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Panic disorders and migraine: As association study with dopaminergic receptor genes
P.3. Anxiety disorders and anxiolytics
•
Evaluation of the open-field behavior in the male rat after elevated T-maze
A. G61geli, A. Kiiqiik*, M. Asian. University of Erciyes, Faculty
of Medicine, Department of Physiology, 38039, Kayseri, Turla'ye For several reasons the open-field test has been a popular measure of the supposed emotional state of animals (1) The elevated T-maze has been developed as an animal model of anxiety to generate both conditioned and unconditioned fears in the same rat (2). This study explores the changes in psychomotor activity in adult male rats. Thus, rats were tested in the open-field after elevated T-maze. As a consequence, it was to invastigate whether the open-field area may be applied for feared rats. Male Wistar rats weighing 160-180 g were used. Elevated T-maze consisted of an enclosed arm at right angles to two open arms eleveted 50 cm above the ground. Its use for the measurement of anxiety is based on the apparent natural aversion of rodents to open and high spaces. While inhibitory avoidance of the open arm is supposed to represent learned fear, the escape response from the open arm would represent innate fear. For evaluating the behaviour parameters, before and after the elevated T- maze test, rats placed in the open field area. The test apparatus was a rectangular area (100 x 100 x 30 era) which was made of plexiglass, divided into 16 squares (3). Number of line crossing, rearing, grooming and defecation was counted during four minutes tests. The changes in the behaviour parameters were statistically treated using Wilcoxon test. After the elevated T-maze, the results in line crossing, rearing, grooming and defecation were decreased, but significant differences were shown in line crossing, rearing and defecation (p < 0.05). Our findings showed that open field was a valid model for analyzing the behaviour parameters in anxiety developed rats.
References [1] Sprott, R.L and Eleflheriou, B.E (1974) Open-field behavior in aging inbred mice. Gerontologia.20, 155-162. [2] Zangrossi, H and Graeff, EG (1997) Behavioral validation of the elevated T-maze, a new animal model of anxiety. Brain Research Bulletin. 44, 1-5. [3] Volke, A., Soosaar, S, K~ks, M et all (1997) 7-Nitroindazole, a nitric oxide synhase inhibitor, has anxiolytic- like properties in exploratory models of anxiety. Psychopharrnaeology.131,399--405.
•
Neuroendocrine effects of citalopram challenge in patients with social anxiety disorder
J. Shlik, E. Maron, A. Aluoja, I. Tfru, V. Vasar. University of
Tartu, Department of Psychiatry and Tartu University Clinics, Tartu, Estonia Purpose: Social anxiety disorder (SAD) is a prevalent and disabling anxiety disorder characterised by unreasonable fear of humiliation in front of other people in social and performance situations. Efficacy of the selective serotonin (5-HT) reuptake inhibitors in the treatment of SAD indicates possible importance of brain 5-HT transmission and 5-HT receptors in the neurobiology of social anxiety. The aim of the current study was to assess the neuroendocrine response to a 5-HT-ergic stimulation test using a highly selective 5-HT reuptake inhibitor citalopram in patients with SAD in comparison to healthy controls. The extent of release
$313
of piatitary hormones in response to citalopram was considered as a marker of central 5-HT activity. Methods: The study subjects were 18 males (n = 9) and females (n --- 9) with mean age of 29.5 (19-52) years diagnosed with SAD according to DSM-IV criteria and 18 matched healthy volunteers. At inclusion, the mean Liebowitz Social Anxiety Scale total score was 67.4 (SD-20) in patients and 16.2 (11) in controls; Hamilton Depression Scale scores were respectively 6.6 (4) and 1.4 (2). Citalopram challenge was given as intravenous infusion (20 mg over 30 min) with placebo control in randomised crossover order separated by an interval of 3-5 weeks. Plasma concentrations of cortisol and prolactin were measured at baseline and on 4 time-points during 2 hours after the infusion. Data were analysed using ANOVA with repeated measures with follow-up analysis of significant effects. Results: Analysis showed significant effects of group, drug and time of assessment for changes in corisol and prolactin concentrations. Citalopram challenge affected the release of hormones differently from placebo with higher concentrations of cortisol and prolactin detected at 90 and 120 minutes after the infusion. This effect of citalopram was evident in both patients and controls without significant between-group differences. Conclusion: In this study, the neuroendocrine sensitivity to 5-HT-stimulation with citalopram in patients with SAD was not different from the response to citalopram in healthy controls. This indicates that in contrast to the findings in Major Depression (1) there are no apparent signs of serotonergic hypofunction in SAD. On the other hand, we did not reveal hypersensitive 5-HT receptors in SAD that have been suggested by some 5-HT-ergic challenge studies (2, 3).
