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F P Bymaster

Publications and source records attributed to F P Bymaster.

At least 19 recordsLinked to original sources
PubMed2006

Towards a muscarinic hypothesis of schizophrenia.

Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre-clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

Animals↗
PubMed2006

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

Acetylcholine↗
PubMed2003

Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.

OBJECTIVES: To compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs haloperidol (HAL) in a double blind, randomized trial. METHODS: Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05. RESULTS: HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties. CONCLUSIONS: In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was haloperidol. Olanzapine was equivalent to haloperidol for anticholinergic-like side effects when corrected for anticholingergic agents.

Age Factors↗
PubMed2003

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice.

Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post- and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2- and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2- and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

Acetylcholine↗
PubMed2003

Muscarinic receptors in schizophrenia.

An increasing body of evidence suggests that the muscarinic receptors may present a potential therapeutic target for the treatment of schizophrenia. This argument is supported by studies using postmortem CNS tissue and a neuroimaging study that have shown there are regionally specific decreases in selective muscarinic receptors in the CNS of subjects with schizophrenia. This raises the possibility that drugs specific to individual muscarinic receptors could have beneficial effects on the symptoms of schizophrenia, a posit supported by studies in receptor knockout/knockdown mice where it has been shown that specific behaviours affected by schizophrenia are also abnormal in mice lacking a single muscarinic receptor. Moreover, drugs have been synthesised that are partial agonists at muscarinic receptors and these drugs have been shown to improve the behavioural deficits in humans which are modulated by the muscarinic receptor family. The widespread distribution of muscarinic receptors in the human CNS and the receptor specific changes identified in postmortem CNS from subjects with schizophrenia would suggest that drugs targeting specific muscarinic receptors would also need to partition into selected CNS regions to achieve optimal responses. Some existing compounds show regional selectivity for the same muscarinic receptor in different CNS regions, suggesting that this characteristic could be engineered into muscarinic receptor targeting drugs. This review presents data from diverse areas of research to argue that it is now imperative that the therapeutic potential of manipulating the activity of muscarinic receptors for the treatment of schizophrenia is fully explored.

Animals↗
PubMed2003

M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system.

A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity of many important functions of the central and peripheral nervous systems. However, identification of the physiological and pathophysiological roles of the individual mAChR subtypes (M(1)-M(5)) has proven a difficult task, primarily due to the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues and organs express multiple mAChRs. To circumvent these difficulties, we used gene targeting technology to generate mutant mouse lines containing inactivating mutations of the M(1)-M(5) mAChR genes. The different mAChR mutant mice and the corresponding wild-type control animals were subjected to a battery of physiological, pharmacological, behavioral, biochemical, and neurochemical tests. The M(1)-M(5) mAChR mutant mice were viable and reproduced normally. However, each mutant line displayed specific functional deficits, suggesting that each mAChR subtype mediates distinct physiological functions. These results should offer new perspectives for the rational development of novel muscarinic drugs.

Animals↗
PubMed2002

Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents.

The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M(4) receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D(2) receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D(2) receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT(2A) receptor antagonism and increasing cortical norepinephrine and dopamine.

Affect↗
PubMed2002

Muscarinic agonist-mediated increases in serum corticosterone levels are abolished in m(2) muscarinic acetylcholine receptor knockout mice.

Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions in the central and peripheral nervous system. Due to the lack of receptor subtype-selective ligands, however, the physiological roles of individual muscarinic receptor subtypes remain to be determined. In this study, we examined the effects of the muscarinic M(2)/M(4) receptor-preferring agonist [5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane (BuTAC) on serum corticosterone levels in M(2) and M(4) receptor single knockout (KO) and M(2,4) receptor double KO mice. Responses were compared with those obtained with the corresponding wild-type (WT) mice. BuTAC (0.03-0.3 mg/kg s.c.) dose dependently and significantly increased serum corticosterone concentrations in WT mice to 5-fold or greater levels compared with vehicle controls. In muscarinic M(2) and M(2,4) KO mice, however, BuTAC had no significant effect on corticosterone concentrations at doses of 0.1, 0.3, and 1 mg/kg s.c. In both WT and muscarinic M(4) KO mice increases in serum corticosterone concentrations induced by BuTAC (0.1 and 0.3 mg/kg) were not significantly different and were blocked by scopolamine. In summary, the muscarinic M(2,4)-preferring agonist BuTAC had no effect on corticosterone levels in mice lacking functional muscarinic M(2) receptors. These data suggest that the muscarinic M(2) receptor subtype mediates muscarinic agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis in mice.

Animals↗
PubMed2001

Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.

Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.

Animals↗
PubMed2001

Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice.

The M(5) muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M(1)-M(5)) to be cloned. At present, the physiological relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M(5) receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology to generate M(5) receptor-deficient mice (M5R(-/-) mice). M5R(-/-) mice did not differ from their wild-type littermates in various behavioral and pharmacologic tests. However, in vitro neurotransmitter release experiments showed that M(5) receptors play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Because M(5) receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M(5) receptors led to changes in vascular tone by using several in vivo and in vitro vascular preparations. Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R(-/-) mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5R(-/-) mice. Our findings provide direct evidence that M(5) muscarinic receptors are physiologically relevant. Because it has been suggested that impaired cholinergic dilation of cerebral blood vessels may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M(5) receptors may represent an attractive therapeutic target.

Acetylcholine↗
PubMed2001

Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine.

