Perinatal 6-Hydroxydopamine Modeling of ADHD

The neonatally 6-hydroxydopamine (n6-OHDA)-lesioned rat has been the standard for 40 years, as an animal model of attention-deficit hyperactivity disorder (ADHD). Rats so lesioned during postnatal ontogeny are characterized by ~99 % destruction of dopaminergic nerves in pars compacta substantia nigra, with comparable destruction of the nigrostriatal tract and lifelong ~99 % dopaminergic denervation of striatum, with lesser destructive effect on the ventral tegmental nucleus and associated lesser dopaminergic denervation of nucleus accumbens and prefrontal cortex. As a consequence of striatal dopaminergic denervation, reactive serotoninergic hyperinnervation of striatum ensues. The striatal extraneuronal milieu of DA and serotonin is markedly altered. Also, a variety of sensitization changes occur for dopaminergic D₁ and D₂ receptors, and for serotoninergic receptors. Behaviorally, these rats in adulthood display spontaneous hyperlocomotor activity, attentional deficits, and cognitive impairment-all of which are acutely attenuated by the psychostimulants amphetamine (AMPH) and methylphenidate (MPH) (i.e., opposite to the acute effects of AMPH and MPH in intact control rats). The acute behavioral effects of AMPH and MPH in intact and lesioned rats are analogous to their respective acute effects in non-ADHD and in ADHD humans. The neurochemical template of brain, and behavioral series of changes in n6-OHDA-lesioned rats, is described in the review. Despite the fact that nigrostriatal damage is not an underlying pathophysiological process of human ADHD (i.e., lacking construct validity), the described animal model has face validity (behavioral profile) and predictive validity (mirror of ADHD/MPH effects, as well as putative and new ADHD treatment effects). Also described in this review is a modification of the n6-OHDA rat, produced by adulthood partial lesioning of the serotoninergic fiber overgrowth. This ADHD model has even more accentuated hyperlocomotor and attentional deficits, counteracted by AMPH-thus providing a more robust means of animal modeling of ADHD. The n6-OHDA rat as a model of ADHD continues to be important in the search for new ADHD treatments.