References [1] Kapitany, T., et al., 1999. The citaloprarn challenge test in patients with major depression and in healthy controls. Psychiatry Research 88, 75-88. [2] Tancer, M.E., et al., 1995. Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1,216--223. [3] Hollander,E., et al., 1998. Serotonergicfunction in social phobia: comparison to normal control and obsessive-compulsivedisorder subjects. Psychiatry Research 79, 213-217.
IP.3.0371 Panic disorders and migraine: As association study with dopaminergic receptor genes M.E. Stochino, A. Cherchi, G. Severino, C. Asuni, M.E Piccardi, M. Del Zompo. Headache Center, Department of Neurosciences
"B.B. Brodie", Universityof Cagliari, Cagliari, Italy Clinical and epidemiological evidence suggests that headache cooccurs with some psychopathologics, including specific anxiety disorders. Various recent studies support the existence of a comorbidity between migraine without aura and panic disorders. We evaluated the presence of panic disorders in a sample of 100 patients with migraine without aura and we tested an association between some candidate genes related to the dopaminergic system, particularly DRD1, DRD2, DRD3, DRD4 and DRDS, and this phenotype. In order to test this association and circumvent the problem of a proper control and to avoid population stratification we used the transmission disequilibrium test (TDT). The sample constituted of 100 triads (a triad is a proband and both living parents). All probands and their parents were interviewed. Out of 100 migraine patients 17 showed panic disorders.
s314
p3. Anxiety disorders and anxiolytics
Migraine and panic diagnoses were made according to IHS criteria 1988 and DSM IV, respectively. All patients and their parents gave informed consent to participate in the study and a venous blood sample was drawn. Genomic DNA was extracted from whole blood. All markers were analysed using PCR. Our data showed a positive association (P = 0.05) between the DRD2 gene and the group with both migraine and panic. Despite the clinical peculiarity of the sample and its exiguity we may suppose a key role of the dopaminergic system in the pathogenesis of migraine and panic phenotype and the likely existence of common genetic factors. This work was supported by Italian “Ministero Universim, e Ricerca Scientifica”.
lp.3.0381
Ph armacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults
E.J. Frackiewicz, PD. Tigel, J.J. Sramek, N.R. Cutler, D.E. Salazar, R. Dockens, G. Kollia, I.E. Fulmor, H.D. Uderman. California Clinical Trials, Beverly Hills, CA; Bristol-Myers Squibb, Princeton, NJ 08543, USA Buspar (buspirone hydrochloride) is an antianxiety agent proven to be clinically effective for the management of anxiety disorders, including GAD at doses as low as 7.5 mg bid. However, to date, relatively few controlled studies have been performed in children and adolescents to evaluate the pharmacodynamics and pharmacokinetics of antianxiety agents. Buspirone may be an attractive treatment option for anxiety disorders in children and adolescents because of its wide range of safe doses, lack of serious adverse events, low abuse potential and low incidence of withdrawal reactions. We performed a 21&y, open-label, multi-site, dose escalation study comprised of three demographic groups (children, adolescents and adults) to determine the pharmacokinetics and tolerability of orally-administered buspirone. Thirteen children and 12 adolescents with anxiety disorder, and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (C,,) were highest in children and lowest in adults at all three dose levels (7.5,15,30 mg bid). However, l-pyrimidinylpiperazine (l-PP), the primary metabolite of buspirone, exhibited a different plasma concentration-time profile; C,,, was significantly higher in children than in either adolescents or adults, at all concentrations. In addition, TAUC(O_T) for l-PP was significantly higher in children relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30 mg bid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%) and dyspepsia (20%); two children withdrew from the study at the higher doses (15 mg and 30 mg bid) due to adverse events. In adults, the most common adverse event was somnolence (21.4%); lightheadedness, nausea, vomiting and diarrhea were also reported, though these were mild in intensity.
