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Muscarinic cholinergic-dopaminergic interactions in schizophrenia: Effects of anticholinergic modulation on REM sleep measures
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abnormalities seen in the disease. Such neuronal deficits may thus result in an elevation/disinhibition of central dopamine metabolism in schizophrenia.
B. 175. N E U R O T E N S I N : CONTROVERSIAL FINDINGS ON ITS NEUROMODULATORY ROLE IN THE MESOLIMBIC DOPAMINE SYSTEM P.E. Holtom, P.L. Needham*, G.W. Bennett, S. Aspley
*Knoll Pharamceuticals Research and Development, Nottingham, NG1 1GF Previous reports have suggested that neurotensin (NT) is an endogenous antipsychotic since it antagonises amphetamineinduced hyperlocomotion (AH; predictive of antipsychotic efficacy) when given acutely 1. However, since the onset of antipsychotic drug action is delayed in man, long-term administration of potential antipsychotic compounds in such behavioural paradigms must be considered. Male Lister-hooded rats (250-300 g; Charles River, UK) housed singly following stereotaxic implantation of bilateral cannulae (AP - 1.0; L + 1.6; V -2.6 from Bregma 2) or unilateral cannulae for infusion via Alzet® osmotic mini-pumps (AP - 1.0; L _ 1.6; V -4.0 from Bregrna2), were used to compare the effect of acute vs. chronic icv administration of NT or its immunoneutralisation, respectively, on AH (2.5mg/kg amphetamine, sc) to assess the potential antipsychotic action of NT. As predicted, acute NT (15 ~g, bilaterally) antagonised AH and a reciprocal effect occurred with acute NT immunoneutralisation. In contrast, chronic NT administration (1.25/~g/h for 21 days) increased basal locomotor activity, whereas chronic immunoneutralisation of NT antagonised AH. These data argue that chronically raised levels of NT may exacerbate the symptoms of psychosis rather than having an antipsychotic action and that antagonists of NT may thus have the potential to treat disorders associated with increased dopamine function.
References 1. Ervin G.N., Birkemo L.S., Nemeroff C.B., Prange A.J. Jr. Neurotensin blocks certain amphetamine-induced behaviours. Nature, 291, 73-76 (1981). 2. Paxinos G., Watson C. The rat brain in stereotaxic coordinates (6 th Edition on CD ROM, Academic Press, New York, 1996).
B. 176. S E C O N D - G E N E R A T I O N ('ATYPICAL') ANTIPSYCHOTICS IN RELATION TO BEHAVIOURAL INDICES OF NOVEL D1-LIKE DOPAMINE RECEPTOR SUBTYPE FUNCTION J.J. Clifford, J.L. Waddington
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland As the role of Dl-like dopamine receptor antagonism in antipsychotic activity remains uncertain, we have examined the interactions of clozapine-like antipsychotics with this family of receptors. SK&F 83959 inhibits adenylyl cyclase yet exhibits the characteristic behavioural effects of essentially all D~-like agonists. Habituated rats were pretreated with vehicle, clozapine (0.6-15.0 mg/kg), olanzapine (0.08-2.0 mg/kg), quetiapine (0.6-15.0mg/kg) or zotepine (0.3-7.5 mg/kg), challenged with SK&F 83959 (0.05mg/kg), and assessed for multiple topographies of behaviour using an ethologically-based approach. Clozapine readily blocked SK&F 83959-induced grooming and intense grooming, characteristic indices of Dl-like receptor function; at lower doses clozapine enhanced chewing, while at higher doses it suppressed chewing. Olanzapine and zotepine readily blocked grooming and intense grooming, whilst quetiapine only partially attenuated grooming and intense grooming. While olanzapine and quetiapine did not influence vacuous chewing, zotepine shared the action of clozapine to enhance vacuous chewing to SK&F 83959 at low-moderate doses; like clozapine, zotepine suppressed chewing at a high dose but, unlike clozapine, did not enhance chewing at lower doses; zotepine uniquely suppressed locomotion. Among these four second-generation ('atypical') antipsychotics, there were varying degrees of similarity to the Dl-like profile of clozapine. These interactions with a putative D~-like site not linked to adenylyl cyclase suggest that its functional significance may have been underestimated and may extend to involvement in antipsychotic activity. These studies were supported by RCSI. We thank Knoll, Lilly, Zeneca and RBI for drugs.
