- Email: [email protected]
Olanzapine: Antidopaminergic ane memory effects in mice
166
doses. PET examinations were performed with both tracers. In parallel, a group of four healthy volunteers was investigated. The D 2 binding potential in the putamen and the caudate nucleus was determined by assuming a three-compartment model and by using the evaluation method proposed by Patlak and Blasberg, (J (i-r Blood Flow Metab (1985) 5:584 590). The occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing seroquel dose was detected with (' ~C )-raclopride (p < 0.01 ), no such trend was apparent for ( *~C )-N-methylspiperone (p > 0.09 ). The range of seroquel occupancy measured by 0~C)-raclopride was twice the (~ ~C )-N-methylspiperone range. In conclusion, (x 1C )-N M S in contrast to (nC)-RAC, fails to detect changes in D 2 receptor binding of the atypical neuroleptic, seroquel.
STRIATAL D O P A M I N E D2 R E C E P T O R O C C U P A N C Y IN PATIENTS T R E A T E D WITH O L A N Z A P I N E T.J. Raedler*, M.B. K n a b l e , T. Lafargue, D. Pickar, D.R. Weinberger
antipsychotics have much improved side effect profiles, but their impact on cognition is unclear. Thus, we have undertaken this study to evaluate the memory effects of a typical antipsychotic, two atypical antipsychotics and a muscarinic agonist and antagonist. The muscarinic antagonist scopolamine is known to cause decreased learning and memory in various paradigms in animal and man and thus served as a positive control. In experiment I, inhibition of apomorphine induced climbing in mice was used to generate functional antidopaminergic efficacy data (EDs0's) for olanzapine (0.42 mg/kg), clozapine (2.6 mg/kg), haloperidol (0.08 mg/kg), oxotremorine (0.08 mg/kg) and scopolamine (>0.3 mg/kg). In experiment 2, these data were used to select dose ranges for subsequent testing in one trial mouse passive avoidance in order to determine potential learning and memory deficits. Drugs were administered prior to training trial. 24 hours later, retention testing suggested learning and memory deficits at the following minimum effective doses: Olanzapine > 3 m g / k g , clozapine I mg/kg, haloperidol > 1 mg/kg, oxotremorine > 3 mg/kg and scopolamine 0.3 mg/kg. Although olanzapine had potent activity in the efficacy assay (apomorphine induced climbing), it did not have effects on learning and memory at seven fold higher doses. Clozapine produced significant learning and memory deficits in the same range as the ED~o for apomorphine induced climbing.
ETmical Bm#~ Disorders Branch. National hzstitute ~?l Mental Health, 2700 Martin Luther King Ave. SE, WashhTgton. DC20032, USA Four male patients (mean age-37.5 years) were studied with 1-123 IBZM-SPECT alter three weeks of treatment on a tow dose (5mg) and a high dose (20rag) of olanzapine without concomitant medications. Subjects received 7 mCi of 1-123 IBZM. Scans of thirty minutes duration were obtained ninety minutes alter the injection, when IBZM-uptake is at equilibrium. The ratio of specific to nonspecific binding in the basal ganglia ((BG-CBL)/CBL) was determined using M R I assisted placement of ROls. Receptor occupancy was calculated using a referencerange from a group of 16 normal volunteers. The mean D2 occupancy on olanzapine 5 mg was 58"/,, (range 52% to 62%): the mean D2 occupancy on olanzapine 20 mg was 83% (range 77% to 97%). Although the D2 occupancy rates on 5 mg and 20 mg olanzapine were significantly different (p<0.03), there were no significant differences in ratings for positive symptoms. negative symptoms or movement disorders on these two doses. The D2 occupancy rate was significantly correlated with olanzapine dose perkg body-weight (r=0.89: 11<0.05). In our small sample, high doses of olanzapine led to higher D2 receptor occupancy without apparent changes in clinical parameters. These findings need to be evaluated in a larger cohort.