(p.3.039/
The ontogenetic aspects of foodderived opioid peptide &casomorphind anxiolytic influence
1u.A. Ivleva, A.V Vylegzanina, 1.V Malinovskaia, L.A. Andreeva, VA. Dubynin. Human and Animal Physiology Department, Faculty of Biology, Moscow State University, Moscow, 119899, Russia It is known that opioid fragments of the p-caseins can influence on activity and development of different newborn’s brain systems. The present study examined behavioural changes after heptapeptide P-casomorphin-7 (YPFPGPI) injection to 3-5 week old albino rat pups. The effects of acutely administered B-casomorphin-7 in the elevated plus-maze were investigated. 21-, 28-, 35-day-old pups were treated with 20 mg/kg pcasomorphin-7 (10 min prior to experiment, i/p). The results obtained clearly demonstrated that the peptide’s effect had a stable anxiolytic direction and increased with aging, In 21-day-old pups only one parameter was altered under peptide influence and the increase in rears on plus-maze open arms was observed. In 28-day-old pups “look out” amount from closed arms, as well as head-dipping and entries to the beginning of open arms were increased in experimental animals. In 35&yold rats we observed that P-casomorphin-7 injection caused the all above mentioned effects and also the increase of time spent on open arms and significantly elevated the number of entries to the end of open arms. Consequently, it is possible to conclude that peptide’s effects become stronger with maturation by the component of opioid system, which regulates anxiety level. Therefore, E-casomorphin7 administration at a dose 5 mg/kg in adult rats produced the same anxiolytic influence, but 20 mgkg, used in the present study, led to locomotor activity decrease in experimental animals. Thus, even in 35-day-old pups the opioid system maturation doesn’t reach the adult’s level. Moreover, even in 45-day-old rats the 20 mg/kg dose didn’t inhibit locomotor activity, but in 14-day-old rats analgetic effect has already occured. It confhmes, that these functional brain systems, which control pain susceptability, locomotor activity and anxiety level are characterized by different dynamic of maturation during individual ontogenesis of albino rat pups. Our results supplement the previous experimental data (Dubinin at al., 2000) concerning chronical peptide administration, and indicate that mechanisms of repeated and single treatment are not similar. Correspondingly, while analysing effect of the milk caseins opioid fragments on the brain of newborn mammals, we have to take into account two components of it’s activity - chronic, which cause delayed influence and acute, correcting current behaviour.
m]
Buspirone prevents sexual motivation in depressed male mice from reduction
A.V Amikishieva, D.F. Avgustinovich, L.A. Koryakina. Institute of Cytology and Genetics SD RAS, Novosibirsk, Russia Depression is often accompanied by a reduction in sexual function, including its motivational and hormonal components. Here we report effects of chronic treatment of C57BL/6J male mice, recurrently losing in daily agonistic confrontations for 20 days, with the anxiolytic and antidepressant buspirone on their sexual function. As was demonstrated earlier, the social and individual behaviours
•
Evaluation of the open-field behavior in the male rat after elevated T-maze
A. G61geli, A. Kiiqiik*, M. Asian. University of Erciyes, Faculty
of Medicine, Department of Physiology, 38039, Kayseri, Turla'ye For several reasons the open-field test has been a popular measure of the supposed emotional state of animals (1) The elevated T-maze has been developed as an animal model of anxiety to generate both conditioned and unconditioned fears in the same rat (2). This study explores the changes in psychomotor activity in adult male rats. Thus, rats were tested in the open-field after elevated T-maze. As a consequence, it was to invastigate whether the open-field area may be applied for feared rats. Male Wistar rats weighing 160-180 g were used. Elevated T-maze consisted of an enclosed arm at right angles to two open arms eleveted 50 cm above the ground. Its use for the measurement of anxiety is based on the apparent natural aversion of rodents to open and high spaces. While inhibitory avoidance of the open arm is supposed to represent learned fear, the escape response from the open arm would represent innate fear. For evaluating the behaviour parameters, before and after the elevated T- maze test, rats placed in the open field area. The test apparatus was a rectangular area (100 x 100 x 30 era) which was made of plexiglass, divided into 16 squares (3). Number of line crossing, rearing, grooming and defecation was counted during four minutes tests. The changes in the behaviour parameters were statistically treated using Wilcoxon test. After the elevated T-maze, the results in line crossing, rearing, grooming and defecation were decreased, but significant differences were shown in line crossing, rearing and defecation (p < 0.05). Our findings showed that open field was a valid model for analyzing the behaviour parameters in anxiety developed rats.
References [1] Sprott, R.L and Eleflheriou, B.E (1974) Open-field behavior in aging inbred mice. Gerontologia.20, 155-162. [2] Zangrossi, H and Graeff, EG (1997) Behavioral validation of the elevated T-maze, a new animal model of anxiety. Brain Research Bulletin. 44, 1-5. [3] Volke, A., Soosaar, S, K~ks, M et all (1997) 7-Nitroindazole, a nitric oxide synhase inhibitor, has anxiolytic- like properties in exploratory models of anxiety. Psychopharrnaeology.131,399--405.
