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P.2.129 Evidence for the involvement of the opioid system in the adenosine antidepressant-like effect in the forced swimming test
P2 Affective disorders and antidepressants
$448
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Evidence for the involvement of the opioid system in the adenosine antidepressant-like effect in the forced swimming test
A . L . S . Rodrigues 1 *, M.P. Kaster 2, J. Budni 2, A.R.S. Santos 3.
1 Universidade Federal de Santa Catarina, Bioquimica, Florian@olis, Brazil; 2UFSC, Bioquimica, Brazil; 3UFSC, Cidncias Fisiol6gicas, Brazil Adenosine is one of a group of substances that behaves as an extracellular signalling molecule influencing synaptic transmission and modulating the activity of the nervous system. We have recently demonstrated that the administration of adenosine elicits an antidepressant-like effect in the forced swimming test (FST) in mice by a mechanism that involves the interaction with A1 and A2A receptors [1] as well as with the nitric oxide (NO)cGMP pathway. Literature data indicate that opioids increase spinal release of adenosine, and that the analgesia from systemic and intrathecal morphine administration is reduced in animals by adenosine receptor antagonists [2]. In addition, opioids have been strongly implicated in mood disorders, a high concentration of opioid peptides and receptors is observed in limbic areas involved in the regulation of mood, and clinical studies have shown that opioid compounds possess antidepressant effects [3]. Thus, the present study sought to investigate the involvement of opioid system in the antidepressant-like effect of adenosine in the FST in mice. Swiss mice of either sex (30M0g, n 6 8), maintained at 22 27°C with free access to water and food, under a 12:12h light:dark cycle (light onset at 7:00h) were used. The animals were individually forced to swim in an open cylindrical container (diameter 10 cm, height 25 cm), containing 19 cm of water at 25°C. The total duration of immobility during a 6 min test was scored. The pre-treatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, s.c., a non-selective opioid receptor antagonist that does not cross the blood-brain barrier) completely prevented the anti-immobility effect of adenosine (10mg/kg, i.p.) in the FST. Furthermore, the pre-treatment of animals with naltrindole (3 mg/kg, i.p., a selective 6-opioid receptor antagonist), clocinnamox (1 mg/kg, i.p., an irreversible ~t-opioid receptor antagonist) or DIPPA (1 mg/kg, i.p., a selective k-opioid receptor antagonist), significantly inhibited the decrease in immobility time elicited by adenosine (10 mg/kg, i.p.) in the FST. Taken together these results demonstrate that the antidepressant-like effect of adenosine in the FST appears to be mediated, at least in part, by an interaction with the opioid system, that involves an activation of 6-, ~t- and k-opioid receptors.
References [1] Kaster, M.P., Rosa, A.O., Rosso, M.M., Goulart, E.C., Santos, A.R.S., S. Rodrigues, A.L. 2004, Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci. Lett. 355:21 24. [2] Eisenach, J.C., Hood, D.D., Curry, R., Sawynok, J., Yaksh, T.L., Li, X. 2004, Intrathecal but not intravenous opioids release adenosine fi'om the spinal cord. J. Pain 5: 64-68. [3] Bodkin, J.A., Zomberg, G.L., Lukas, S.E., Cole, J.O. 1995, Buprenorphin treatment of refi'actory depression. J. Clin. Psychopharmacol. 15: 4~57.
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Efficacy of ziprasidone in dysphoric mania
J. Zajecka 1 *, S. Murray 2, T.S. Ramey 3, F. Mandel 2. ]Rush
University Medical Centet; Psychiatty, Chicago, IL, USA;
2Pfizer htc, Medical, USA; 3Pfizer htc, Global Research and Development, USA Purpose: To evaluate efficacy of ziprasidone 40 80mg BID in patients with bipolar mania who also exhibited dysphoria at baseline. Methods: Data were pooled from 2 similar randomized, doubleblind, 3-week placebo-controlled trials and the first 3 weeks of a third study comparing ziprasidone and haloperidol with placebo. Dysphoria was defined as scores greater than or equal to 2 on 2 or more of the SADS-C items 1 6, 16, and 20. Results: On the SADS-C Mania Rating Scale (MRS), the primary efficacy variable, improvement with ziprasidone (n 160) was rapid and significantly greater than with placebo (n 70) at all visits, starting at Day 2 (LOCF) (P less than or equal to 0.01). Haloperidol (n 30) was superior to placebo (P less than or equal to 0.01) at Days 4 and 14. On CGI-S, ziprasidone was superior to placebo at all visits starting at Day 4 (P less than or equal to 0.01); haloperidol was superior at Day 4 only (P less than or equal to 0.01). On HAM-D (SADS-C extracted), significant improvement with ziprasidone versus placebo occurred at Day 7 (P 0.008). Ziprasidone but not haloperidol demonstrated significant improvement versus placebo (P less than or equal to 0.01) in MRS Manic Syndrome (Days 2, 7, 14, endpoint) and Behavior and Ideation subscales (Day 2 on), PANSS Total and Positive, and GAF scores (endpoint). Conclusions: In patients with dysphoric mania, ziprasidone demonstrated rapid symptom control and reduction of illness severity, with significantly improved overall functioning.
