| Objective: (1) To explore the relationship between Hypothalamus–pituitary–adrena (HPA) and ADHD, The function of HPA axis in children with ADHD was been investigated before and after treatment of methylphenidate (MPH) and atomoxetine (ATX). (2) HPA axis function and expression of glucocorticoid receptor (GR) in rats with ADHD established by 6-Hydroxydopamine was been investigated to explore the relationship between HPA and ADHD, and the study has also investigated to evaluate the effects of both MPH and ATX on HPA in ADHD rats.Methods: (1) The clinical study was a prospective, double-blind, randomized case-control trail. 111 male children with ADHD (n=111) at age of 6 and 14 years old were included in this study. The diagnosis of ADHD and its three subtypes were according to the handbook for diagnosis and treatment of ADHD by American Psychiatric Association (DSM-IV). In all of cases, there were 33 children with ADHD-predominantly inattention type (ADHD-I), 30 children with ADHD- predominantly hyperactive impulsive type (ADHD-HI) and 48 children with ADHD-combined type (ADHD-C).Meanwhile, 35 healthy male children were as the control group.31 children with ADHD were randomly given MPH and ATX therapy. At 8:00 am, the levels of cortisol were evaluated at pre-treatment and post-treatment by Automatic particle enzyme immunoassay.(2) 6-Hydroxydopamine was used to injure dopamine system of neonatal rat to establish ADHD model. SD neonatal male rats were randomly divided into neonatal model rat of ADHD and normal control group. ADHD rats were randomly divided into MPH group(n=18), ATX group(n=18) and non-drug group(n=17) according to the results of behavior.. The MPH group(treated by MPH, 6.25 mg/kg.d)and ATX group(treated by ATX, 4 mg/kg.d )were administrated from P24 to P30.The control group and non-drug group were treated by an equal volume of saline.A open-field test and a lat maze were used to evaluate the behavior of hyperactivity and inattention of rat at P21and P30. The cat stress test was used to build the rat stess.The levels of serum cortisol or GR were evaluated by ELISA or immunohistochemistry separately.Results: (1) The level of cortisol in ADHD group (236.12±109.77) nmol/L was significantly lower than in the control group (353.32±112.75nmol/L, P<0.01). The level of cortisol was the lowest in ADHD-HI group (177.62±62.99) nmol/L comparing with that in ADHD-I group (246.71±129.27 nmol/L,P<0.05) and ADHD-C group (265.41±106.00 nmol/L,P<0.01). 31 children with ADHD after treatment had higher cortisol level (249.84±87.86) nmol/L than those before treatment (164.94±48.98 nmol/L,P<0.01). However,children with ADHD after treatment had less symptom counts M(QR) 10(3) than those M(QR) 12(4) before treatment,P<0.01. (2) The passed panels and the times of straightening were (78.50±27.48) and (34.17±13.39) in P21 MPH–treaed rat in group, while (78.41±25.51) and (35.12±10.99) in non-drug treated ADHD rat group. Both of them were more than those in the control group (45.58±11.88,15.26±6.28,P<0.01). In the open-field test, both the passed panels in MPH group(49.64±16.08) and ATX group(48.13±17.64) were fewer than those in non-drug group (62.62±21.33,P<0.05). And both the times of straightening in MPH group(19.29±8.37) and ATX group(18.50±7.74) were fewer than in the non-drug group (28.23±10.07,P<0.01). In the lat maze, P21 rat had more frequency of running across the corner and the times of straightening in MPH group(84.89±26.06,89.17±31.72),ATXgroup(85.06±28.08,81.06±36.45) and non-drug group(82.65±27.11,88.06±32.28) before treatment,comparing with those in the control group (40.63±7.24, 43.79±10.78,P<0.01). In the LAT maze test, P30 rats had fewer the frequency of running across the corner both in MPH group(51.00±19.77) and ATX group(53.25±16.83) comparing with that in the non-drug group (71.00±22.59,P<0.05), while the times of straightening in MPH group(47.00±19.75) and ATX group(50.75±20.86) were fewer than in the non-drug group (77.62±20.70,P<0.01). There was no significant differences in the concentration of based cortisol among different groups (P>0.05). But before drug administration,comp -aring with the control group(315.31±113.34) ng/mL, ADHD rats (192.73±113.86 ng/mL in MPH group,177.19±97.65 ng/mL in ATX group and 200.43±120.51 ng/ mL in the non-drug group) had lower the level of serum cortisol after stress test,which was no significant differences among MPH group,ATX group and the non-drug group (P>0.05). After administration, both cortisol level of MPH group(281.71±102.07) ng/mL and ATX group(274.75±95.03) ng/mL were higher than that of the non-drug group (198.38±108.66 ng/mL,P<0.05).By immunohistochemistry, there were lower integrated optical density (IOD) in hippocampus of MPH group(81.42±25.19),ATX group(76.65±25.47) and the non-drug group (85.63±28.50) comparing with in the control group(173.42±29.33,P<0.01), but there was no significant differences in IOD of the frontal lobe among different groups(P>0.05).Conclusions: (1) In the non-stress state, chidren with ADHD exist dysfunction of HPA, which may be due to the underreactivity of HPA. Both MPH and ATX can improve the cortisol level, and the elevation of cortisol is closely related to improvement of behavior. (2) Under the stress state, ADHD rats established by 6-Hydroxydopamine exist hyporeactivity of HPA, low expression of glucocorticoid receptor (GR) . The hyporeactivity of HPA may be due to low GR expression.
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