Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats

Rationale: The dopamine D-3 receptor has been extensively studied in animal models of drug abuse and psychosis; however, less is known on its possible role in cognitive functions. Objectives: This study investigated the effects of different D-3 antagonists and a partial agonist on spatial learning performance in a water labyrinth test. Methods: Rats had to swim through a labyrinth system by making correct directional turns at three choice-points. The number of errors was recorded in three daily trials for 3 days. Results: D-3 antagonists such as the highly selective SB-277011 ( 24 mg/kg p.o.) and RGH-1756 ( 1 mg/kg p.o.), the moderately selective U-99194A ( 12 mg/kg s. c.) and the selective partial D-3 agonist BP-897 ( 1 mg/kg i. p.) all significantly attenuated the learning deficit caused by FG-7142. Against scopolamine-induced amnesia, SB-277011 ( 24 mg/kg p.o.) was equally potent in showing protective efficacy; however, two times higher dose levels of U-99194A ( 24 mg/kg s. c.) and RGH-1756 ( 2 mg/kg p.o.) were required to attenuate the scopolamine-induced impairment. In contrast to the full antagonists, against scopolamine-induced amnesia, the partial agonist BP-897 ( 2 mg/kg i. p.) was inactive, even at the two times higher dose level. Conclusions: These data suggest that dopamine D-3 receptor antagonists possess cognition-enhancing activity which may be of benefit in the treatment of cognitive dysfunction associated with several psychiatric disorders.