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Trends in antidepressants use in different European Union countries
G. Rubio 1 *, B. Marfin-Agueda 2, F. Ldpez-Mufioz 2, P. GarciaGarcia 2, C. Alamo 2. JServices Mental Health, Psychiatry,
Madrid, Spain; 2Faculty of Medicine, University of Alcala, Pharmacology, Spain Objective: To describe the pattern of use of antidepressant drugs in some of the European Union countries from different geographic areas (South, Center and North Europe): Spain, France, Italy, Germany, United Kingdom and Sweden. Method: Consumption data of each pharmaceutical speciality have been obtained from IMS Health (International Marketing Services) December 2002. The usage data are expressed in DHD, corresponding to the defined daily dose (DDD) for 1000 inhabitants and day. The DDD is defined as maintenance daily medium dose of a drug when used as main indication in adults. It has been used the DDD list from the WHO (World Health Organization). For those antidepressants for which there was not DDD list established, it has been taken into consideration the medium dose recommended in the product Technical Sheet Results: The total consumption of antidepressants during 2002 was very similar among Spain (43.15 DHD), France (43.61 DHD) and United Kingdom (44.85 DHD), being considerably surpassed by Sweden (60.83 DHD). Lower antidepressants consumption was observed in Italy (22.21 DHD) and Germany (19.86 DHD). In all the analyzed countries, the selective serotonin reuptake inhibitors (SSRI) are the most consumed drugs, Germany excepted, where the tricyclic antidepressants (TCAs) are more usually consumed. In France, Italy and Sweden the monoaminooxidase inhibitors (MAOIs) are not available and in France reboxetine and nefazodone are not either available. France is the European country
$448
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Evidence for the involvement of the opioid system in the adenosine antidepressant-like effect in the forced swimming test
A . L . S . Rodrigues 1 *, M.P. Kaster 2, J. Budni 2, A.R.S. Santos 3.
1 Universidade Federal de Santa Catarina, Bioquimica, Florian@olis, Brazil; 2UFSC, Bioquimica, Brazil; 3UFSC, Cidncias Fisiol6gicas, Brazil Adenosine is one of a group of substances that behaves as an extracellular signalling molecule influencing synaptic transmission and modulating the activity of the nervous system. We have recently demonstrated that the administration of adenosine elicits an antidepressant-like effect in the forced swimming test (FST) in mice by a mechanism that involves the interaction with A1 and A2A receptors [1] as well as with the nitric oxide (NO)cGMP pathway. Literature data indicate that opioids increase spinal release of adenosine, and that the analgesia from systemic and intrathecal morphine administration is reduced in animals by adenosine receptor antagonists [2]. In addition, opioids have been strongly implicated in mood disorders, a high concentration of opioid peptides and receptors is observed in limbic areas involved in the regulation of mood, and clinical studies have shown that opioid compounds possess antidepressant effects [3]. Thus, the present study sought to investigate the involvement of opioid system in the antidepressant-like effect of adenosine in the FST in mice. Swiss mice of either sex (30M0g, n 6 8), maintained at 22 27°C with free access to water and food, under a 12:12h light:dark cycle (light onset at 7:00h) were used. The animals were individually forced to swim in an open cylindrical container (diameter 10 cm, height 25 cm), containing 19 cm of water at 25°C. The total duration of immobility during a 6 min test was scored. The pre-treatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, s.c., a non-selective opioid receptor antagonist that does not cross the blood-brain barrier) completely prevented the anti-immobility effect of adenosine (10mg/kg, i.p.) in the FST. Furthermore, the pre-treatment of animals with naltrindole (3 mg/kg, i.p., a selective 6-opioid receptor antagonist), clocinnamox (1 mg/kg, i.p., an irreversible ~t-opioid receptor antagonist) or DIPPA (1 mg/kg, i.p., a selective k-opioid receptor antagonist), significantly inhibited the decrease in immobility time elicited by adenosine (10 mg/kg, i.p.) in the FST. Taken together these results demonstrate that the antidepressant-like effect of adenosine in the FST appears to be mediated, at least in part, by an interaction with the opioid system, that involves an activation of 6-, ~t- and k-opioid receptors.
