Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

Rationale: Dopamine D-4 receptor gene polymorphism has been repeatedly associated with attention deficit hyperactivity disorder (ADHD) and related personality traits. We recently reported that motor hyperactivity in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D-4 receptor-selective antagonist. However, behavioral effects of this agent may not be attributed exclusively to D-4 receptor blockade, since it interacts with other sites including serotonin receptors. Objectives: To test further the hypothesis that D-4 receptor blockade can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically dissimilar D-4 antagonists were compared to that of ketanserin, a serotonin 5-HT2A/2C antagonist. Methods: Selective dopamine lesions were made in male rats at postnatal day (PD) 5 with intracisternal 6-hydroxydopamine (100 mug) after desipramine pretreatment (25 mg/kg, SC) to protect nor-adrenergic neurons. Effects of D-4 receptor-selective antagonists and ketanserin on lesion-induced motor hyperactivity were examined during the periadolescent period (postnatal days 23-26) with an infrared photobeam activity system. Results: The D-4 antagonists L-745,870 and U-101,958 dose-dependently inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior in sham control rats. In contrast, ketanserin produced apparent sedative effects in both lesioned and intact control rats without normalizing hyperactivity. Conclusions: Motor hyperactivity in this ADHD model was selectively antagonized by three of four dopamine D-4 receptor antagonists evaluated, encouraging clinical assessment of D4 antagonists in patients with ADHD.