B. 177. M U S C A R I N I C C H O L I N E R G I C DOPAMINERGIC INTERACTIONS IN SCHIZOPHRENIA: EFFECTS OF ANTICHOLINERGIC MODULATION ON REM SLEEP MEASURES R. Tandon, A. Eiser, J.R. DeQuardo, S.F. Taylor, M. Jibson
University of Michigan Schizophrenia Program, Ann Arbor, MI48109-0120, U.S.A. Although the cholinergic system receives relatively little attention in schizophrenia, considerable recent evidence suggests that cholinergic (ACh) mechanisms may play a significant role in schizophrenic pathophysiology and be differentially related to positive and negative symptoms. It appears that muscarinic cholinergic activity may be increased during psychotic exacerbations and that cholinergic-dopaminergic (DA) interactions are relevant to the production of sleep-EEG abnormalities and the expression of positive and negative symptoms. To test the hypothesis that ACh and DA activity are increased in schizophrenia and ACh/DA interactions contribute to the production of REM sleep abnormalities in
240
schizophrenia, we compared REM sleep measures at drug-free baseline and after 6 and 10mg of biperiden (a relatively M-1 specific antimuscarinic agent) in 24 medication-free schizophrenic patients and an equal number of healthy controls. REM latency was a marker of ACh activity, plasma HVA a marker of DA activity, and REM density a measure of ACh/DA interaction. We observed a significantly shorter REM latency in schizophrenic patients than controls in all conditions (consistent with a hypothesis of increased ACh activity), similar REM density at drug-free baseline in the two groups but a steeper dose-dependent decline in REM density in the schizophrenia group following biperiden, and a significant association between plasma HVA and decline in REM density (consistent with the hypothesized DA-ACh interaction).
B. 178. T H E S E L E C T I V E M U S C A R I N I C RECEPTOR AGONIST PTAC EXHIBITS FUNCTIONAL DOPAMINE ANTAGONISM AND DECREASES SCOPOLAMINEINDUCED HYPERACTIVITY IN RODENTS. ROLE OF TEGMENTAL CHOLINERGIC NEURONS A. Fink-Jensen ~, T. Rasmussen ~, H.E. Shannon 2, D.O. Calligaro 2, N.W. Delapp z, K. Rasmussen 2, J.S. Ward 2, M.J. Sheardown ~, L. Jeppesen 1, P. Sauerberg, F.P. Bymaster 2 1Novo Nordisk A/S, 2760 Mdlov, Denmark and 2Eli Lilly and Company, Indianapolis, Indiana PTAC ([5R,6R]6-(3-propylthio)- 1,2,5-thiadiazol-4-yl]- 1azabi-cyclo[3.2.1 ]-octane) is a selective muscarinic ligand with partial agonist mode of action at muscarinic M2 and M4 receptors and antagonistic effects at muscarinic M1, M3 and M5 receptors. PTAC exhibits functional dopamine antagonism which could be antagonized by the muscarinic receptor antagonist scopolamine, indicating that muscarinic partial agonists may be a new approach in the medical treatment of schizophrenia. PTAC also decreases hyperactivity induced by scopolamine. It has earlier been hypothesized that the effect of scopolamine is induced by blockade of muscarinic receptors on mesopontine cholinergic neurons, since local injections of the cholinergic full agonist carbachol into the pedunculopontine tegmental nucleus attenuates scopolamine-induced hyperactivity. In order to investigate the possible anatomical site of action of PTAC, carbachol, as well as PTAC, were injected into the pedunculopontine tegmental nucleus and scopolamine-induced hyperactivity was measured. Carbacol blocked the effect of scopolamine whereas PTAC increased the scopolamine-induced hyperactivity. The data indicates that PTAC, in contrast to the cholinergic full receptor agonist carbachol, does not antagonize scopolamine-induced hyperactivity by stimulating muscarinic autoreceptors on cholinergic neurons in the pedunculopontine tegmental nucleus.
