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EFFECT OF NMDA GLYCINE SITE ANTAGONIST L-701, 324 ON COCAINE-STIMULATED DOPAMINE RELEASE IN THE RAT NUCLEUS ACCUMBENS Toomas Kivastik 1 ; , Sture Liljequist 2 ; 1 ; Department of Pharmacology, University of Tartu; 2 ; Department of Clinical Neuroscience, Division of Alcohol and Drug Dependence Research, Karolinska Institutet Antagonists at the NMDA glycine site have been shown to significantly attenuate some behavioural effects of addictive drugs including cocaine-induced behavioural sensitization as well as the place preference induced by amphetamine and morphine. In the present study we investigated the role of NMDA glycine site in the pharmacodynamics of cocaine with regard to its effect on dopamine release in the nucleus accumbens. Microdialysis was conducted in freely moving male Wistar rats. The NMDA glycine site antagonist L-701, 324 was administered 2, 4, or 8 mg kg IP 40 min prior to cocaine 15 or 30 mg kg IP ; . As expected, cocaine brought about a significant increase in the accumbal dopamine release. None of the doses of L-701, 324 had any significant influence on this effect, neither did L-701, 324 alone reliably affect the levels of accumbal dopamine. Our results indicate that a systemically administered NMDA glycine site antagonist fails to alter the dopamine release in the nucleus accumbens by itself, neither does it reliably modify the effect of cocaine Beta-Blockers on Admission Patient Characteristics Age mean SD ; , yrs Female % ; White % ; First half of trial % ; Systolic blood pressure mean SD ; , mm Hg Heart rate mean SD ; , beats min Pulse rate 100 beats min % ; Ejection fraction % ; Medical history Hypertension % ; Diabetes % ; Atrial fibrillation % ; Stroke or transient ischemic attack % ; Myocardial infarction % ; Signs and symptoms Dyspnea at rest or on exertion % ; S3 gallop % ; Increased jugular venous pressure % ; Rales % ; Respiratory rate 24 breaths min % ; Peripheral edema % ; Laboratory results Sodium mean SD ; , mmol l Sodium 135 mmol l % ; Creatinine mean SD ; , mmol l Blood urea nitrogen mean SD ; , mmol l Hemoglobin mean SD ; , mg dl Medications ACE inhibitors or ARB % ; Calcium channel blockers % ; Diuretics % ; Digoxin % ; Antiarrhythmic % ; Hemodynamic characteristics PAC arm ; Right atrial pressure, mm Hg Pulmonary artery systolic pressure, mm Hg Pulmonary wedge pressure, mm Hg Cardiac output, l min Cardiac index, l min m2 Overall n 432 ; No n 164 ; Yes n 268 ; p Value 0.16 0.91 0.02 * 0.80 0.54 * 0.07 0.39 0.05 * 0.58 0.03 0.07. B. Nitroglycerin 1. Nitroglycerin is the drug of choice for hypertensive emergencies with coronary ischemia. It should not be used with hypertensive encephalopathy because it increases intracranial pressure. 2. Nitroglycerin increases venous capacitance, decreases venous return and left ventricular filling pressure. It has a rapid onset of action of 2-5 minutes. Tolerance may occur within 24-48 hours. 3. The starting dose is 15 mcg IV bolus, then 5-10 mcg min 50 mg in 250 mL D5W ; . Titrate by increasing the dose at 3- to 5-minute intervals. Generally doses 1.0 mcg kg min are required for afterload reduction max 2.0 mcg kg hr ; . Monitor for methemoglobinemia. C. Labetalol IV Normodyne ; 1. Labetalol is a good choice if BP elevation is associated with hyperadrenergic activity, aortic dissection, an aneurysm, or postoperative hypertension. 2. Labetalol is administered as 20 mg slow IV over 2 min. Additional doses of 20-80 mg may be administered q5-10min, then q3-4h prn or 0.5-2.0 mg min IV infusion. Labetalol is contraindicated in obstructive pulmonary disease, CHF, or heart block greater than first degree. D. Enalaprilat IV Vasotec ; 1. Enalaprilat is an ACE-inhibitor with a rapid onset of action 15 min ; and long duration of action 11 hours ; . It is ideal for patients with heart failure or accelerated-malignant hypertension. 2. Initial dose, 1.25 mg IVP over 2-5 min ; q6h, then increase up to 5 mg q6h. Reduce dose in azotemic patients. Contraindicated in bilateral renal artery stenosis. E. Esmolol Brevibloc ; is a non-selective beta-blocker with a 1-2 min onset of action and short duration of 10 min. The dose is 500 mcg kg min x 1 min, then 50 mcg kg min; max 300 mcg kg min IV infusion. F. Hydralazine is a preload and afterload reducing agent. It is ideal in hypertension due to eclampsia. Reflex tachycardia is common. The dose is 20 mg IV IM q4-6h. G. Nicardipine Cardene IV ; is a calcium channel blocker. It is contraindicated in presence of CHF. Tachycardia and headache are common. The onset of action is 10 min, and the duration is 2-4 hours. The dose is 5 mg hr continuous infusion, up to 15 mg hr. H. Fenoldopam Corlopam ; is a vasodilator. It may cause reflex tachycardia and headaches. The onset of action is 2-3 min, and the duration is 30 min. The dose is 0.01 mcg kg min IV infusion titrated, up to 0.3 mcg kg min. I. Phentolamine Regitine ; is an intravenous alphaadrenergic antagonist used in excess catecholamine states, such as pheochromocytomas, rebound hypertension due to withdrawal of clonidine, and drug ingestions. The dose is 2-5 mg IV every 5 to 10 minutes. J. Trimethaphan Arfonad ; is a ganglionic-blocking agent. It is useful in dissecting aortic aneurysm when beta-blockers are contraindicated; however, it is rarely used because most physicians are more familiar with nitroprusside. The dosage of trimethoprim is 0.3-3 mg min IV infusion.