•
Neuroendocrine effects of citalopram challenge in patients with social anxiety disorder
J. Shlik, E. Maron, A. Aluoja, I. Tfru, V. Vasar. University of
Tartu, Department of Psychiatry and Tartu University Clinics, Tartu, Estonia Purpose: Social anxiety disorder (SAD) is a prevalent and disabling anxiety disorder characterised by unreasonable fear of humiliation in front of other people in social and performance situations. Efficacy of the selective serotonin (5-HT) reuptake inhibitors in the treatment of SAD indicates possible importance of brain 5-HT transmission and 5-HT receptors in the neurobiology of social anxiety. The aim of the current study was to assess the neuroendocrine response to a 5-HT-ergic stimulation test using a highly selective 5-HT reuptake inhibitor citalopram in patients with SAD in comparison to healthy controls. The extent of release
$313
of piatitary hormones in response to citalopram was considered as a marker of central 5-HT activity. Methods: The study subjects were 18 males (n = 9) and females (n --- 9) with mean age of 29.5 (19-52) years diagnosed with SAD according to DSM-IV criteria and 18 matched healthy volunteers. At inclusion, the mean Liebowitz Social Anxiety Scale total score was 67.4 (SD-20) in patients and 16.2 (11) in controls; Hamilton Depression Scale scores were respectively 6.6 (4) and 1.4 (2). Citalopram challenge was given as intravenous infusion (20 mg over 30 min) with placebo control in randomised crossover order separated by an interval of 3-5 weeks. Plasma concentrations of cortisol and prolactin were measured at baseline and on 4 time-points during 2 hours after the infusion. Data were analysed using ANOVA with repeated measures with follow-up analysis of significant effects. Results: Analysis showed significant effects of group, drug and time of assessment for changes in corisol and prolactin concentrations. Citalopram challenge affected the release of hormones differently from placebo with higher concentrations of cortisol and prolactin detected at 90 and 120 minutes after the infusion. This effect of citalopram was evident in both patients and controls without significant between-group differences. Conclusion: In this study, the neuroendocrine sensitivity to 5-HT-stimulation with citalopram in patients with SAD was not different from the response to citalopram in healthy controls. This indicates that in contrast to the findings in Major Depression (1) there are no apparent signs of serotonergic hypofunction in SAD. On the other hand, we did not reveal hypersensitive 5-HT receptors in SAD that have been suggested by some 5-HT-ergic challenge studies (2, 3).
References [1] Kapitany, T., et al., 1999. The citaloprarn challenge test in patients with major depression and in healthy controls. Psychiatry Research 88, 75-88. [2] Tancer, M.E., et al., 1995. Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1,216--223. [3] Hollander,E., et al., 1998. Serotonergicfunction in social phobia: comparison to normal control and obsessive-compulsivedisorder subjects. Psychiatry Research 79, 213-217.
IP.3.0371 Panic disorders and migraine: As association study with dopaminergic receptor genes M.E. Stochino, A. Cherchi, G. Severino, C. Asuni, M.E Piccardi, M. Del Zompo. Headache Center, Department of Neurosciences
"B.B. Brodie", Universityof Cagliari, Cagliari, Italy Clinical and epidemiological evidence suggests that headache cooccurs with some psychopathologics, including specific anxiety disorders. Various recent studies support the existence of a comorbidity between migraine without aura and panic disorders. We evaluated the presence of panic disorders in a sample of 100 patients with migraine without aura and we tested an association between some candidate genes related to the dopaminergic system, particularly DRD1, DRD2, DRD3, DRD4 and DRDS, and this phenotype. In order to test this association and circumvent the problem of a proper control and to avoid population stratification we used the transmission disequilibrium test (TDT). The sample constituted of 100 triads (a triad is a proband and both living parents). All probands and their parents were interviewed. Out of 100 migraine patients 17 showed panic disorders.
s314
p3. Anxiety disorders and anxiolytics
Migraine and panic diagnoses were made according to IHS criteria 1988 and DSM IV, respectively. All patients and their parents gave informed consent to participate in the study and a venous blood sample was drawn. Genomic DNA was extracted from whole blood. All markers were analysed using PCR. Our data showed a positive association (P = 0.05) between the DRD2 gene and the group with both migraine and panic. Despite the clinical peculiarity of the sample and its exiguity we may suppose a key role of the dopaminergic system in the pathogenesis of migraine and panic phenotype and the likely existence of common genetic factors. This work was supported by Italian “Ministero Universim, e Ricerca Scientifica”.
