P.6.017 Study of dependence effects of semax analogues in dependence on their structure

Pd, Ot~er topics

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JP.6.015J Age-related changes in erythropoietin Jmmunoreactivity in the cerebral cortex and hippocarnpus of rats

IP.6.0161 Association between serotonin 2A and 1B receptor gene polyrnorphisrn and suicidal attempt using drug intoxication in Koreans

S,I, Kim, H,W, Woo, College of Medicine, Ewha Unioersi~ Psychiatry, Seoul, Republic of Korea

Y.I. Kwon 1, D.H. Kim 2, Y.S. Na 1, S.H. Hart 2. 1Soonchunhyang

Pttrpese-" Many experimental studies have shown that erythropoietin (Epo) has a neuroprotective effect during cerebral ischemia. The expression of the Epo/Erythropoietin receptor (EPOR) system in particular areas containing neurons vulnerable to ischemic insult, such as the hippocampus and the cerebral cortex and finally the induction of both Epo and EpoR gone expression by hypoxi% suggest that Epo could act on the CNS as a neuroprotective factor in conditions of neural damage, such as hypoxia, ischemia or brain hemorrhage. Although oxidative stress as well as amyloids may influence the fluid properties of blood, resulting in a potential decrement in blood flow and oxygen delivery to the brain during aging, very little is known about age-related changes in Epo expression in the cerebral cortex and hippocampus. Therefore, we examined age-related changes in Epo expression in the cerebral cortex and hippocampus with an immunohistochemical technique. lVletlaods: Twelve adult (4? month old) and 15 aged (24?9 month old) male Sprague-Dawley rats were examined in this study. Brains were cryoprotected in a series of cold sucrose solutions, and were cut at 40micrometers in the coronal plane. Immunohistochemistry was performed in accordance with the free-floating method. We selected five slides from rostra] to caudal level at the same intervals for each region of control (n=12) and aged rats (n=15). Visual assessment and densitemetric measurement using a NIH image program (Scion Image) determined the staining density. Finally, a student t-test was performed to investigate whether age-related changes in Epo immunoreactivity were statistically significant (*p<0.05). Resttltn: In the present study, decreased expression of Epo was obvious in the cerebral cortex and hippocampus in aged rats. In aged rats, there was a significant decrease in Epo immunoreactivity in the pyramidal cells in the cortical regions. In the hippocampus of adult rats, a distinct immunoreactivitv/pattern was observed in the CA1-3 areas and dentate gyrus. In aged hippocampus, Epo immunoreactivity was significantly deceased in the pyramidal layer of CA1 regions, and the granule cell layer of dentate gyms. It was noted that there was distinct pattern of Epo immunoreactivity in the pyramidal layer of CA2-CA3 region of aged rats. Epo immunoreactivity was relatively strong, but was observed only in the periphery of the cytoplasm. Concision-- The first demonstration of age-related decreases in Epo expression in the cerebral cortex and hippocampus may provide useful data for investigating the pathogenesis of agerelated neurodegenerative diseases, suggesting that age-related decreases in Epo may contribute to degenerative events following age-related damage.

University Ci~eonal~nHospital, Psycl~iatry, Cl~eonal~m 8epublic of Korea; 2Soonchunhyang Unioersity Hospital, Psychiatry, Seo~, Republic of Korea Accumulating evidence indicates that the suicidal behavior and impulsivity is related with impaired serotonergic system. However, in spite of the complex of inheritance patterns of suicidal behavior, there is still rare causal association bebveen suicidal behavior and specific biological markers. Recently, polymorphisms of the genes of several types with serotonin have been suggested to be associated with suicide, but the results are still unclear. We examined whether the T102C polymorphisms of the serotonin 2A receptor gone and G861C polymorphisms of the serotonin 1t) receptor gone were associated with suicidal behavior using drug intoxication. The suicide subjects consisted of 52 patients visited emergency roomwith suicidal behaviors (26 males and 26 females; mean age = 31.94-7.8 yr). Fifty controls (28 males and 22 females; mean age = 35.04-12.8 yr) were selected from healthy volunteer to be matched for sex and age to the suicide subjects. The polymorphisms were analyzed with TaqMan assay using primers based on previous studies. The genotype distribution and allele frequencies of the T102C or the G861C polymorphism between the suicide and the controls were compared with a chi-square test. Probability differences of P<0.05 were considered statistically significant. The genotype distributions in all the groups were in Hardy-Weinberg equilibrium. The T102C polymorphism showed no significant difference between the suicides and controls in either the genotype distribution or the allele frequencies (p=0.981, p=0.554). And there was no statistically significant differences between the suicides and the controls (p=0.781). Also, any significant effect of the genotype distributions or the allele frequencies was not observed (p=0.287). There were fewer studies with association studies of serotenergic system in Koreans. We hypothesized it would be related between suicidal attempters with drug intoxication and controls, but there were no association between suicidal attempters and controls. To clarify the genetic influences of the serotonergic system on suicidal behavior, the polymorphisms of other candidate genes in the serotonergic system should be studied with larger groups.

