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PubMed2002

Muscarinic receptors as a target for drugs treating schizophrenia.

The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and Fos expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M(4) receptors are hyperactive and hyper-responsive to dopamine D(1) agonists, suggesting a dynamic balance between the dopamine and M(4) receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M(1) agonist to promote cognition and a M(4) agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects.

Animals↗

PubMed2000

Norepinephrine dysfunction in depression.

The study of the noradrenergic neurotransmitter system remains one of the cornerstones of depression research. Better understanding of the action of norepinephrine and other catecholamines at the synaptic and intracellular level holds the potential for providing clues to the etiology of depression and introduces exciting possibilities for the development of novel medications for the treatment of depression. The following review of norepinephrine as it relates to depression will shed light on the current understanding of the noradrenergic system and the role for selective norepinephrine reuptake inhibitors (selective NRIs) in the treatment of depression.

Adrenergic Uptake Inhibitors↗

PubMed1993

Therapeutic intervention in dementia.

The search for novel therapeutics for human cognitive disorders has intensified. Neurotransmitter replacement therapies represent a short-term hope for treating cognitive dysfunction associated with Alzheimer's disease (AD). AD, however, is clearly a neurodegenerative disease and is characterized by a loss of synaptic elements. Ultimately, synaptic loss must be halted to alter the disease course. Agents mimicking or modulating the actions of neurotrophic factors may be useful. They may restore lost function and exert anabolic effects on existing neurons, making treated cells less susceptible to neurotoxic insult (i.e., excitotoxicity, oxidative stress, etc.). Intervening in the biogenesis of amyloid plaques and blunting local inflammatory responses may provide the ultimate treatment for AD. The success of any treatment, however, rests on early diagnosis. Early intervention in the neurodegenerative disease process will be required. Without early intervention, the risk of maintaining patients in a premorbid state is high. Therefore, it is likely that no single approach will provide optimal therapy for the AD patient and multifactorial treatment strategies may be required.

Alzheimer Disease↗

PubMed2002

Inhibition of Na+, K+-ATPase activity by the metabolites accumulating in homocystinuria.

Homocystinuria is an inborn error of sulfur amino acid metabolism characterized predominantly by vascular and nervous system dysfunction. In this study we determined the in vitro effects of homocysteine and methionine, metabolites which accumulate in homocystinuria, on Na+, K+-ATPase, and Mg2+-ATPase activities in synaptic membranes from the hippocampus of rats. The results showed that both metabolites significantly inhibit Na+, K+-ATPase but not Mg2+-ATPase activity at concentrations usually observed in plasma of homocystinuric patients. Furthermore, incubation of hippocampal homogenates with homocysteine also elicited an inhibition of the enzyme activity which was however prevented by the simultaneous addition of cysteine to the medium. In addition, cysteine or methionine per se did not modify the two enzymatic activities. These findings indicate that oxidation of critical groups in the enzyme may possibly be involved in homocysteine inhibitory effect. Moreover, kinetic studies performed to investigate the interaction between homocysteine and methionine on Na+, K+-ATPase inhibition suggested a common site for the two amino acids in the enzyme. Considering the critical role exerted by Na+, K+-ATPase in brain, it is proposed that the inhibition provoked by homocysteine and methionine on the enzyme activity may be possibly related to the brain dysfunction characteristic of homocystinuria.

Animals↗

PubMed1991

Synaptophysin and chromogranin A immunoreactivities in senile plaques of Alzheimer's disease.

Immunolabelling for synaptophysin and chromogranin A, two polypeptides associated with small clear and large dense core synaptic vesicles respectively, has been performed on tissue sections of the temporal cortex in Alzheimer's disease in combination with anti-A4 amyloid labelling. The dystrophic neurites in many senile plaques were observed to be labelled by the anti-synaptophysin or anti-chromogranin A antibodies. Some diffuse amyloid deposits, demonstrated by antibodies against synthetic amyloid A4 peptides, were associated with a punctuate increase in synaptophysin or chromogranin A immunoreactivity. The labelling of dystrophic plaque neurites may reflect the accumulation in these processes of synaptic vesicles or material derived from them. We suggest also that the punctuate increase in synaptophysin and chromogranin A immunoreactivities associated with some A4 amyloid deposits may be an early event reflecting neuronal dysfunction.