OLANZAPINE: ANTIDOPAMINERGIC AND M E M O R Y EFFECTS IN M I C E T.R. R a s m u s s e n , M . D . B . Swedberg, F.P. B y m a s t e r *
*Lilly Research Laboratories, h~dkmapolis. IN 46285. USA Cognitive deficits are a serious problem in schizophrenia and impact the vocational ability of the patients. The new atypical
IN VIVO EFFECTS OF O L A N Z A P I N E ON R A D I O L I G A N D B I N D I N G , D O P A M I N E D2 AUTORECEPTOR BLOCKADE, AGONISTI N D U C E D IN VIVO P H O S P H O I N O S I T I D E HYDROLYSIS AND NEUROTRANSMITTER RELEASE W. Z h a n g , K . W . Perry, F.P. B y m a s t e r
Eli Lilly and Omlpany. bMianapolis, Lilly Corporate Center hTdiamt, 46285, USA Olanzapine is an efficacious atypical antipsychotic with high affinity in vitro for dopamine, serotonin_, (5HT2), 5HT~, muscarmic, a:adrenergic and histamine H1 receptor subtypes. However. side effects produced by blockade of these receptors, particularly muscarinic receptors, have not been prominent in clinical studies. Thus, we have investigated in rats the effect of olanzapine on in vivo receptor binding, functional blockade of receptors and neurotransmitter release. Olanzapine inhibited specific radioligand binding in vivo to 5HT 2 (spiperone in frontal cortex), DI (SCH23390 in neostriatum), D2 (raclopride in neostriatum), and muscarinic (QNB in hippocampus) receptors with EDso values of 0.15, 15, 0.6, and >10mg/kg, respectively. Agonist activation of 5HT, and muscarinic phosphoinositide coupled receptors ill vivo was determined by prelabeling phospholipid stores with intraventricularly injected -~H-myoinositoI and measuring phosphoinositide hydrolysis after administration of lithium. In studies utilizing this novel
doses. PET examinations were performed with both tracers. In parallel, a group of four healthy volunteers was investigated. The D 2 binding potential in the putamen and the caudate nucleus was determined by assuming a three-compartment model and by using the evaluation method proposed by Patlak and Blasberg, (J (i-r Blood Flow Metab (1985) 5:584 590). The occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing seroquel dose was detected with (' ~C )-raclopride (p < 0.01 ), no such trend was apparent for ( *~C )-N-methylspiperone (p > 0.09 ). The range of seroquel occupancy measured by 0~C)-raclopride was twice the (~ ~C )-N-methylspiperone range. In conclusion, (x 1C )-N M S in contrast to (nC)-RAC, fails to detect changes in D 2 receptor binding of the atypical neuroleptic, seroquel.
STRIATAL D O P A M I N E D2 R E C E P T O R O C C U P A N C Y IN PATIENTS T R E A T E D WITH O L A N Z A P I N E T.J. Raedler*, M.B. K n a b l e , T. Lafargue, D. Pickar, D.R. Weinberger
antipsychotics have much improved side effect profiles, but their impact on cognition is unclear. Thus, we have undertaken this study to evaluate the memory effects of a typical antipsychotic, two atypical antipsychotics and a muscarinic agonist and antagonist. The muscarinic antagonist scopolamine is known to cause decreased learning and memory in various paradigms in animal and man and thus served as a positive control. In experiment I, inhibition of apomorphine induced climbing in mice was used to generate functional antidopaminergic efficacy data (EDs0's) for olanzapine (0.42 mg/kg), clozapine (2.6 mg/kg), haloperidol (0.08 mg/kg), oxotremorine (0.08 mg/kg) and scopolamine (>0.3 mg/kg). In experiment 2, these data were used to select dose ranges for subsequent testing in one trial mouse passive avoidance in order to determine potential learning and memory deficits. Drugs were administered prior to training trial. 24 hours later, retention testing suggested learning and memory deficits at the following minimum effective doses: Olanzapine > 3 m g / k g , clozapine I mg/kg, haloperidol > 1 mg/kg, oxotremorine > 3 mg/kg and scopolamine 0.3 mg/kg. Although olanzapine had potent activity in the efficacy assay (apomorphine induced climbing), it did not have effects on learning and memory at seven fold higher doses. Clozapine produced significant learning and memory deficits in the same range as the ED~o for apomorphine induced climbing.