B. 179. N E W F I N D I N G S I N D I C A T E T H A T OLANZAPINE HAS A LOW LEVEL OF CHOLINERGIC INTERACTION IN VITRO, IN VIVO AND IN HUMANS Frank P. Bymaster, Julie F. Falcone, J6rg Czekalla, Jamie Street, Bruce Basson, John Kennedy, Nicholas A. Moore, Pierre Tran Lilly Research Laboratories, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN46285-0510 USA Olanzapine has high affinity for muscarinic M l-M5 receptors (Ki=2.5, 18, 13, 10, 6riM, respectively) in radioligand binding studies using hypotonic medium and broken membranes, but has up to 29 fold lower affinity using intact clonal cell lines and cerebrospinal fluid-like medium (Ki=73, 96, 132, 32, 48rim, respectively). Olanzapine blocked muscarinic agonist induced effects with Ki values for M1-M5 receptors from 70622nM, less than 1/100 as active as the muscarinic antagonist atropine. Olanzapine had relatively low levels of muscarinic receptor occupancy in ex vivo autoradiology and in vivo binding studies. Olanzapine, unlike the muscarinic antagonist scopolamine, did not appreciably impair spatial memory in the Morris Water Maze, suggesting a mild anticholinergic profile. Clinically, measures of salivary flow in patients treated with olanzapine (n=8; 1.9+l.7ml/5mn) was comparable to those treated with other antipsychotics (n = 19; 1.5 + 0.7 ml/5 mn). In a double-blind study (n=339) comparing olanzapine (mean modal dose 17.2 mg) to risperidone (mean modal dose 7.2 mg), no significant difference was found in anticholinergic-like event rates between the two drugs, even after excluding anticholinergic usage. In a double-blind study (n=206) comparing 3 fixed doses of olanzapine (5, 10, and 15 mg) versus placebo in elderly patients with Alzheimer's disease, no statistical differences were found between the olanzapine and placebo groups for the peripheral anticholinergic-like events of dry mouth, constipation, urinary retention, intestinal obstruction or fecal impaction. We conclude that olanzapine, in clinically effective doses, possesses relatively minimal anticholinergic effects.
B. 180. T H E A T Y P I C A L A N T I P S Y C H O T I C CLOZAPINE SENSITIZES FOR GRANULOCYTE APOPTOSIS A. Klimke 1, S. L6ffler a, U. Henning 1, V. Kolb-Bachofen 2, K. Fehsel 2 1Psychiatric Department and ZResearch Group lmmunobiology in the Biomedical Research Centre, Heinrich-Heine-University of Duesseldorf 1Bergisehe Landstrasse 2, D-40629 Duesseldorf Germany A substantial subgroup of therapy-resistant schizophrenic patients is treated with the atypical drug clozapine. Its use is limited by the risk of clozapine-induced agranulocytosis (CIA). We here propose that both, sudden onset of CIA and the
abnormalities seen in the disease. Such neuronal deficits may thus result in an elevation/disinhibition of central dopamine metabolism in schizophrenia.
B. 175. N E U R O T E N S I N : CONTROVERSIAL FINDINGS ON ITS NEUROMODULATORY ROLE IN THE MESOLIMBIC DOPAMINE SYSTEM P.E. Holtom, P.L. Needham*, G.W. Bennett, S. Aspley
*Knoll Pharamceuticals Research and Development, Nottingham, NG1 1GF Previous reports have suggested that neurotensin (NT) is an endogenous antipsychotic since it antagonises amphetamineinduced hyperlocomotion (AH; predictive of antipsychotic efficacy) when given acutely 1. However, since the onset of antipsychotic drug action is delayed in man, long-term administration of potential antipsychotic compounds in such behavioural paradigms must be considered. Male Lister-hooded rats (250-300 g; Charles River, UK) housed singly following stereotaxic implantation of bilateral cannulae (AP - 1.0; L + 1.6; V -2.6 from Bregma 2) or unilateral cannulae for infusion via Alzet® osmotic mini-pumps (AP - 1.0; L _ 1.6; V -4.0 from Bregrna2), were used to compare the effect of acute vs. chronic icv administration of NT or its immunoneutralisation, respectively, on AH (2.5mg/kg amphetamine, sc) to assess the potential antipsychotic action of NT. As predicted, acute NT (15 ~g, bilaterally) antagonised AH and a reciprocal effect occurred with acute NT immunoneutralisation. In contrast, chronic NT administration (1.25/~g/h for 21 days) increased basal locomotor activity, whereas chronic immunoneutralisation of NT antagonised AH. These data argue that chronically raised levels of NT may exacerbate the symptoms of psychosis rather than having an antipsychotic action and that antagonists of NT may thus have the potential to treat disorders associated with increased dopamine function.
References 1. Ervin G.N., Birkemo L.S., Nemeroff C.B., Prange A.J. Jr. Neurotensin blocks certain amphetamine-induced behaviours. Nature, 291, 73-76 (1981). 2. Paxinos G., Watson C. The rat brain in stereotaxic coordinates (6 th Edition on CD ROM, Academic Press, New York, 1996).