Alzheimer Disease↗

PubMed2001

Long-term synaptic alteration in the rat hippocampal CA3 field following an entorhinal cortex lesion.

The entorhinal cortex is a key initial relay for cortical input to the hippocampus. To better understand hippocampal dysfunction resulting from early entorhinal cortex involvement in Alzheimer's disease, we stereotaxically injected ibotenic acid to produce unilateral entorhinal cortex lesions in rats. We then serially examined the CA3 hippocampal region by neuronal counts, histochemistry for acetylcholinesterase, and synaptophysin immunohistochemistry. Over 12 months, the neuronal counts did not change. Acetylcholinesterase-positive fibers were persistently but non-progressively beginning at 3 months. Synaptophysin immunoreactivity progressively declined over 12 months. Since much of the entorhinal cortex output proceeds to CA3 via the dentate gyrus, transsynaptic degeneration is suspected.

Acetylcholinesterase↗

PubMed1998

Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells.

1. CB-1 cannabinoid receptors are strongly expressed in the molecular layer of the cerebellar cortex. We have analysed, in patch-clamped Purkinje cells (PCs) in rat cerebellar slices, the effect of the selective CB-1 agonists WIN55,212-2 and CP55,940 and of the selective CB-1 antagonist SR141716-A on excitatory synaptic transmission and synaptic plasticity. 2. Bath application of both agonists markedly depressed parallel fibre (PF) EPSCs. This effect was reversed by SR141716-A. In contrast, responses of PCs to ionophoretic application of glutamate were not affected by WIN55, 212-2. 3. The coefficient of variation and the paired-pulse facilitation of these PF-mediated EPSCs increased in the presence of WIN55,212-2. 4. WIN55,212-2 decreased the frequency of miniature EPSCs and of asynchronous synaptic events evoked in the presence of strontium in the bath, but did not affect their amplitude. 5. WIN55, 212-2 did not change the excitability of PFs. 6. WIN55,212-2 impaired long-term depression induced by pairing protocols in PCs. This effect was antagonized by SR141716-A. The same impairment of LTD was produced by 2-chloroadenosine, a compound that decreases the probability of release of glutamate at PF-PC synapses. 7. The present study demonstrates that cannabinoids inhibit synaptic transmission at PF-PC synapses by decreasing the probability of release of glutamate, and thereby impair LTD. These two effects might represent a plausible cellular mechanism underlying cerebellar dysfunction caused by cannabinoids.

Animals↗

PubMed2002

Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.

A central question in Alzheimer's disease concerns the mechanism by which beta-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months before the appearance of beta-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal beta-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before beta-amyloid plaque pathology, suggesting that intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's disease.

Aging↗

PubMed2005

Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice.

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.

Alzheimer Disease↗

PubMed2002

The effects of chronic ethanol consumption on neurotrophins and their receptors in the rat hippocampus and basal forebrain.

Damage to the basal forebrain frequently results in deficits in learning and memory. Mnenonic dysfunction also occurs following prolonged ethanol consumption in humans and in animal models of chronic ethanol intake, accompanied by specific abnormalities in synaptic transmission between the basal forebrain and hippocampus. The integrity of at least some of the reciprocal neuronal connections between these brain regions is influenced by target-derived neurotrophic factors. We used a semiquantitative reverse transcription polymerase chain reaction technique to measure the messenger RNA for neurotrophins BDNF and NGF, and for their receptors trkB, trkA, and the low affinity receptor, p75(NTR) in the hippocampus and basal forebrain of rats after 28 weeks of alcohol consumption without malnutrition. This chronic ethanol treatment (CET) resulted in a marked and selective reduction in basal forebrain trkA mRNA. Western blotting revealed a similar reduction of basal forebrain trkA protein. CET effects on basal forebrain trkA may reflect impaired NGF signaling that could compromise septohippocampal synaptic connections, cholinergic differentiation, and emergent functional abilities dependent on these properties.

