Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Rationale: Attention-deficit/hyperactivity disorder (ADHD) is thought to involve hypofunctional catecholamine systems in the striatum, nucleus accumbens, and prefrontal cortex (PFC); however, recent clinical evidence has implicated glutamate dysfunction in the pathophysiology of ADHD. Recent studies show that increased stimulation of dopamine D2 and D4 receptors causes inhibition of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, respectively. The spontaneously hypertensive rat (SHR) model of ADHD combined type (C) has been found to have a hypofunctional dopamine system in the ventral striatum, nucleus accumbens, and PFC compared to the control Wistar Kyoto (WKY) strain. Objectives: Based on the current understanding of typical dopamine-glutamate interactions, we hypothesized that the SHR model of ADHD would have a hyperfunctional glutamate system terminating in the striatum, nucleus accumbens, and PFC. Results: High-speed amperometric recordings combined with four-channel microelectrode arrays to directly measure glutamate dynamics showed increased evoked glutamate release in the PFC (cingulate and infralimbic cortices, p<0.05) and also in the striatum (p<0.05) of the SHR (ADHD-C) as compared to the WKY. Finally, glutamate uptake was discovered to be aberrant in the PFC, but not the striatum, of the SHR when compared to the control WKY strain. Conclusions: These results suggest that the glutamatergic system in the PFC of the SHR model of ADHD is hyperfunctional and that targeting glutamate in the PFC could lead to the development of novel therapeutics for the treatment of ADHD.