S.07.07 Increased opioid receptor binding in early abstinence from dependent opioid and alcohol use and relationship to craving

S.07 Hot Topics 2 sion was predictive of the subsequent responsiveness of inpatient treatment of their depression. Background: Treatment Resistant Depression (TRD) patients have reduced glucocorticoid receptor function, leading to high cortisol levels. We propose a suppressive test using prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics. Methods: We recruited 2 groups: (a) TRD patients, (b) controls. We compared the effects of placebo (AUCPLACEBO ) and prednisolone (AUCPRED ) on salivary cortisol secretion at 9:00, 12 h and 17:00 h in TRD inpatients on admission and controls. We described the utility of the prednisolone suppression test in predicting response to inpatient treatment for resistant depression. Responders and non-responders to treatment were defined by reduction of HAMD-21 score 50%. Results: There was a significant difference in the AUCPRED between those who subsequently responded to treatment and those who did not [responders 23.5 (4.2) vs. non-responders 41.9 (7.7) nmol X h/L: p = 0.046]. On the other hand, the comparison of AUCPLACEBO did not show a significant difference between treatment responders 53.1 (8.2) vs. non-responders 57.2 (5.7) nmol X h/L: p = 0.694. Moreover, comparing the percentage suppression of salivary cortisol on admission after prednisolone, there was a difference between subsequent treatment responders and nonresponders [responders −52.5% (4.7) vs. non-responders −30.6% (8.2); p = 0.022]. Conclusions: The prednisolone suppression test on admission predicts the outcome on discharge and distinguishes between subsequent treatment responders and non-responders in TRD patients. References [1] Pariante CM, Papadopoulos AS, Poon L, Checkley SA, English J, Kerwin RW, Lightman S, 2002, A novel prednisolone suppression test for the hypothalamic–pituitary–adrenal axis. Biol Psychiatry 51, 922– 930. [2] Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern N, Kunzel HE, Pfennig A, Uhr M, Holsboer F, 2006 Nov 20, Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression – a potential biomarker? Biol Psychiatry 2006; ahead of print. [3] Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM, 2006 Dec, Different responses to dexamethasone and prednisolone in the same depressed patients. Psychopharmacology Berlin 2, 225–235.

S.07.06 Changes in serotonin-1A receptor binding after long-term treatment with escitalopram in patients with anxiety disorders C. Spindelegger1 ° , R. Lanzenberger1 , M. Mitterhauser2 , L.K. Mien2 , P. Stein1 , W. Wadsak2 , U. Moser1 , A. Holik1 , K. Kletter2 , S. Kasper1 . 1 Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, Department of Nuclear Medicine, Vienna, Austria Background: The serotonin-1A (5-HT1A) receptor regulates serotonergic firing in raphe nuclei and serotonergic inhibition on postsynaptic neurons. Patients with anxiety disorders [1] showed reduced 5-HT1A receptor binding potential (RBP). Anxiolytic treatment with selective serotonin reuptake inhibitors (SSRIs) increases the serotonin level in the synaptic cleft and might change postsynaptic receptor densities. This study investigated the effects of treatment with escitalopram on 5-HT1A receptors.

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Methods: 12 male outpatients (30.6±5.9years) with anxiety disorders were measured with PET. All were na¨ıve to psychotropic drugs and PET scanned prior to and after 12 weeks of escitalopram treatment (11±6.1mg/d). Scans started simultaneously with a bolus injection of [carbonyl-11C]WAY-100635. ROIs were delineated on co-registered MR images: orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortices, raphe nucleus and cerebellum. Quantification of 5-HT1A binding was performed using Lammertsma’s Simplified Reference Tissue Model (SRTM). Results: 5-HT1A-RBP was significantly reduced after 12 weeks of escitalopram treatment in the hippocampus (p = 0.006). Likewise, the 5-HT1A-RBP was significantly lowered in subgenual (p = 0.017) and posterior cingulate cortex (p = 0.034). Statistical significance for hippocampus survived Bonferroni correction for multiple comparison. Conclusions: Sargent et al. found a reduced 5-HT1A RBP following treatment with paroxetine in 10 depressed patients that did not reach statistical significance [2]. Our findings might be based on the difference in patient group, sample size, SSRI type and treatment period. Additionally, these data complement the results of Meyer et al., who found decreased binding of 5-HT2A receptors [3], after paroxetine treatment in depressed patients. References [1] Lanzenberger RR et al, 2006, Reduced serotonin-1a receptor binding in social anxiety disorder. Biol Psychiatry. [2] Sargent PA et al, 2000, Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57, 174– 180. [3] Meyer JH et al, 2001, The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 158, 78−85.