References [1] Kaster, M.P., Rosa, A.O., Rosso, M.M., Goulart, E.C., Santos, A.R.S., S. Rodrigues, A.L. 2004, Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci. Lett. 355:21 24. [2] Eisenach, J.C., Hood, D.D., Curry, R., Sawynok, J., Yaksh, T.L., Li, X. 2004, Intrathecal but not intravenous opioids release adenosine fi'om the spinal cord. J. Pain 5: 64-68. [3] Bodkin, J.A., Zomberg, G.L., Lukas, S.E., Cole, J.O. 1995, Buprenorphin treatment of refi'actory depression. J. Clin. Psychopharmacol. 15: 4~57.
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Efficacy of ziprasidone in dysphoric mania
J. Zajecka 1 *, S. Murray 2, T.S. Ramey 3, F. Mandel 2. ]Rush
University Medical Centet; Psychiatty, Chicago, IL, USA;
2Pfizer htc, Medical, USA; 3Pfizer htc, Global Research and Development, USA Purpose: To evaluate efficacy of ziprasidone 40 80mg BID in patients with bipolar mania who also exhibited dysphoria at baseline. Methods: Data were pooled from 2 similar randomized, doubleblind, 3-week placebo-controlled trials and the first 3 weeks of a third study comparing ziprasidone and haloperidol with placebo. Dysphoria was defined as scores greater than or equal to 2 on 2 or more of the SADS-C items 1 6, 16, and 20. Results: On the SADS-C Mania Rating Scale (MRS), the primary efficacy variable, improvement with ziprasidone (n 160) was rapid and significantly greater than with placebo (n 70) at all visits, starting at Day 2 (LOCF) (P less than or equal to 0.01). Haloperidol (n 30) was superior to placebo (P less than or equal to 0.01) at Days 4 and 14. On CGI-S, ziprasidone was superior to placebo at all visits starting at Day 4 (P less than or equal to 0.01); haloperidol was superior at Day 4 only (P less than or equal to 0.01). On HAM-D (SADS-C extracted), significant improvement with ziprasidone versus placebo occurred at Day 7 (P 0.008). Ziprasidone but not haloperidol demonstrated significant improvement versus placebo (P less than or equal to 0.01) in MRS Manic Syndrome (Days 2, 7, 14, endpoint) and Behavior and Ideation subscales (Day 2 on), PANSS Total and Positive, and GAF scores (endpoint). Conclusions: In patients with dysphoric mania, ziprasidone demonstrated rapid symptom control and reduction of illness severity, with significantly improved overall functioning.
•
Trends in antidepressants use in different European Union countries
G. Rubio 1 *, B. Marfin-Agueda 2, F. Ldpez-Mufioz 2, P. GarciaGarcia 2, C. Alamo 2. JServices Mental Health, Psychiatry,
Madrid, Spain; 2Faculty of Medicine, University of Alcala, Pharmacology, Spain Objective: To describe the pattern of use of antidepressant drugs in some of the European Union countries from different geographic areas (South, Center and North Europe): Spain, France, Italy, Germany, United Kingdom and Sweden. Method: Consumption data of each pharmaceutical speciality have been obtained from IMS Health (International Marketing Services) December 2002. The usage data are expressed in DHD, corresponding to the defined daily dose (DDD) for 1000 inhabitants and day. The DDD is defined as maintenance daily medium dose of a drug when used as main indication in adults. It has been used the DDD list from the WHO (World Health Organization). For those antidepressants for which there was not DDD list established, it has been taken into consideration the medium dose recommended in the product Technical Sheet Results: The total consumption of antidepressants during 2002 was very similar among Spain (43.15 DHD), France (43.61 DHD) and United Kingdom (44.85 DHD), being considerably surpassed by Sweden (60.83 DHD). Lower antidepressants consumption was observed in Italy (22.21 DHD) and Germany (19.86 DHD). In all the analyzed countries, the selective serotonin reuptake inhibitors (SSRI) are the most consumed drugs, Germany excepted, where the tricyclic antidepressants (TCAs) are more usually consumed. In France, Italy and Sweden the monoaminooxidase inhibitors (MAOIs) are not available and in France reboxetine and nefazodone are not either available. France is the European country