The interaction of the psychotropic agent olanzapine with serotonin 5-HT(3) and 5-HT(6) receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT(3) receptor agonist 2-methyl serotonin (2-CH(3) 5-HT) with a pK(B) value of 6.38+/-0.03, close to the affinity of the 5-HT(3) receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 microM) did not significantly inhibit 2-CH(3) 5-HT-induced contractions. Olanzapine had high affinity (pK(i)=8.30+/-0.06) for human 5-HT(6) receptors in radioligand binding studies. Olanzapine did not stimulate [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding to the G protein G(s) in cells containing human 5-HT(6) receptors, but inhibited 5-HT-stimulated [35S]GTPgammaS binding (pK(B)=7.38+/-0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT(6) receptors with a pK(B)=7.42+/-0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT(6) receptors and had marked antagonism at 5-HT(3) receptors.

Animals↗
PubMed2001

Receptor reserve of phosphoinositide-coupled muscarinic receptors in mouse hippocampus in vivo.

The ability of the partial muscarinic agonist pilocarpine to increase in vivo phosphoinositide (PI) hydrolysis in mouse brain was compared to two full agonists. Pilocarpine increased in vivo phosphoinositide (PI) hydrolysis in cortex, striatum, and to the greatest extent in the hippocampus. Pilocarpine injected either subcutaneously or intracerebroventricularly robustly increased in vivo PI hydrolysis in hippocampus up to 500% of control levels and the increases were blocked by the muscarinic antagonist scopolamine. The increases in vivo PI hydrolysis induced by pilocarpine were 60-75% of the magnitude of the full muscarinic agonists oxotremorine-M and cis-dioxolane. The muscarinic M(1) preferring antagonist pirenzepine potently blocked pilocarpine-induced increases in in vivo PI hydrolysis, consistent with the increase being mediated by M(1) receptors. Since pilocarpine is a relatively weak partial agonist, these data suggest a substantial level of receptor reserve for the PI response in mouse hippocampus.

Acetylcholine↗
PubMed2001

The cannabinoid CB(1) receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus.

The effects of the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride (SR141716A) on extracellular concentrations of norepinephrine and 5-hydroxytryptamine (5-HT) were assessed by in vivo microdialysis in the anterior hypothalamus of freely moving rats. SR14716A (0.3, 1, 3 mg/kg, i.p.) dose-dependently increased norepinephrine efflux to about 300% of baseline, without affecting 5-HT levels. This increase in norepinephrine outflow could play an important role in the pharmacological and potentially therapeutic actions of SR141716A.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice.

Muscarinic acetylcholine receptors (M1-M5) play important roles in the modulation of many key functions of the central and peripheral nervous system. To explore the physiological roles of the two Gi-coupled muscarinic receptors, we disrupted the M2 and M4 receptor genes in mice by using a gene targeting strategy. Pharmacological and behavioral analysis of the resulting mutant mice showed that the M2 receptor subtype is critically involved in mediating three of the most striking central muscarinic effects, tremor, hypothermia, and analgesia. These studies also indicated that M4 receptors are not critically involved in these central muscarinic responses. However, M4 receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses following drug-induced activation of D1 dopamine receptors. This observation is consistent with the concept that M4 receptors exert inhibitory control over D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are known to be coexpressed. These findings emphasize the usefulness of gene targeting approaches to shed light on the physiological and pathophysiological roles of the individual muscarinic receptor subtypes.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice.

Determination of muscarinic agonist-induced parasympathomimetic effects in wild type and M2 and M4 muscarinic receptor knockout mice revealed that M2 receptors mediated tremor and hypothermia, but not salivation. The M4 receptors seem to play a modest role in salivation, but did not alter hypothermia and tremor. In the M2 knockout mice, agonist-induced bradycardia in isolated spontaneously beating atria was completely absent compared to their wild type litter mates, whereas agonist-induced bradycardia was similar in the M4 knockout and wild type mice. The potency of carbachol to stimulate contraction of isolated stomach fundus, urinary bladder and trachea was reduced by a factor of about 2 in the M2 knockout mice, but was unaltered in the M4 knockout mice. The binding of the muscarinic agonist, [3H]-oxotremorine-M, was reduced in cortical tissue from the M2 knockout mice and to a lesser extent from the M4 knockout mice, and was reduced over 90% in the brain stem of M2 knockout mice. The data demonstrate the usefulness of knockout mice in determining the physiological function of peripheral and central muscarinic receptors.

Animals↗
PubMed2001

Elucidating the role of muscarinic receptors in psychosis.

Muscarinic receptors have been implicated in the regulation of cognition and psychosis based on pharmacological evidence from pre-clinical and clinical studies. Muscarinic agonists have shown promise in the clinic in improving cognition and reducing psychotic episodes in Alzheimer's patients. However, lack of selective muscarinic ligands has limited their use due to troublesome side effects observed at higher doses. Without selective ligands, it has been difficult to assign a specific muscarinic receptor subtype to these high order mental processes. Recent development of muscarinic receptor knockout mice has provided additional tools to investigate cognition and psychosis in behavioral assays and to determine the receptor subtypes associated with parasympathomimetic physiology. Biochemical studies indicate that the M1 receptor plays a significant role in regulating G alpha q-mediated signal transduction in the hippocampus and cortex. Behavioral studies suggest that the M4 receptor is involved in movement regulation and prepulse inhibition of the startle reflex, a measure of attention. These findings support a role for the development of M1 and M4 receptor agonists for diseases in which symptoms include cognitive impairment and psychotic behaviors.

Alzheimer Disease↗