S.07.07 Increased opioid receptor binding in early abstinence from dependent opioid and alcohol use and relationship to craving T.M. Williams1 ° , A. Lingford-Hughes1 , S.J.C. Davies1 , M.R.C. Daglish1 , L.G. Taylor1 , A. Hammers2 , D.J. Brooks2 , P. Grasby2 , J.S. Myles1 , D.J. Nutt1 . 1 University of Bristol, Psychopharmacology Unit, Bristol, United Kingdom; 2 Imperial College School of Medicine, MRC Clinical Sciences Centre, London, United Kingdom Recent PET studies have reported increased binding of [11C]carfentanil in early abstinence from cocaine dependence that is associated with craving (Zubieta et al., 1996). In this study we present data on availability of the opioid receptor using the PET tracer [11C]diprenorphine in opioid and alcohol dependent subjects in early abstinence compared to controls and the relationship to craving. We recruited ten opioid and eleven alcohol dependent patients undergoing detoxification and twenty healthy control subjects. All subjects underwent one [11C]diprenorphine PET scan following standard protocols. Subjects were compared with controls using paired t-tests, and clinical variables were tested for correlations with volume of distribution (VD). Global [11C]diprenorphine VD was significantly higher in opioid dependent subjects than controls (p = 0.019). This was also found in 15 of the 21 a priori regions of interest (t-test p < 0.05 uncorrected). Alcohol dependent patients showed a trend towards

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S.08 The nitric oxide pathway in psychiatric disease: avenues and perspectives

an increase in global, and no significant changes were found in the regions of interest studied. Although the opioid dependent patients craved at a high level there was no association with opioid receptor availability. However, in the alcohol dependent group, an increase in craving was significantly associated with increased availability of opioid receptors in the striatum and whole brain. We have shown an increase in opioid receptors in early abstinence from dependent alcohol and opioid use. Although the results in our alcohol dependent group did not reach significance they are consistent with another recent study (Heinz et al., 2005). This finding is most likely due to an acute increase in receptor number in early abstinence. References [1] Heinz A, Riemold M, Wrase J, et al, 2005, Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry 62(1), 57−64. [2] Zubieta J, Gorelick DA, Stauffer R, et al, 1996, Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving. Nat Med 2(11), 1225–1229.

S.07.08 Localized gray matter deficits in adolescents with first-episode psychosis J. Janssen1 ° , S. Reig1 , V. Garcia1 , M. Parellada2 , D. Moreno2 , M. Desco1 , C. Arango2 . 1 Hospital Universitario Gregorio Mara˜non, Laboratorio de Imagen M´edica, Madrid, Spain; 2 Hospital Universitario Gregorio Mara˜ non, Unidad de Adolescentes, Madrid, Spain In a cross-sectional study, we have found decreased grey matter (GM) and increased cerebrospinal fluid (CSF) in the frontal lobe of male adolescent patients with early onset psychosis compared with age-matched controls (Moreno et al., 2005). Subjects had a clinical and neuroimaging follow up after two years to assess brain volume changes between baseline and follow up and their relationship with individual psychiatric diagnoses. MRI was performed at baseline and after 2 year follow up in 31 male patients (mean age at baseline = 15.1 yrs); and 28 male healthy controls (mean age = 15.7 yrs). An automated Talairachbased method was used to assess GM, white matter (WM) and CSF volumes of all lobes. Voxel-based morphometry (VBM) was used for focal changes in volume. Volume changes over time were tested with a one way repeated measures ANCOVA model, using TIME (baseline and follow-up volumes) as the within-subjects factor and DIAGNOSIS (patients vs. controls) as the betweensubjects factor and age and intracranial volume as covariates. For whole brain volumes, age related volume changes were observed in both groups: total GM volume decreased and total WM volume increased. For regional GM volumes, the left frontal lobe showed a significant TIME x DIAGNOSIS interaction effect (p < 0.035) meaning that patients had increased progression of GM volume loss relative to controls in this region. Male adolescents with early-onset psychosis show increased loss of frontal GM volume compared to age-matched controls. Aberrant neurodevelopmental processes and/or neurodegeneration could account for these findings. References [1] Moreno D, Burdalo M, Reig S, Parellada M, Zabala A, Desco M, BacaBaldomero E, Arango C, 2005, Structural neuroimaging in adolescents

