Effect Of ABT-724on Behaviours And Dopamine D4Receptor In Cerebellum Of SHR, An Animal Model Of ADHD

[Background]Attention deficit hyperactivity disorder (ADHD) is a clinical neurobehavioral disorder with onset in childhood. It is characterized by age-inappropriate hyperactivity, impulsiveness, and inattention. If without an effective treatment,70%ADHD often persist into adolescence, even30%ADHD children chronically persist into adulthood. It had a negative affect on the education, behavior regulation, and social life. The etiology has not been determined. Some researches indicated that dopamine D4receptor expression in prefrontal cortex, striatum, basal ganglia may have an important relationship with ADHD, but its expression in cerebellum has not been studied thoroughly. In recent years, researches on brain magnetic resonance imaging of ADHD children showed that the total capacity of their cerebellum, especially cerebellar vermis, were significantly lower than normal children. And the role of cerebellum on attention, impulsivity, emotional control and cognitive, had been reevaluated. These findings provided a new point of studying the pathogenesis of ADHD. To investigate this relationship, we chose spontaneously hypertensive rat (SHR), an animal model of ADHD, as subject, and a selective dopamine D4receptor agonist, ABT-724as research instrument. By observing the effect of ABT-724on cognitive behaviors of SHR, the possible role of cerebellar dopamine system in the pathogenesis of ADHD was explored.[Methods] 1. To evaluate juvenile spontaneously hypertensive rats (SHR) as an animal model of ADHD, Open-field test, Morris water maze, and Lat maze were using to examine spontaneous activity, spatial learning and memory, non-selective attention.2. The effect of ABT-724on spontaneous activity, spatial learning and memory, non-selective attention. Three different doses of ABT-724(0.04mg/kg,0.16mg/kg,0.64mg/kg) and methylphenidate (5mg/kg) were injected i.p on SHRs. The control group was treated with NS (1ml/kg). Spontaneous activity was evaluated by using open-field test, spatial learning and memory were tested by Morris water maze, and non-selective attention was tested by Lat maze.3. After behavioral tests, the effects of ABT-724on dopamine D4receptor expression in cerebellum were examined by immunohisto chemistry and real-time quantitative PCR.[Results]1. Number of square crossing in SHR (94.50±22.51) was more than in WKY/SD rats (6±3.12,63.63±22.33)(p<0.05). During Morris water maze, SHRs (21.38±5.01) had a worse spatial memory ability than SD rats (41.13±6.10)(p<0.05). WKY rats (24.88±9.31) showed the characteristic of floating. In Lat maze, number of rearing in SHRs (138.63±31.89) was more than WKY/SD rats (19.36±17.69,76.88±32.80)(p<0.05), and two control groups had no differences (p>0.05).2. Number of square crossing after intervention of methylphenidate and ABT-724in SHRs (70.67±8.59,76.50±10.75,79.17±10.44,65.67±20.62) was less than the saline control group (130.33±11.40)(p<0.05). During Morris water maze, SHRs(52.50±4.04,52.17±2.99,61±8.15,53.83±9.87) after intervention of both had a better spatial memory ability than control group(38.83±7.17)(p<0.05). In Lat maze, number of rearing after intervention of both in SHRs (57.17±5.67,60.83±8.28,55.17±9.45,65.33±9.50) was less than saline control group (78.00±13.84)(p<0.05). 3. Integrated optical density (IOD) and mRNA level of DRD4in cerebellum of SHRs were significantly lower than WKY/SD rats (p<0.05). Same as methylphenidate, all three doses of ABT-724significantly elevated the expression level of DRD4in cerebellum.[Conclusion]1. Juvenile SHR is a traditional used animal model of ADHD. In ethological test, SHRs showed significantly hyperactivity, cognitive and attention deficit. These results made an important evidence for supplying the further study.2. After intervention of ABT-724, SHRs showed improvements in spontaneous activity, spatial learning and memory, non-selective attention. The results indicated that selective DRD4agonist may better the performances of SHRs.3. The expression of DRD4in cerebellum of SHRs was lower than WKY/SD rats; it made a basis of research for the further interventional studies. ABT-724could improve cognitive ability of SHRs, and increase the expression of DRD4in cerebellum of SHRs. The results suggested that abnormal expression of DRD4in cerebellum may be involved in the cognitive disorder of ADHD, and provided a theoretical basis of new therapeutic for ADHD.