Alcohol Drinking↗

PubMed2005

Serotonergic cell signaling in an animal model of aging and depression: olfactory bulbectomy elicits different adaptations in brain regions of young adult vs aging rats.

Aging involves neuronal and synaptic loss, and maintenance of function depends on adaptations in cellular responsiveness. We studied olfactory bulbectomy (OBX), a model that recapitulates monoaminergic dysfunction in depression, in 10-week vs 19-month-old rats, and evaluated 5HT (5-hydroxytryptamine, serotonin) mechanisms. OBX elicited little change in 5HT1A receptors in the cerebral cortex or striatum of either age group. In contrast, 5HT2 receptors showed disparate effects, with a decrease in the cerebral cortex of young OBX but not aging OBX rats, whereas the latter group showed a selective decrease in striatal 5HT2 receptors. Greater differences were apparent for 5HT-mediated cell signaling, assessed for the adenylyl cyclase (AC) cascade. In young animals, 5HT had a stimulatory effect on AC that was unaltered by OBX. However, in aging animals, the pattern of 5HT responses showed marked alterations in response to OBX: under basal conditions, stimulatory effects were enhanced but when AC was activated with forskolin, 5HT became markedly inhibitory in the striatum of aged OBX animals. Assessment of the relative AC responses to two direct stimulants that act on different epitopes of the enzyme, forskolin and Mn2+, pointed to a shift in the AC isoform and/or its ability to associate with G-proteins as the mechanism underlying the age-related differences for OBX effects. These data indicate that there are biological distinctions in the response of 5HT systems to OBX in young adult vs aging animals, which, if present in geriatric depression, could provide a mechanistic basis for differences in responses to antidepressants that act on 5HT.

Adaptation, Physiological↗

PubMed1999

Breakthroughs in molecular and cellular mechanisms underlying X-linked mental retardation.

Although genetic causes of X-linked mental retardation (XLMR) are heterogeneous and complex, recent concerted actions between physicians and biologists have allowed some major difficulties to be overcome and led to the identification of an increasing number of genes involved in these conditions. Indeed, over the past 2 years significant progress has been made in understanding the molecular basis underlying not only XLMR, where there are distinguishing phenotypic or genetic markers (syndromal forms of XLMR), but also non-specific (or idiopathic) mental retardation (MRX). Recent breakthroughs have shown that genes responsible for these latter conditions encode for proteins involved in signalling pathways which regulate cytoskeleton organization, synaptic vesicle transport and, maybe, other cellular functions. Also, they suggest a provacative picture that conceptualizes MRX as disorders resulting from a dysfunctioning of genes required for processes such as the remodelling, establishment and stabilization of connections between neuronal cells. Such processes are crucial for the development of intellectual and cognitive functions. As these functions begin to evolve mainly in post-natal stages through contact with diverse stimuli and environments, a potential therapeutic approach would be the development of drugs that target cellular signalling pathways shown to be implicated in MRX.

Genetic Linkage↗

PubMedDate not supplied

Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia.

Memantine is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists, Memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of Memantine in several animal models of ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of Memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with Memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.

Brain Ischemia↗

PubMed2005

Loss of synaptic D1 dopamine/N-methyl-D-aspartate glutamate receptor complexes in L-DOPA-induced dyskinesia in the rat.

