Hypersensitive Glutamate Signaling Correlates with the Development of Late-Onset Behavioral Morbidity in Diffuse Brain-Injured Circuitry

“…Since synapses throughout the afferent circuit are primarily glutamatergic (Kidd and Isaac, 1999), we propose that alterations in glutamate regulation contribute to late-onset post-traumatic behavioral morbidity. Novel glutamate-selective microelectrode arrays capable of subsecond in vivo electrochemical recordings by amperometry can be used to determine transient changes in extracellular glutamate neurotransmission as a gauge for circuit function (Burmeister et al, 2004;Pomerleau et al, 2003;Thomas et al, 2009).…”