- Email: [email protected]
P1-012: Differential effects of nicotine, donepezil, and memantine in an animal model of cholinergic hypofunction
Poster Presentations P1 rates following protein inhibition with cycloheximide were similar in 12-month-old Ts65Dn and 2N mice. Instead, the increase in APP levels reflects an increase in App message levels in the Ts65Dn mice at 12 months of age. Similar to APP, the levels of sAPP␣ and sAPP were increased in Ts65Dn mice compared to 2N mice at 12 months, but not 4 months of age. Unexpectedly given the increase in APP levels, brain levels of both A40 and A42 were similar between Ts65Dn and 2N mice at all ages examined between 2 and 12 months. Conclusions: Gene dosage in the App trisomic Ts65Dn mice does not determine APP protein levels while the animals are young. Indeed, brain APP levels are normal until the animals reach the age at which cholinergic neurodegeneration is substantial, further suggesting that there is an interrelationship between alterations in APP metabolism and neurodegeneration in this DS model. Additionally, normal A levels are maintained in the brain of Ts65Dn mice in spite of an increase in APP and sAPP levels. Supported by the NIA, AG017617 to RAN and PMM, and AG029787 to JHKC. P1-012
DIFFERENTIAL EFFECTS OF NICOTINE, DONEPEZIL, AND MEMANTINE IN AN ANIMAL MODEL OF CHOLINERGIC HYPOFUNCTION
Kathy L. Kohlhaas, Katherine Salte, Michael W. Decker, Peter Curzon, Abbott Laboratories, Abbott Park, IL, USA. Contact e-mail: [email protected] Background: Specific bilateral cholinergic lesions to the Nucleus Basalis Magnocelullaris (NBM) using 192- IgG Saporin (SAP) produce cortical cholinergic hypofunction similar to that present in Alzheimer’s Disease (AD) (McGaughy et al, 2002). In rats, these lesions produce only minimal disruptive effects on learning and memory but can result in attentional deficits. Using this lesion model we investigated the importance of cortical cholinergic input in the cognition-enhancing effects of nicotine and two current AD treatments-the cholinesterase inhibitor donepezil and the NMDA antagonist memantine. Methods: Following bilateral SAP injections (21 nmol) to the NBM, SpragueDawley rats were allowed to recover for 12 - 14 days before being tested in the rat social recognition assay of short-term memory. An adult rat was placed in a clean cage with a juvenile, and the investigation time by the adult rat of the juvenile was measured in two-5 minute sessions separated by 2 hours. Drug was administered i.p. to the adult rat immediately following the first trial. The ratio of investigation times was used as a memory index. Results: Histological examination of the brain revealed lesion-induced reductions of cholinergic fibers in the frontal cortex (35 -42 %) and the parietal cortex (45 - 50 %). Donepezil (0.25 mg/kg) enhanced memory in non-lesioned rats, but not in lesioned rats, whereas nicotine (0.3 mg/kg) and memantine (2.2 mg/kg) were each effective in both lesioned and non-lesioned animals. Conclusions: Thus, intact cortical cholinergic tone is more critical for the efficacy of donepezil than for the efficacy of nicotine and memantine in this model. This may have implications for the therapeutic potential of these different approaches in AD, which is characterized by cholinergic hypofuntion. Moreover, this model of cholinergic hypofunction may have relevance in identifying potential palliative therapies in AD. P1-013
ANTIPSYCHOTIC-LIKE ACTIVITY OF PIMAVANSERIN, A 5-HT2A INVERSE AGONIST, IN PUTATIVE ANIMAL MODELS OF ALZHEIMER’S DISEASE PSYCHOSIS
Krista McFarland, Sean A. Gorman, Douglas W. Bonhaus, ACADIA Pharmaceuticals, San Diego, CA, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functioning. Many AD patients display symptoms of psychosis, including hallucinations and delusions, and these patients show more severe and more rapid cognitive decline and frequently require earlier hospitalization. Despite the acknowledged problem, no appropriate treatment for Alzheimer’s disease psychosis currently exists. Methods: The present study employed animal models of
T209
both AD and psychosis in order to examine a potential mechanism for reversing psychosis in AD. Results: Mice with deletion of the M1 muscarinic receptor (M1 KO) or receiving ICV infusion of amyloid  protein fragment (25-35) displayed augmented locomotor response to amphetamine challenge, a model frequently used to study psychosis. Treatment with the novel, selective serotonin 5-HT2A receptor inverse agonist pimavanserin reversed the augmented locomotor response to amphetamine in both A treated mice and in M1 KO mice. Conclusions: These data suggest that 5HT2A inverse agonism might have potential therapeutic benefits in the treatment of AD psychosis. P1-014
AT THERAPEUTIC, NEUROPROTECTIVE DOSES, MEMANTINE BLOCKS NMDA RECEPTORS AND DOES NOT AFFECT LEARNING IN NONIMPAIRED RATS