B. 176. S E C O N D - G E N E R A T I O N ('ATYPICAL') ANTIPSYCHOTICS IN RELATION TO BEHAVIOURAL INDICES OF NOVEL D1-LIKE DOPAMINE RECEPTOR SUBTYPE FUNCTION J.J. Clifford, J.L. Waddington
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland As the role of Dl-like dopamine receptor antagonism in antipsychotic activity remains uncertain, we have examined the interactions of clozapine-like antipsychotics with this family of receptors. SK&F 83959 inhibits adenylyl cyclase yet exhibits the characteristic behavioural effects of essentially all D~-like agonists. Habituated rats were pretreated with vehicle, clozapine (0.6-15.0 mg/kg), olanzapine (0.08-2.0 mg/kg), quetiapine (0.6-15.0mg/kg) or zotepine (0.3-7.5 mg/kg), challenged with SK&F 83959 (0.05mg/kg), and assessed for multiple topographies of behaviour using an ethologically-based approach. Clozapine readily blocked SK&F 83959-induced grooming and intense grooming, characteristic indices of Dl-like receptor function; at lower doses clozapine enhanced chewing, while at higher doses it suppressed chewing. Olanzapine and zotepine readily blocked grooming and intense grooming, whilst quetiapine only partially attenuated grooming and intense grooming. While olanzapine and quetiapine did not influence vacuous chewing, zotepine shared the action of clozapine to enhance vacuous chewing to SK&F 83959 at low-moderate doses; like clozapine, zotepine suppressed chewing at a high dose but, unlike clozapine, did not enhance chewing at lower doses; zotepine uniquely suppressed locomotion. Among these four second-generation ('atypical') antipsychotics, there were varying degrees of similarity to the Dl-like profile of clozapine. These interactions with a putative D~-like site not linked to adenylyl cyclase suggest that its functional significance may have been underestimated and may extend to involvement in antipsychotic activity. These studies were supported by RCSI. We thank Knoll, Lilly, Zeneca and RBI for drugs.
B. 177. M U S C A R I N I C C H O L I N E R G I C DOPAMINERGIC INTERACTIONS IN SCHIZOPHRENIA: EFFECTS OF ANTICHOLINERGIC MODULATION ON REM SLEEP MEASURES R. Tandon, A. Eiser, J.R. DeQuardo, S.F. Taylor, M. Jibson
University of Michigan Schizophrenia Program, Ann Arbor, MI48109-0120, U.S.A. Although the cholinergic system receives relatively little attention in schizophrenia, considerable recent evidence suggests that cholinergic (ACh) mechanisms may play a significant role in schizophrenic pathophysiology and be differentially related to positive and negative symptoms. It appears that muscarinic cholinergic activity may be increased during psychotic exacerbations and that cholinergic-dopaminergic (DA) interactions are relevant to the production of sleep-EEG abnormalities and the expression of positive and negative symptoms. To test the hypothesis that ACh and DA activity are increased in schizophrenia and ACh/DA interactions contribute to the production of REM sleep abnormalities in
240
schizophrenia, we compared REM sleep measures at drug-free baseline and after 6 and 10mg of biperiden (a relatively M-1 specific antimuscarinic agent) in 24 medication-free schizophrenic patients and an equal number of healthy controls. REM latency was a marker of ACh activity, plasma HVA a marker of DA activity, and REM density a measure of ACh/DA interaction. We observed a significantly shorter REM latency in schizophrenic patients than controls in all conditions (consistent with a hypothesis of increased ACh activity), similar REM density at drug-free baseline in the two groups but a steeper dose-dependent decline in REM density in the schizophrenia group following biperiden, and a significant association between plasma HVA and decline in REM density (consistent with the hypothesized DA-ACh interaction).