Glutamate-mediated mechanisms are related to the motor complications of L-DOPA therapy in Parkinson's disease (PD). In striatal postsynaptic densities (PSD), the dopamine D1 receptor (D1R) is part of an oligomeric complex with the glutamate N-methyl-D-aspartate receptor (NMDAR), determining the strength of corticostriatal transmission. We studied D1R/NMDAR complex alterations induced by L-DOPA in the 6-hydroxydopamine-lesioned rat model of PD. L-DOPA-treated hemiparkinsonian rats were determined to be dyskinetic or nondyskinetic based on behavioral testing. D1R/NMDAR assemblies containing NR1-C2 and NR2B subunits were decreased in the PSD of lesioned striatum. Short-term L-DOPA administration improved akinesia and restored the synaptic abundance of D1R, NR1-C2 and NR2B. Prolonged L-DOPA treatment also normalized synaptic D1R/NMDAR complexes in nondyskinetic rats, but remarkably reduced them in the dyskinetic group without changing their interaction. This decrease involved NR1-C2, NR1-C2', NR2A, and NR2B subunits. The composition of residual synaptic D1R/NMDAR complexes in dyskinetic rats may thus be different from that observed in lesioned rats, suggesting that expression of different motor dysfunctions might be related to the receptor profile at corticostriatal synapses. The levels of D1R/NMDAR complexes were unchanged in total striatal membrane proteins, suggesting that the decrease of these species in the PSD is likely to reflect an altered receptor trafficking. In human embryonic kidney 293 cells expressing the D1R/NMDAR, complex costimulation of both D1R and NMDAR, but not individual receptor activation, promoted internalization, suggesting that development of dyskinesias might be related to agonist-mediated down-regulation of the D1R/NMDAR complex at corticostriatal synapses.

Animals↗

PubMed2004

Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome.

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.

2-Amino-5-phosphonovalerate↗

PubMed2006

Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders.

Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer's disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA. The regulation of apoptotic cascades is complex and involves transcriptional control as well as posttranscriptional protein modifications, such as protease-mediated cleavage, ubiquitination or poly(ADP-ribosylation). More recently, the regulation of protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. A better understanding of the molecular underpinnings of neuronal apoptosis will lead to novel preventive and therapeutic approaches to the neurodegenerative processes in Alzheimer's disease and other neurological disorders where programmed cell death is prominent.

Alzheimer Disease↗

PubMed1989

Adverse health consequences of cocaine abuse.

Cocaine creates a strong physical addiction and is becoming recognized as one of the most dangerous illicit drugs abused today. The myth is that cocaine is harmless and nonaddictive. An estimated 30 million Americans have used cocaine, but the number may be as high as 40 million. Five to six million individuals are compulsive users. A review of the current literature revealed multiple reports of acute myocardial infarction and cerebrovascular accident with a temporal relation to cocaine use. Cocaine has also been associated with acute rupture of the aorta, cardiac arrhythmia, and sudden death. Cocaine has multisystem toxicity involving neurologic, psychiatric, obstetric, pulmonary, dermatologic, and gastrointestinal systems. The dopamine depletion hypothesis may explain why cocaine is repeatedly administered; cocaine produces a transient increase in synaptic dopamine. Alterations in dopamine neurotransmission may be responsible for the development of compulsive use patterns. When cocaine use becomes compulsive, psychosocial dysfunction, deviant behaviors, and a wide spectrum of social, financial, and family problems invariably result. Addiction, major medical complications, and death are true hazards of cocaine use.

Adult↗

PubMed1980

Brain cholinergic dysfunction and memory in aged rats.

Age related alterations in mnemonic ability and in the functional status of muscarinic receptors were evaluated and compared to biochemical measures of pre and post-synaptic cholinergic functioning. Retention of a single trial passive avoidance task was considerably disturbed as a function of aging. The functional status of muscarinic receptors, as measured by the ability of microiontophoretically applied acetylcholine to stimulate the firing of hippocampal pyramidal cells, was similarly disturbed in aged rats. A small, but significant decrease in muscarinic receptors was detected in the dorsal hippocampi of these same aged rats, while choline acetyltransferase activity did not change. When considered with prior psychopharmacological studies, these data suggest that specific muscarinic receptor impairments may play a critical role in the memory disturbances associated with old age.

Acetylcholine↗