15. Neuroimaging, Neurochemical 239 regimen believed to induce sensitization. Endogenous DA release was assessed during three separate PET emission scans: following 1st dose, 4th AMPH (14 days after the 3rd dose), and during a drug-free scan conducted prior or after sensitization.Voxel-wise t-maps were calculated and binding potential (BP) by region of interest (ROI) were analyzed for significant change. A t-statistic map of significant differences between AMPH response pre- and post-sensitization indi- cated maximal areas of decreased BP localized in the ventral stria- turn [t max = 6.5; x: -30; y = -1; z -- 0]. ROI analysis confirmed that, relative to the 1st dose, the 4th dose of AMPH decreased BP by an additional 10 sd 9 % in the Nucleus Accumbens [paired t-test p = 0.04]. This effect did not occur in the dorsal caudate or putamen. Re- exposure to AMPH after 14-days of latency also resulted in a rela- tively greater increase in positive mood states (POMS), subjective drug-related ratings and eye-blink activity (1 st < 4th Dose, p< 0.05). Sensitization to psychostimulants may, under certain conditions, be achieved transiently and safely in humans. This study suggests that sensitization in humans appears to be associated with increased AMPH-induced release of DA in the ventral striatum. This paradigm will be useful to test the hypothesis that sensitization may be an important biological correlate of drug-induced psychosis and schiz- ophrenia. HYPERPROLACTINEMIA IS UNCOUPLED FROM D2/D3 DOPAMINE RECEPTOR OCCUPANCY IN LONG-TERM AMISULPRIDE TREATED PATIENTS R. A. Bressan,* K. Erlandsson, R. J. Flanagan, R J. Ell, L. S. Pilowsky Division of Psychological Medicine, Institute of Psychiatry, King's College London, London, UnitedKingdom Prolactin (PRL) elevation is a common consequence of antipsychot- ic drug treatment. It results from blockade of dopamine D2 receptors on the lactotroph cells of the anterior pituitary. Previous studies have shown a positive correlation between typical antipsychotic striatal D2 receptor occupancy and hyperprolactinemia in patients treated for a few weeks (Nordstrom et a11998, Kapur et al 2000). Objective: To evaluate the relationship between D2/D3 receptor occupancy and prolactin in vivo in schizophrenic patients receiving treatment with amisulpride. Methods: Single photon emission tomography (SPET) and the high affinity D2/D3 receptor ligand [123I]-epidepride were used to determine receptor occupancy. PRL and amisulpride plasma concentration were measured during the SPET scan. Results: Eight amisulpride treated patients were evaluated, 4 on short-term treat- ment (-2 month) and 4 on long-term treatment (-12 months). The mean (range) prolactin level obtained was 1166 (499-1892 mU/L; upper limit of normal 550 mU/L). Amisulpride plasma concentra- tion and D2/D3 receptor occupancy was positively correlated in stria- turn, thalamus and temporal cortex (p<0.01). Conversely, no corre- lations were observed between PRL and amisulpride dally dose or plasma concentration, or with D2/D3 receptor occupancy in stria- tum, thalamus and temporal cortex. PRL correlated positively with the treatment duration (r=0.78, d.f.=6, p<0.01). The mean PRL of acutely treated patients (1622mU/L) was significantly higher than those patients on long-term treatment (709mU/L) (t=4.7, d.f.=6, p<0.01), even though patients on short-term treatment received low- er amisulpride doses and lower plasma concentration, and had low- er D2/D3 receptor occupancy than long-term treated patients. Con- clusion: For amisulpride, striatal, thalamic, and temporal cortical D2/D3 receptor occupancy did not directly predict effects on PRL. This is not the case for short-term typical antipsychotic treatment, and may be due to pharmacokinetic factors or pharmacodynarnic effects including selective amisulpride action at dopamine D2-1ike receptor subtypes in striatal, cortical and pituitary regions. • ! AlifisUlpl'idc D2/D3 Amtsulp, ,de concen'tral,on Tl'eat nlent Proiactin leceptor Temporal Daily dose Pl a.gma Thalamus Treatnlent duration (mUlL) Occupancy Col~ex (days) (mg/day) I ! (mg/I ,) Slrialum ShoJX term 53 (42) 1622 (<4months) (358) 337 ([25) 213(88) 46(20) 74(15) 77(10) Long-term 325 709 475(150) 342(142) 65 (16) gl (g) 85(8) (>4nlonths) (137)* (I40)* ..... [ p<0.01 p<0.0l ....................... 1 DU127090: A NOVEL PARTIAL DOPAMINE AGONIST WITH ANTIPSYCHOTIC ACTIVITY: PILOT STUDY OF DOPAMINE D 2 RECEPTOR OCCUPANCY AFTER MULTIPLE ORAL ADMINISTRATION OF DU 127090 TO HEALTHY MALE VOLUNTEERS, USING 11 C_ RACLOPRIDE BY MEANS OF POSITRON EMISSION TOMOGRAPHY M. de Vries,* J. Udo de Haes, A. Grahn6n, L. Nyman, M. BergstrSm, A. Wall, B. Langstr6m Solvay Pharmaceuticals, Weesp,Netherlands The extend and duration of striatal dopamine D 2 receptor occupan- cy by the putative antipsychotic DU127090 in humans was studied using positron emission tomography (PET) with 11C_raclopride" An open label multiple rising dose study design was used. Six healthy male volunteers were divided in two groups. In the first group of two subjects (group 1), the D 2 receptor occupancy was investigated 2 hours after administration of 0.25 mg, 2 mg and 20 mg DU127090. All doses were reached using a titration schedule. The final dose lev- el of the group 2 (four subjects) was based on the D 2 receptor occu- pancy results from the first group. In group 2, the D 2 receptor occu- pancy was investigated at both 2 and 24 hours after administration of DU127090. To control for the inter-subject variability on receptor density each subject served as his own control by taking a PET scan prior to administration of DU127090. Plasma levels of DU127090 and prolactine were measured and the relation with D 2 receptor occu- pancy was investigated. Safety and tolerability were assessed by measuring ECG, heart rate, blood pressure, hematology, blood chem- istry, urinalysis and monitoring of adverse events. Results from Group 1 showed that DU127090 induced dose-dependent occupan- cy of D 2 receptors. The approximate displacement of 11 C-raclopride 2 hours after administration of DU 127090 was 13%, 46% and 90% at 0.25, 2 and 20 mg respectively. On basis of this data, a dose level of 10 mg was chosen for the second group. Results from group 2 showed that the D 2 receptor occupancy 2 hours after administration of 10 mg was also around 90%. Based on the dose response curve, it can be concluded that there is a plateau in occupancy of D 2 recep- tors at a dose of 10 mg DU127090. Although the plasma elimination half-life time of DU127090 is 9 hours, the D 2 receptor occupancy 24 hours after adminsitration was still around 79%. The time course of D 2 receptor occupancy would, if a high and stable occupancy at this receptor were the pivotal determinant for clinical response, indicate a once daily dosing regimen for DU127090. A marked decrease in prolactine levels was observed: to 43%, 12%, 2.5% and 5.5% of base- line levels at 0.25, 2, 10 and 20 rag. Levels were still suppressed at International Congress on Schizophrenia Research 2003