Lorenzo More`, Andreas Gravius, Jens Nagel, Barbara Valastro, Sergio Greco, Wojciech Danysz, Merz Pharmac., Frankfurt am Main, Germany. Contact e-mail: [email protected] Methods: We used Sub-chronic treatment with memantine using osmotic pumps in male rats to verify whether plasma levels previously shown to be neuroprotective actually impair learning, as suggested by Creeley et al., 2006. Treatment with 6.27, 12.53, and 18.8 mg/rat/day provided respective plasma levels of 1.03 ⫾ 0.08, 5.07 ⫾ 0.68, and 11.68 ⫾ 0.90 M. Only the lowest dose is therapeutically relevant and has previously been shown to be neuroprotective. Results: Microdialysis experiments with in vivo recovery showed that infusion of memantine at 6.27 mg/rat/d (ca. 23 mg/kg/d) produced a concentration of 990 ⫾ 105 nM in extracellular fluid (27.4% recovery). In vivo receptor occupancy experiments, demonstrated a significant, dose-dependent receptor occupancy by memantine: 32.7 and 65.7% at the doses producing 1 and 5 M plasma levels respectively. Moreover, acute administration of memantine (2.5 mg/kg i.p.) to mature female rats (as used by Creeley et al.) produced approximately two fold higher plasma levels than when administered to young male rats. Significant deficits in a passive avoidance task were only observed at the highest dose. Working memory, tested in a spontaneous alternation in the radial maze, was impaired by the middle and highest doses, and these doses induced hyperlocomotion. In conclusion, a dose of memantine which produces the therapeutic plasma level (1 M) reported to be neuroprotective leads to intracellular brain levels similar to the affinity of memantine for NMDA receptors. Conclusions: Memantine at such dose occupies NMDA receptors in the brain without producing cognitive impairment. Arguments are provided as to why Creeley et al. arrived at a different conclusion. P1-015
S100 BETA DISTRIBUTION AND DYNAMICS IN THE RAT BRAIN
Maria Ines Nogueira1, Leila M. G. Campos1, Wilma Allemandi1, Silvia H. Takada1, Efraim C. Azmitia2, 1Biomedical Sciences Institute Universidade de Sao Paulo, Sao Paulo, Brazil; 2New York Univerty, New York, NY, USA. Contact e-mail: [email protected], [email protected] Background: The key role played by the serotonergic system in the plasticity of the nervous tissue, is attributed to the glial factor S100, whose expression is induced by the activation of the receptor 5-HT1A. This factor has been considered neurotrophic, lsince it promotes neurite maturation and outgrowth during development. This protein is also involved in neuronal stability and Long Term Potentiation in adult brains by modifying the polymerization of microtubules, it has key relations with tau protein and NF-KB. S100 interestingly is distributed in CNS, specially around the ventricles, choroids plexus, near the pyramidal cells of the Cerebral Cortex and near the Cerebellar Purkinje Cells. Methods: Adult female and male rats 2 months old, housed in normal light dark cycle (12:12 h, lights on at 7.00 h) were used for this study. The animals were transcardiacly perfused with saline followed by PF 4%, pH 7, in four groups as follows: 5.00 h, 13.00 h, 17.00 h and 21.00 h. The brains were removed, overnight post-fixed, sliced in 50 m thicknesses, and collected in 12 coronal series.
DIFFERENTIAL EFFECTS OF NICOTINE, DONEPEZIL, AND MEMANTINE IN AN ANIMAL MODEL OF CHOLINERGIC HYPOFUNCTION
Kathy L. Kohlhaas, Katherine Salte, Michael W. Decker, Peter Curzon, Abbott Laboratories, Abbott Park, IL, USA. Contact e-mail: [email protected] Background: Specific bilateral cholinergic lesions to the Nucleus Basalis Magnocelullaris (NBM) using 192- IgG Saporin (SAP) produce cortical cholinergic hypofunction similar to that present in Alzheimer’s Disease (AD) (McGaughy et al, 2002). In rats, these lesions produce only minimal disruptive effects on learning and memory but can result in attentional deficits. Using this lesion model we investigated the importance of cortical cholinergic input in the cognition-enhancing effects of nicotine and two current AD treatments-the cholinesterase inhibitor donepezil and the NMDA antagonist memantine. Methods: Following bilateral SAP injections (21 nmol) to the NBM, SpragueDawley rats were allowed to recover for 12 - 14 days before being tested in the rat social recognition assay of short-term memory. An adult rat was placed in a clean cage with a juvenile, and the investigation time by the adult rat of the juvenile was measured in two-5 minute sessions separated by 2 hours. Drug was administered i.p. to the adult rat immediately following the first trial. The ratio of investigation times was used as a memory index. Results: Histological examination of the brain revealed lesion-induced reductions of cholinergic fibers in the frontal cortex (35 -42 %) and the parietal cortex (45 - 50 %). Donepezil (0.25 mg/kg) enhanced memory in non-lesioned rats, but not in lesioned rats, whereas nicotine (0.3 mg/kg) and memantine (2.2 mg/kg) were each effective in both lesioned and non-lesioned animals. Conclusions: Thus, intact cortical cholinergic tone is more critical for the efficacy of donepezil than for the efficacy of nicotine and memantine in this model. This may have implications for the therapeutic potential of these different approaches in AD, which is characterized by cholinergic hypofuntion. Moreover, this model of cholinergic hypofunction may have relevance in identifying potential palliative therapies in AD. P1-013