ETmical Bm#~ Disorders Branch. National hzstitute ~?l Mental Health, 2700 Martin Luther King Ave. SE, WashhTgton. DC20032, USA Four male patients (mean age-37.5 years) were studied with 1-123 IBZM-SPECT alter three weeks of treatment on a tow dose (5mg) and a high dose (20rag) of olanzapine without concomitant medications. Subjects received 7 mCi of 1-123 IBZM. Scans of thirty minutes duration were obtained ninety minutes alter the injection, when IBZM-uptake is at equilibrium. The ratio of specific to nonspecific binding in the basal ganglia ((BG-CBL)/CBL) was determined using M R I assisted placement of ROls. Receptor occupancy was calculated using a referencerange from a group of 16 normal volunteers. The mean D2 occupancy on olanzapine 5 mg was 58"/,, (range 52% to 62%): the mean D2 occupancy on olanzapine 20 mg was 83% (range 77% to 97%). Although the D2 occupancy rates on 5 mg and 20 mg olanzapine were significantly different (p<0.03), there were no significant differences in ratings for positive symptoms. negative symptoms or movement disorders on these two doses. The D2 occupancy rate was significantly correlated with olanzapine dose perkg body-weight (r=0.89: 11<0.05). In our small sample, high doses of olanzapine led to higher D2 receptor occupancy without apparent changes in clinical parameters. These findings need to be evaluated in a larger cohort.
OLANZAPINE: ANTIDOPAMINERGIC AND M E M O R Y EFFECTS IN M I C E T.R. R a s m u s s e n , M . D . B . Swedberg, F.P. B y m a s t e r *
*Lilly Research Laboratories, h~dkmapolis. IN 46285. USA Cognitive deficits are a serious problem in schizophrenia and impact the vocational ability of the patients. The new atypical
IN VIVO EFFECTS OF O L A N Z A P I N E ON R A D I O L I G A N D B I N D I N G , D O P A M I N E D2 AUTORECEPTOR BLOCKADE, AGONISTI N D U C E D IN VIVO P H O S P H O I N O S I T I D E HYDROLYSIS AND NEUROTRANSMITTER RELEASE W. Z h a n g , K . W . Perry, F.P. B y m a s t e r
Eli Lilly and Omlpany. bMianapolis, Lilly Corporate Center hTdiamt, 46285, USA Olanzapine is an efficacious atypical antipsychotic with high affinity in vitro for dopamine, serotonin_, (5HT2), 5HT~, muscarmic, a:adrenergic and histamine H1 receptor subtypes. However. side effects produced by blockade of these receptors, particularly muscarinic receptors, have not been prominent in clinical studies. Thus, we have investigated in rats the effect of olanzapine on in vivo receptor binding, functional blockade of receptors and neurotransmitter release. Olanzapine inhibited specific radioligand binding in vivo to 5HT 2 (spiperone in frontal cortex), DI (SCH23390 in neostriatum), D2 (raclopride in neostriatum), and muscarinic (QNB in hippocampus) receptors with EDso values of 0.15, 15, 0.6, and >10mg/kg, respectively. Agonist activation of 5HT, and muscarinic phosphoinositide coupled receptors ill vivo was determined by prelabeling phospholipid stores with intraventricularly injected -~H-myoinositoI and measuring phosphoinositide hydrolysis after administration of lithium. In studies utilizing this novel