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Study of neurotropic effects of semax analogues in dependence on their structure

N,Y, Glczova 1, N,G, Levitskaya 1, L,A, Andreeva 1, N,E Myasoedov j , A,A, Karnensky 2, lInstlmte of Molecular

Genetics P~4S, Deivar~mem of C#emistry of Physiological AGioe Substances, Mcceow, Rux~ian Federation; 2Lomonosoo Mo~eow State Unioersi~ Department of Human and Animal 2hysiology, Moscow, ~uxsian Federation It is well known that pituitary hormones ACTI-I and MSH apart from their endocrine effects improve m e m o r y and learning protenses in men and animals [I], Semax is the ACTH(4-10) analogue in which three C-terminal residues replace by the sequence Pro-Gly-Pro, It was shown that Semax as A C T H and its native fragments stimulated learning processes but did not exert the hormonal activity,This peptide has increased metabolic stability

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and longer-lasting effects in comparison to ACTH(4-10) fragment [2, 3]. The aim of the present study was to investigate the influence of the modification of N-terminal part of the Semax molecule on its neurotropic activity. We have studied the effects of Semax analogue deprived N-terminal Met - hexapeptide Glu-Kis-PhePro-@ly-Pro (EHFPGP) and analogue in which theMet is modified by addition of gluconic acid residue - heptapeptide rMet-Glu-Z-lisPhe-Pro-Gly-Pro (rMEKFPGP). The experiments was performed on male white rats weighing 200-250 g. Peptides were administered intraperitonealy in dose 0,05 mg/kg 15 rain or 1 h prior to training. We studied the peptide effects on the acquisition of foodreinforced T-maze task and active and passive avoidance tasks. It was shown that the first step of Semax proteolytic degradation was the cleavage of the N-terminal Met. On the basis of these results we studied the neurotropic effects of Serrm: analogue EHFPGE The experiments showed that hexapeptide EHFPGP injected 15 rain prior to training improved learning in all tests used. Moreover the peptide was significantly more effective than S e ~ . When peptides were injected 1 h prior to training EHFPGP effect was comparable to that of Semax. In the second part of our experiments we investigated the behavioural effects of Semax analogue in which Met is modified by addition of gluconic acid residue. We presumed that this modification would ameliorate the permeability of peptide molecules of the Blood-Brain Barrier and would increase peptide metabolic stability. It was shown that heptapeptide rMEI-IFPGP facilitated the acquisition of conditioned tasks when injected 15 rain or 1 h before tests. Moreover it was more effective than Semax in 1 h after injection. So we can conclude that heptapeptide has longer-lasting influence on animal behaviour in comparison to Semax. We suggest that the addition of g h c o n i c acid residue to Met leads to increase of the peptide metabolic stability. Based on data obtained we can conclude that although Semax analogue deprived N-terminal Met retain behavioural activity modification of the first N-terminal residue in Semax molecule change the duration of its effects. We suggest that the different degradation rate determines the different nenrotropic effects of Semax and its analogues. The work was supported by Russian Found of Basic Research (Grant 04-04-48511).

References [1] Wikberg JES, Muceniece P,, Mandrilca I, et al, Pharmacological Research. 2000. 42. 393-420. [2] Ashmarin IP, Ne~avibatko VN, Levitskaya NG, et al, Neurosci. Res. Ccmmun, 1995. 16. 105-112. [3] Potaman VN, Alfeeva L¥, K_amenslcy AA, et al, Bioehem. Bicphys. Res. Cornrnun. 1991. 176. 741-746.