B. 178. T H E S E L E C T I V E M U S C A R I N I C RECEPTOR AGONIST PTAC EXHIBITS FUNCTIONAL DOPAMINE ANTAGONISM AND DECREASES SCOPOLAMINEINDUCED HYPERACTIVITY IN RODENTS. ROLE OF TEGMENTAL CHOLINERGIC NEURONS A. Fink-Jensen ~, T. Rasmussen ~, H.E. Shannon 2, D.O. Calligaro 2, N.W. Delapp z, K. Rasmussen 2, J.S. Ward 2, M.J. Sheardown ~, L. Jeppesen 1, P. Sauerberg, F.P. Bymaster 2 1Novo Nordisk A/S, 2760 Mdlov, Denmark and 2Eli Lilly and Company, Indianapolis, Indiana PTAC ([5R,6R]6-(3-propylthio)- 1,2,5-thiadiazol-4-yl]- 1azabi-cyclo[3.2.1 ]-octane) is a selective muscarinic ligand with partial agonist mode of action at muscarinic M2 and M4 receptors and antagonistic effects at muscarinic M1, M3 and M5 receptors. PTAC exhibits functional dopamine antagonism which could be antagonized by the muscarinic receptor antagonist scopolamine, indicating that muscarinic partial agonists may be a new approach in the medical treatment of schizophrenia. PTAC also decreases hyperactivity induced by scopolamine. It has earlier been hypothesized that the effect of scopolamine is induced by blockade of muscarinic receptors on mesopontine cholinergic neurons, since local injections of the cholinergic full agonist carbachol into the pedunculopontine tegmental nucleus attenuates scopolamine-induced hyperactivity. In order to investigate the possible anatomical site of action of PTAC, carbachol, as well as PTAC, were injected into the pedunculopontine tegmental nucleus and scopolamine-induced hyperactivity was measured. Carbacol blocked the effect of scopolamine whereas PTAC increased the scopolamine-induced hyperactivity. The data indicates that PTAC, in contrast to the cholinergic full receptor agonist carbachol, does not antagonize scopolamine-induced hyperactivity by stimulating muscarinic autoreceptors on cholinergic neurons in the pedunculopontine tegmental nucleus.
B. 179. N E W F I N D I N G S I N D I C A T E T H A T OLANZAPINE HAS A LOW LEVEL OF CHOLINERGIC INTERACTION IN VITRO, IN VIVO AND IN HUMANS Frank P. Bymaster, Julie F. Falcone, J6rg Czekalla, Jamie Street, Bruce Basson, John Kennedy, Nicholas A. Moore, Pierre Tran Lilly Research Laboratories, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN46285-0510 USA Olanzapine has high affinity for muscarinic M l-M5 receptors (Ki=2.5, 18, 13, 10, 6riM, respectively) in radioligand binding studies using hypotonic medium and broken membranes, but has up to 29 fold lower affinity using intact clonal cell lines and cerebrospinal fluid-like medium (Ki=73, 96, 132, 32, 48rim, respectively). Olanzapine blocked muscarinic agonist induced effects with Ki values for M1-M5 receptors from 70622nM, less than 1/100 as active as the muscarinic antagonist atropine. Olanzapine had relatively low levels of muscarinic receptor occupancy in ex vivo autoradiology and in vivo binding studies. Olanzapine, unlike the muscarinic antagonist scopolamine, did not appreciably impair spatial memory in the Morris Water Maze, suggesting a mild anticholinergic profile. Clinically, measures of salivary flow in patients treated with olanzapine (n=8; 1.9+l.7ml/5mn) was comparable to those treated with other antipsychotics (n = 19; 1.5 + 0.7 ml/5 mn). In a double-blind study (n=339) comparing olanzapine (mean modal dose 17.2 mg) to risperidone (mean modal dose 7.2 mg), no significant difference was found in anticholinergic-like event rates between the two drugs, even after excluding anticholinergic usage. In a double-blind study (n=206) comparing 3 fixed doses of olanzapine (5, 10, and 15 mg) versus placebo in elderly patients with Alzheimer's disease, no statistical differences were found between the olanzapine and placebo groups for the peripheral anticholinergic-like events of dry mouth, constipation, urinary retention, intestinal obstruction or fecal impaction. We conclude that olanzapine, in clinically effective doses, possesses relatively minimal anticholinergic effects.
B. 180. T H E A T Y P I C A L A N T I P S Y C H O T I C CLOZAPINE SENSITIZES FOR GRANULOCYTE APOPTOSIS A. Klimke 1, S. L6ffler a, U. Henning 1, V. Kolb-Bachofen 2, K. Fehsel 2 1Psychiatric Department and ZResearch Group lmmunobiology in the Biomedical Research Centre, Heinrich-Heine-University of Duesseldorf 1Bergisehe Landstrasse 2, D-40629 Duesseldorf Germany A substantial subgroup of therapy-resistant schizophrenic patients is treated with the atypical drug clozapine. Its use is limited by the risk of clozapine-induced agranulocytosis (CIA). We here propose that both, sudden onset of CIA and the