PREVALENCE OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC DRUG USE The monthly proportions of study children and adolescents who were prevalent users of antidepressants also decreased following the CSM warning in December 2003 Figure 3 ; . Twenty-one months after the warning, there were an estimated 143 antidepressant users per 10 000 persons per month, a reduction of 31% 95% CI, 25% to 37%; P .001 ; from the trend established prior to the warning. However, there was no evidence that discontinuation of antidepressant therapy increased Figure 3 ; . By months after the warning, the estimated monthly discontinuation proportion was 30%, which did not differ significantly from the 29% predicted from the trend established prior to the regulatory warning increase of 4%; 95% CI, -6% to 15%; P .47 ; . There was no evidence that the decrease in antidepressant use in the study population was accompanied by a corresponding increase in the use of other psychotropic drugs Figure 4 ; . For psychostimulants, mood stabilizers, antipsychotics, and benzodiazepines, we compared the monthly proportion of prevalent users predicted from the trend established prior to the CSM warning with that estimated from the entire study period. In no case was there a statistically significant increase P .50.

Tissue was prepared for electron microscopy by freeze substitution, as described previously 9 ; . Ultrathin Lowicryl HM20 sections were incubated overnight at 4C with anti-AQP5 antibodies and visualized with goat anti-rabbit IgG conjugated to 10-nm colloidal gold particles at 1: 50 GAR.EM10, BioCell Research Laboratories, Cardiff, UK ; . Sections stained with uranyl acetate and lead citrate were examined with Philips CM100 or Philips Morgagni electron microscopes Philips, Eindhoven, The Netherlands ; . Semi-quantitative assessment of immunogold labeling at the APM and the intracellular compartments from interlobular ducts of rat parotid glands from three different animals within each group was performed.

Exploration of the costs . Infectious Diseases Bulletin 2000; 11 12 ; : 262-6 . 30. Postma M, Bos J, Beutels P, Schilthuis H, Hoek Jvd. Pharmaco-economic evaluation of targeted hepatitis A vaccination for children of ethnic minorities in Amsterdam The Netherlands ; . Vaccine 2004; 22 : 1862-7. 31. Reintjes R, Bosman A, Zwart Od. Screening policy for travellers from Rotterdam for hepatitis A antibodies prior to eventual immunisation: favourable cost-benefit ratio [in Dutch]. Neth J Med 1999; 143 35 ; : 1777-80. 32. Whitney CG, Farley MM, Hadler J et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348 18 ; : 1737-46. 33. Jacobsen K, Koopmans J. Declining hepatitis A seroprevalence: a global review and analysis. Epidemiol Infect 2004; 132 6 ; : 1005-22. 34. Dijkshoorn H, Schilthuis HJ, Hoek JAvd, Verhoeff AP. Travel advice on the prevention of infectious diseases insufficiently obtained by indigenous and non-native inhabitants of Amsterdam, the Netherlands [in Dutch]. Neth J Med 2003; 147 14 ; : 658-62. 35. Steenbergen JE van, Tjon G, Hoek A van der, Koek A, Coutinho RA, Bruisten SM. Two years' prospective collection of molecular and epidemiological data shows limited spread of hepatitis A virus outside risk groups in Amsterdam, 2000-2002. J Infect Dis 2004; 189 3 ; : 471-82. 36. MHS NL. Association of Municipal Health Services. RIVM reports an increase in hepatitis A among MSM in the Netherlands. News Report of Municipal Health Service the Netherlands 2004; 41: 2-3. World Health Organization. Hepatitis A vaccines: WHO position paper. Wkly Epidemiol Rec 2000; 75: 38-42. Lopalco P, Malfait P, Salmaso S et al. A persisting outbreak of hepatitis A in Puglia, Italy, 1996: epidemiological follow-up. Eurosurveillance Weekly 1997; 2 4 ; : 31-2. 39. Frank C, Stark K. Cases of travel-associated hepatitis A in Germany: international alert. Eurosurveillance Weekly 2004; 8 35 ; . 40. Frank C, Stark K. Cases of travel-associated hepatitis A in Germany: update. Eurosurveillance Weekly 2004; 8 37 and norco.

51. Jones PL, Veenstra GJC, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19: 187, 1998 Orkin SH: Regulation of globin gene expression in erythroid cells. Eur J Biochem 231: 271, 1995 Martin DIK, Fiering S, Groudine M: Regulation of -globin gene expression: Straightening out the locus. Curr Opin Genet Dev 6: 488, 1996 Wijgerde M, Grosveld F, Fraser P: Transcription complex stability and chromatin dynamics in vivo. Nature 377: 209, 1995 Reddy PMS, Shen C-KJ: Erythroid differentiation of mouse erythroleukemia cells results in reorganization of protein-DNA complexes in the mouse maj globin promoter but not its distal enhancer. Mol Cell Biol 13: 1093, 1993 and norpramin.

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