Selective Brain Dopamine Depletion in Developing Rats: An Experimental Model of Minimal Brain Dysfunction

Abstract

Administration of 6-hydroxydopamine to neonatal rats produces a rapid and profound depletion of brain dopamine. Total activity of treated animals is significantly greater than that of controls between 12 and 22 days of age, but then declines, an activity pattern similar to that seen in affected children. This suggests a functional deficiency of brain dopamine in the pathogenesis of minimal brain dysfunction.

Plasticity of Dopamine D4 Receptors in Rat Forebrain Temporal Association with Motor Hyperactivity Following Neonatal 6-Hydroxydopamine Lesioning

“…In agreement with previous reports (Shaywitz et al 1976;Heffner and Seiden 1982;Zhang et al 2001b), neonatal 6-OHDA lesioning of developing DA projections in rat forebrain resulted in robust motor hyperactivity. This behavioral response appears to represent deficient Figure 2.…”

“…habituation to a novel environment, since motor activity in the initial testing period did not differ appreciably between lesioned rats and sham controls (Figure 2, PD 24). Also in accord with previous studies (Shaywitz et al 1976;Erinoff et al 1979), lesion-induced motor hyperactivity was evident only during early development (PD 24 in this study), and no longer present at PD 36 or 59 (Figure 2). Neonatal 6-OHDA lesions resulted in a substantial and sustained decrease in DAT binding in CPu.…”

“…On PD 5, pups received a subcutaneous (s.c.) injection of desipramine hydrochloride (25 mg/kg), followed by randomized intracisternal (i.c.) injections of either 6-OHDA hydrobromide (equivalent to 100 g free base) or vehicle (320 mM NaCl containing 0.1% ascorbic acid) under hypothermal anesthesia 60 min later (Shaywitz et al 1976;Zhang et al 2001b). Pups were returned to nursing dams after regaining consciousness.…”

“…One such allele is the D 4.7 receptor, containing seven repeats of this sequence. It has repeatedly been associated with ADHD, as well as related behavioral traits such as novelty-seeking and impulsivity (Benjamin et al 1996;Ebstein et al 1996;La Hoste et al 1996;Bailey et al 1997;Rowe et al 1998;Swanson et al 1998;Faraone et al 1999;Barr et al 2000).Some features of ADHD are simulated in several laboratory models, including: (1) rats with neonatal lesions of the central DA system induced by the neurotoxin 6-hydroxydopamine (6-OHDA; Shaywitz et al 1976); (2) the spontaneously hypertensive Kyoto-Wistar rat (Tucker and Johnson 1981); (3) nonhuman primates treated with the DA neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Roeltgen and Schneider 1991); and (4) genetic knock-out mice lacking functional DAT (Giros et al 1996). Juvenile male rats with neonatal 6-OHDA lesions are a particularly appropriate model for the hyperactivity of ADHD in that lesion-induced motor hyperactivity is most prominent at an age corresponding to human periadolescence (Shaywitz et al 1976;Erinoff et al 1979), and is dose-dependently antagonized by stimulants used to treat clinical ADHD (Heffner and Seiden 1982).…”

“…Juvenile male rats with neonatal 6-OHDA lesions are a particularly appropriate model for the hyperactivity of ADHD in that lesion-induced motor hyperactivity is most prominent at an age corresponding to human periadolescence (Shaywitz et al 1976;Erinoff et al 1979), and is dose-dependently antagonized by stimulants used to treat clinical ADHD (Heffner and Seiden 1982). In addition, the model is associated with learning deficits that are also antagonized by stimulants (Takasuna and Iwasaki 1996;Wool et al 1987).…”