ANTIPSYCHOTIC-LIKE ACTIVITY OF PIMAVANSERIN, A 5-HT2A INVERSE AGONIST, IN PUTATIVE ANIMAL MODELS OF ALZHEIMER’S DISEASE PSYCHOSIS
Krista McFarland, Sean A. Gorman, Douglas W. Bonhaus, ACADIA Pharmaceuticals, San Diego, CA, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functioning. Many AD patients display symptoms of psychosis, including hallucinations and delusions, and these patients show more severe and more rapid cognitive decline and frequently require earlier hospitalization. Despite the acknowledged problem, no appropriate treatment for Alzheimer’s disease psychosis currently exists. Methods: The present study employed animal models of
T209
both AD and psychosis in order to examine a potential mechanism for reversing psychosis in AD. Results: Mice with deletion of the M1 muscarinic receptor (M1 KO) or receiving ICV infusion of amyloid  protein fragment (25-35) displayed augmented locomotor response to amphetamine challenge, a model frequently used to study psychosis. Treatment with the novel, selective serotonin 5-HT2A receptor inverse agonist pimavanserin reversed the augmented locomotor response to amphetamine in both A treated mice and in M1 KO mice. Conclusions: These data suggest that 5HT2A inverse agonism might have potential therapeutic benefits in the treatment of AD psychosis. P1-014
AT THERAPEUTIC, NEUROPROTECTIVE DOSES, MEMANTINE BLOCKS NMDA RECEPTORS AND DOES NOT AFFECT LEARNING IN NONIMPAIRED RATS
Lorenzo More`, Andreas Gravius, Jens Nagel, Barbara Valastro, Sergio Greco, Wojciech Danysz, Merz Pharmac., Frankfurt am Main, Germany. Contact e-mail: [email protected] Methods: We used Sub-chronic treatment with memantine using osmotic pumps in male rats to verify whether plasma levels previously shown to be neuroprotective actually impair learning, as suggested by Creeley et al., 2006. Treatment with 6.27, 12.53, and 18.8 mg/rat/day provided respective plasma levels of 1.03 ⫾ 0.08, 5.07 ⫾ 0.68, and 11.68 ⫾ 0.90 M. Only the lowest dose is therapeutically relevant and has previously been shown to be neuroprotective. Results: Microdialysis experiments with in vivo recovery showed that infusion of memantine at 6.27 mg/rat/d (ca. 23 mg/kg/d) produced a concentration of 990 ⫾ 105 nM in extracellular fluid (27.4% recovery). In vivo receptor occupancy experiments, demonstrated a significant, dose-dependent receptor occupancy by memantine: 32.7 and 65.7% at the doses producing 1 and 5 M plasma levels respectively. Moreover, acute administration of memantine (2.5 mg/kg i.p.) to mature female rats (as used by Creeley et al.) produced approximately two fold higher plasma levels than when administered to young male rats. Significant deficits in a passive avoidance task were only observed at the highest dose. Working memory, tested in a spontaneous alternation in the radial maze, was impaired by the middle and highest doses, and these doses induced hyperlocomotion. In conclusion, a dose of memantine which produces the therapeutic plasma level (1 M) reported to be neuroprotective leads to intracellular brain levels similar to the affinity of memantine for NMDA receptors. Conclusions: Memantine at such dose occupies NMDA receptors in the brain without producing cognitive impairment. Arguments are provided as to why Creeley et al. arrived at a different conclusion. P1-015
S100 BETA DISTRIBUTION AND DYNAMICS IN THE RAT BRAIN
Maria Ines Nogueira1, Leila M. G. Campos1, Wilma Allemandi1, Silvia H. Takada1, Efraim C. Azmitia2, 1Biomedical Sciences Institute Universidade de Sao Paulo, Sao Paulo, Brazil; 2New York Univerty, New York, NY, USA. Contact e-mail: [email protected], [email protected] Background: The key role played by the serotonergic system in the plasticity of the nervous tissue, is attributed to the glial factor S100, whose expression is induced by the activation of the receptor 5-HT1A. This factor has been considered neurotrophic, lsince it promotes neurite maturation and outgrowth during development. This protein is also involved in neuronal stability and Long Term Potentiation in adult brains by modifying the polymerization of microtubules, it has key relations with tau protein and NF-KB. S100 interestingly is distributed in CNS, specially around the ventricles, choroids plexus, near the pyramidal cells of the Cerebral Cortex and near the Cerebellar Purkinje Cells. Methods: Adult female and male rats 2 months old, housed in normal light dark cycle (12:12 h, lights on at 7.00 h) were used for this study. The animals were transcardiacly perfused with saline followed by PF 4%, pH 7, in four groups as follows: 5.00 h, 13.00 h, 17.00 h and 21.00 h. The brains were removed, overnight post-fixed, sliced in 50 m thicknesses, and collected in 12 coronal series.