Prenatal elevation of endocannabinoids corrects the unbalance between dopamine systems and reduces activity in the Naples High Excitability rats.

Several evidences suggest that endocannabinoids exert a neurotrophic effect on developing mesencephalic dopamine neurons. Since an altered mesocorticolimbic system seems to underlie hyperactivity and attention deficit in clinical and animal studies of attention deficit hyperactivity disorder (ADHD), prenatal elevation of anandamide has been induced in Naples high excitability (NHE) rats by inhibition of its reuptake. To this aim, pregnant NHE and random-bred females received a subcutaneous injection of AM-404 (1 mg/kg) or vehicle daily from E11 until E20. Young adult male offsprings were exposed to a spatial novelty (Làt-maze) for 30 min and the behavior was videotaped and analysed for indices of activity (travelled distance, rearing frequency) and attention (rearing duration). Moreover, morphological analysis of the brains was carried out that pertained to cytochrome oxydase as marker of metabolic activity and thyrosine hydroxylase as marker of the dopamine systems. The results indicate that prenatal AM-404 treatment significantly reduces activity by about 20% during the entire testing period and modifies the distribution of scanning times towards short duration episodes in the first part of the test only in NHE-treated rats. In addition, image analysis revealed a significant increase in relative optical density of TH+terminals in the dorsal striatum and substantia nigra of AM-404 treated NHE rats and minor changes in the dorsal cortex of AM-404 treated NRB rats. The data suggest a corrected unbalance between the two dopamine systems that apparently leads to reduced hyperactivity and modified scanning times in this animal model of ADHD. This, in turn, might open new strategies in the treatment of a subset of ADHD cases.