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Modafinil as therapy for ADHD in children: A 4-week, double-blind, placebo-controlled study

I. Biederman 1, J.M. Swanson 2, S.W. Boellner 3, FA, Lopez 4,

1Massachusetts C~neral Hospital, Department of Pediatric PsycJ~opflarmaco[ogy, Boston, MassaeJ~usetts, U.2A, ; 2 Unioer#i~y of CalforniaGrvine, Department of 2ediatrios, Zrvine, California, U~S,A,; 3Neurology and Clinical Study Center, n/a, Little ,Rock, Arka~as, U,E.A,; ° C~ildren~ Developmental Center, 2A,, Department of NeurodeoelopmeWal PediaXrics, Maitland, Florida, US.A.

impulsivity, and hyperactivity [2]. The stimulants methylphenidate and amphetamine are commonly used in the management of pediatric ADHD. Although these agents effectively treat core symptoms in many ADI-ID patients, 20-40% either do not respond adequately or are unable to tolerate therapy. Use of these stimulants may also be limited by fears about abuse potential. Modafinil, a novel wake-promoting agent, has a relatively low risk of abuse. Published reports suggest that modafinil may be a useful treatment for children with ADHD [3]. This doubleblind, placebo-controlled study assessed the efficacy of 4 dosing regimens of modaflnil 300-400 mg in children with ADKD. l~ethods: 248 children (age 6-14) meeting DSM-IV criteria for ADI-ID were enrolled. Following a 7-10 day placebo run-in, patients received 4 weeks of treatment with placebo, modafinil 300 mg/day as a single morning dose, modafinil 300 mg/day as a split morning/midday dose (100/200 mg or 200/100 rag), or modaknil 400 mg as a split morning/midday dose (200/200 rag). Only children weighing ) 3 0 kg received the modafinil 200/200 mg regimen. Efficacy measures included the teacher-rated school and clinician-rated home versions of the ADHD Rating Scale-IV and the parent-rated version of the Conners' ADI-ID/DSM-IV Scale (CADS-P). Restdts: 223 patients completed the study. Modafinil 300 mg/day administered as a single dose significantly improved ADHD symptoms across all rating scales and subscales (all P<05 vs. placebo) in teacher-, clinician-, and parent-rated assessments. The modafinil 200/100 mg split dose regimen significantly (2=.03) improved ADND symptoms at school compared with placebo (ADI-ID Rating Scale-IV teaches-rated school version, total score). The modafinil 100/200 mg split dose regimen significantly improved ADI-ID symptoms summarized by the total score and inattentive and hyperactive-impulsive subscale scores on the CADS-P (P<.05). In patients weighing ) 3 0 kg, modafinil 400 mg/day was significantly superior to placebo but did not add any significant beneficial effects over modafinil 300 mg/day administered as a single dose. All modafinil dosing regimens were well tolerated. The most common adverse events were insomnia, abdominal pain, anorexia, cough, fever, and rhinitis. Most events were mild to moderate in nature and tra.nsient. Conel~ions-" Modafinil 300 mg once daily significantly improved ADKD symptoms as rated by clinicians, teachers, and parents. Modafinil may be a new treatment option for children with ADI-D. Settree ef Ftt~lRlg: CepMlon, Inc., West Chester, PA References

[I] American Academy of Pediatrics, (2000) Clinical practice guiddine: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder, Pediatrics, 105, 1158-1170, [2] American Psychiatric Association, (2000) Diagnostic and Statistical Manual of Mental Disorders IV-TR (Fourth Edition, Text Revision), American Psydaiatric Association, Washingon, [3] Rugino TA and Samsock TC, (2003) Modafinil in &il&en with attention-deficithyperactivity disorder, Pediatr Neurol, 29, 136-142,

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Quetiapine augmentation of serotonin reuptake inhibitors in refractory-obsessive compulsive disorder

M.C. Cupillari. ASL L'Aqui[a, Mentcg Healt~ L'Aquila, L'Aqu~la,

Ztaly Objeeti~: Attention deficit/hyperactivity disorder (ADt-ID) affects an estimated 8 - 1 0 % of school-aged children [1]. Characteristic behaviors include developmentally inappropriate inattention,

Intl'edtlelio~ Quetiapine is an antipsycotic drug with a good balance efficiency-tolerability. Atypical antipsychotic have been