with a first psychotic episode. J Am Assoc Child Adolesc Psychiatry 44, 1151–1157.

S.08 The nitric oxide pathway in psychiatric disease: avenues and perspectives S.08.01 Innovative technologies to investigate nitric oxide in brain and in vivo: the example of the sleep–wake cycle pathways R. Cespuglio ° , C. Rousset, A. Lefebvre-Descamps. Claude Bernard University, Team EA 2734, Lyon Cedex 08, France Discovery that the gas nitric oxide (NO) is a modulatory neurotransmitter has opened a new dimension about how chemical information is transmitted. Because NO is a small and non-polar molecule, it can diffuse isotropically within limited brain areas. NO violates some of the key tenets of point-to-point chemical transmission and is the first member of a new class of transmitter, the gaseous diffusible neuromodulators or messengers. We prepared an electrochemical sensor (active part: a carbon fiber 30mm in diameter, layered with porphyrines-nickel and Nafion) capable to measure NO directly in the brain tissue of non-anaesthetized animals. In rats equipped with this sensor and with polygraphic (EEG, EMG) electrodes, we demonstrate that NO facilitates the occurrence of REM sleep. Indeed, inhibitors (7-NI: 7-nitro-indazole) of the neuronal NO-synthase (nNOS) or NO donors (Sin-1: molsidomine) are capable to reduce or increase respectively this state of sleep when injected within the pontin structures involved in its genesis. We also investigate how the NO production evolves during ageing. Data obtained in this respect indicate that, during ageing, an additive production of NO take place by way of the inducible NO-synthase (iNOS). Indeed, when iNOS is blocked by an inhibitor (AMT: 2-amino5−6-dihydro-6-methyl-4H-1−3-thiazine) REM sleep production is more drastically reduced as compared with young adult animals. Such a production reinforces thus the part played by the gaseous messenger NO in the production of REM sleep. Data as yet obtained illustrates clearly that NO brain signalling constitutes a new direction for understanding brain physiology and physiopathology. No conflict of interest References [1] Burlet S, Cespuglio R, 1997, Voltammetric detection of nitric oxide (no) in the rat brain: its variations throughout the sleep–wake cycle. Neurosci Lett 226, 131–135. [2] Burlet S, Leger L, Cespuglio R, 1999, Nitric oxide and sleep in the rat: A puzzling relationship. Neuroscience 92, 627–639. [3] Gautier-Sauvign´e S, Colas D, Parmantier P, Cl´ement P, Sarda N, Cespuglio R, 2005, Nitric oxide and sleep. Sleep Med Rev 9, 1001– 1013.

S.08.02 Animal models for the assessment of cognitive dysfunctions in schizophrenia: focus on the nitric oxide pathway D.S. Klamer1 ° , E.N. P˚alsson1 , C.E. Wass1 , K.W. Fejgin1 , N.J. Finnerty2 , J.P. Lowry2 , J.A. Engel1 , L.I. Svensson1 . 1 Institute of Neuroscience and Physiology The Sahlgrenska Academy at G¨oteborg University, Department of Pharmacology,