lp.3.0381
Ph armacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults
E.J. Frackiewicz, PD. Tigel, J.J. Sramek, N.R. Cutler, D.E. Salazar, R. Dockens, G. Kollia, I.E. Fulmor, H.D. Uderman. California Clinical Trials, Beverly Hills, CA; Bristol-Myers Squibb, Princeton, NJ 08543, USA Buspar (buspirone hydrochloride) is an antianxiety agent proven to be clinically effective for the management of anxiety disorders, including GAD at doses as low as 7.5 mg bid. However, to date, relatively few controlled studies have been performed in children and adolescents to evaluate the pharmacodynamics and pharmacokinetics of antianxiety agents. Buspirone may be an attractive treatment option for anxiety disorders in children and adolescents because of its wide range of safe doses, lack of serious adverse events, low abuse potential and low incidence of withdrawal reactions. We performed a 21&y, open-label, multi-site, dose escalation study comprised of three demographic groups (children, adolescents and adults) to determine the pharmacokinetics and tolerability of orally-administered buspirone. Thirteen children and 12 adolescents with anxiety disorder, and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (C,,) were highest in children and lowest in adults at all three dose levels (7.5,15,30 mg bid). However, l-pyrimidinylpiperazine (l-PP), the primary metabolite of buspirone, exhibited a different plasma concentration-time profile; C,,, was significantly higher in children than in either adolescents or adults, at all concentrations. In addition, TAUC(O_T) for l-PP was significantly higher in children relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30 mg bid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%) and dyspepsia (20%); two children withdrew from the study at the higher doses (15 mg and 30 mg bid) due to adverse events. In adults, the most common adverse event was somnolence (21.4%); lightheadedness, nausea, vomiting and diarrhea were also reported, though these were mild in intensity.
(p.3.039/
The ontogenetic aspects of foodderived opioid peptide &casomorphind anxiolytic influence
1u.A. Ivleva, A.V Vylegzanina, 1.V Malinovskaia, L.A. Andreeva, VA. Dubynin. Human and Animal Physiology Department, Faculty of Biology, Moscow State University, Moscow, 119899, Russia It is known that opioid fragments of the p-caseins can influence on activity and development of different newborn’s brain systems. The present study examined behavioural changes after heptapeptide P-casomorphin-7 (YPFPGPI) injection to 3-5 week old albino rat pups. The effects of acutely administered B-casomorphin-7 in the elevated plus-maze were investigated. 21-, 28-, 35-day-old pups were treated with 20 mg/kg pcasomorphin-7 (10 min prior to experiment, i/p). The results obtained clearly demonstrated that the peptide’s effect had a stable anxiolytic direction and increased with aging, In 21-day-old pups only one parameter was altered under peptide influence and the increase in rears on plus-maze open arms was observed. In 28-day-old pups “look out” amount from closed arms, as well as head-dipping and entries to the beginning of open arms were increased in experimental animals. In 35&yold rats we observed that P-casomorphin-7 injection caused the all above mentioned effects and also the increase of time spent on open arms and significantly elevated the number of entries to the end of open arms. Consequently, it is possible to conclude that peptide’s effects become stronger with maturation by the component of opioid system, which regulates anxiety level. Therefore, E-casomorphin7 administration at a dose 5 mg/kg in adult rats produced the same anxiolytic influence, but 20 mgkg, used in the present study, led to locomotor activity decrease in experimental animals. Thus, even in 35-day-old pups the opioid system maturation doesn’t reach the adult’s level. Moreover, even in 45-day-old rats the 20 mg/kg dose didn’t inhibit locomotor activity, but in 14-day-old rats analgetic effect has already occured. It confhmes, that these functional brain systems, which control pain susceptability, locomotor activity and anxiety level are characterized by different dynamic of maturation during individual ontogenesis of albino rat pups. Our results supplement the previous experimental data (Dubinin at al., 2000) concerning chronical peptide administration, and indicate that mechanisms of repeated and single treatment are not similar. Correspondingly, while analysing effect of the milk caseins opioid fragments on the brain of newborn mammals, we have to take into account two components of it’s activity - chronic, which cause delayed influence and acute, correcting current behaviour.
m]
Buspirone prevents sexual motivation in depressed male mice from reduction
A.V Amikishieva, D.F. Avgustinovich, L.A. Koryakina. Institute of Cytology and Genetics SD RAS, Novosibirsk, Russia Depression is often accompanied by a reduction in sexual function, including its motivational and hormonal components. Here we report effects of chronic treatment of C57BL/6J male mice, recurrently losing in daily agonistic confrontations for 20 days, with the anxiolytic and antidepressant buspirone on their sexual function. As was demonstrated earlier, the social and individual behaviours