Role of Dopamine D4 Receptors in Motor Hyperactivity Induced by Neonatal 6-Hydroxydopamine Lesions in Rats

Regulation of Working Memory by Dopamine D4 Receptor in Rats

“…An important distinction between the present experiments and several previous studies that reported behavior effects of L-745,870 (Mansbach et al, 1998;Patel et al, 1997;Zhang et al, 2001Zhang et al, , 2002 was the finding of significant effects at much lower doses, with presumably greater selectivity at the D 4 receptor. Although we do not have direct evidence for the in vivo specificity for the D 4 receptor, other studies using surrogate markers such as plasma prolactin level (Patel et al, 1997) indicate that L-745,870 is devoid of any noticeable affect on the D 2 receptor at doses used in this study.…”

“…Genetic studies have strongly implicated D 4 receptor polymorphism in ADHD (La Hoste et al, 1996;Faraone et al, 2001). Using young rats with neonatal 6-hydroxydopamine lesions as a model for ADHD, we reported that locomotor hyperactivity in this model was inhibited by several selective D 4 antagonists as by the stimulant methylphenidate, but not antagonists that bind preferentially to the D 2 or 5-HT 2A receptor Zhang et al, 2001Zhang et al, , 2002. Given a hypothesized role of working memory deficits in ADHD (Pennington and Ozonoff, 1996;Denney and Rapport, 2001), beneficial effects of L-745,870 on cognition identified in the current study encourage further consideration of D 4 antagonists as novel treatments for clinical ADHD and other disorders of attention and cognition.…”

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

“…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).We found recently that motor hyperactivity following 6-OHDA lesioning of neonatal rats can be reversed dose-dependently by selective antagonists for D 4 but not D 2 receptors, and exacerbated by a D 4 agonist (Zhang et al 2001b). In addition, motor hyperactivity correlated closely with the magnitude of increased D 4 , but not D 2 receptor binding in basal forebrain.…”

“…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.…”

“…Sections were then washed twice (5 min in ice-cold buffer), rinsed in deionized water, and air-dried. Dried sections were exposed to tritium-sensitive Kodak Hyperfilm for 2-6 weeks before standard photographic processing (Tarazi et al 1998a;Zhang et al 2001b). Radioligand binding was quantified with a computerized image analyzer (Image Research Inc.; St. Catherines, Ontario), and converted to nCi/mg tissue using [ 3 H]reference standards, with specific binding expressed as mean Ϯ S.E.M.…”