Excitatory amino acids in the forebrain of the Naples high-excitability rats: neurochemical and behavioural effects of subchronic d-aspartate and its diethyl ester prodrug

The excitatory amino acids (EAA) l-glutamate (l-Glu), l-aspartate (l-Asp) and d-aspartate (d-Asp) are thought to play a neurotransmitter/neuromodulator role in neuronal communications. Recently, a high level of EAA l-Glu, d- and l-Asp isomers has been found in the forebrain of Naples high-excitability (NHE) rat line that models the mesocortical variant of Attention-Deficit Hyperactivity Disorder (ADHD). The aim of this study was to assess the functions of d-Asp using two forms, i.e. free d-Asp or d-Asp diethyl ester (DEE) as prodrug, on brain and behaviour. Thus, prepuberal rats were given, for two weeks daily, an i.p. injection of d-Asp or DEE or vehicle. Then rats were exposed to two spatial novelties i.e. Làt and radial Olton maze. Behaviour was monitored for indices of activity, non-selective attention (NSA), selective spatial attention (SSA) and emotional reactivity. l-Glu and d- and l-Asp were detected by HPLC in cognitive and non-cognitive brain areas such as prefrontal cortex, striatum, hippocampus and hypothalamus. Results indicate that subchronic d-Asp or DEE (i) reduced EAA levels in the NHE and increased it in the random-bred controls (NRB) rats, (ii) in the Làt-maze d-Asp increased horizontal activity in NHE but DEE decreased it in NRB rats, (iii) in the Olton maze d-Asp and DEE decreased vertical activity in NHE and NRB rats respectively, (iv) d-Asp impaired attention only in NRB decreasing number of arms visited before first repetition. Therefore, data demonstrate differential effects of prepuberal subchronic d-Asp and DEE that may be related to different basal EAA levels in NHE and NRB rats.