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Receptors in the nucleus accumbens and hippocampal CA1 tissue, suggesting a functional relationship between DRD4, DRD1, and NMDA receptors. 180 These relationships carry over into the striatum, following more recent experiments with DRD4-deficient mice, which show that resting extracellular levels of glutamate are increased in the striatum, and glutamate clearance kinetics are significantly decreased in the dorsal striatum. 181 PKA, an intracellular target of DRD1 stimulation, is also implicated in attentional performance. Inhibition of PKA both reduces attentional performance and increases locomotor activity. In turn, PKA activates cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), a transcription factor that binds to DNA responsive elements intracellularly, increasing the transcription of c-Fos, BDNF, somatostatin, VGF, enkephalin, and corticotrophin releasing hormone, among others. 182 Inhibition of PKA reduces the accuracy of a serial reaction time task in rodents, a test that parallels the continuous performance test in humans. The same effect is observed with the disruption of CREB. 165 The interplay of glutamate signaling and CREB influences attentional and locomotor systems in animal models. Among these models, glutamate homeostasis in the ventromedial prefrontal cortex (vmPFC) is an important framework for exploring the symptoms of ADHD. Infusion of rat vmPFC with the NMDA antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ([R]-CPP) decreases attentional performance, while increasing impulsivity and perseverative responses. These changes are accompanied by increased excitotoxic glutamate efflux in the vmPFC and changes in CREB expression in the vmPFC (increased) and striatum (decreased). Counteraction of the glutamate imbalance produced by (R)-CPP is achieved with the mGluR2 3 agonist agent, LY379268, which restores attentional performance and impulsivity, but not perseverative responses. This model suggests that the NMDA and mGluR2 3 pathways may underlie the core components of ADHD. 183 Another rodent model of ADHD is the Naples high-excitability rat, which is bred to display behavioral arousal to novelty. 184 Forebrain levels of glutamate, as well as d- and l-aspartate, are elevated in Naples high-excitability rats, suggesting that these levels may be causing neurotoxicity in the frontostriatal pathways. 185. insomnia / Early / 8.0-31.0.

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