Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Memantine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 757 records · Page 42Linked to original sources

[Pharmacological treatment options in frontotemporal dementia].

In contrast to Alzheimer's disease, there are only few systematic trials for drug therapy of frontotemporal dementia (FTD). Neurochemically, a strong serotonergic deficit is supposed in FTD. This is the rationale for treatment, especially of behavioral abnormalities, with serotonergic antidepressants. However, only paroxetine and trazodone have been studied in trials with class I and II evidence so far. The results of paroxetine are inconsistent; and for trazodone a number of potential side-effects must be considered. Moreover, there is class II evidence for rivastigmine in FTD, even though a cholinergic deficit in this type of dementia is questionable. There are no published data from controlled trials for the use of memantine in FTD so far.

Aged↗

Effects of a methanolic extract and a hyperforin-enriched CO2 extract of St. John's Wort (Hypericum perforatum) on intracerebral field potentials in the freely moving rat (Tele-Stereo-EEG).

Two extracts of St. John's Wort (Hypericum perforatum) were investigated in the animal model "Tele-Stereo-EEG" which consisted of continuous recording of intracerebral field potentials in the freely moving rat. One was a CO2 extract for research purposes containing 30.14% hyperforin, a phloroglucine derivative known to occur within the reproductive parts of the plant, and lacking other major constituents like naphtodianthrones and flavonoids according to HPLC fingerprint. The other extract was the methanolic extract LI 160S (4.67% hyperforin). The dosage schedule was elaborated for the application of identical amounts of hyperforin in both extracts in each dosing group. Both extracts produced nearly identical patterns of electrical power changes during the first two hours of recording. These changes mainly consisted of reproducible power increases within the alpha1 band of the striatum. Comparison with earlier data obtained by identical protocols revealed that the early action was very similar to that following the application of serotonin reuptake inhibitors, thus matching biochemical in vitro data previously reported. These changes might be due to the presence of hyperforin. Only LI 160S developed a late action not seen with the CO2 extract, consisting in increases in delta activity. This late action of LI 160S matched data obtained by analysis of the action of NMDA-antagonists like MK 801 or memantine. Again, these results support previously reported biochemical findings of the interaction of hypericum extract with the glutamatergic system. In all probability, this action stems from substances only present in LI 160S, not in the CO2 extract. Which of the components contained within hypericum extracts are responsible for the clinical efficacy of St. John's wort in depression remains to be determined.

Animals↗

[NMDA-receptor antagonist in pain therapy].

The treatment of patients suffering from chronic neuropathic pain remains a clinical challenge, particularly in cases where opioid therapy fails to provide sufficient pain relief. Spinal sensitization might be one cause for induction and maintenance of such states of pain, frequently accompainied by symptoms like allodynia, hyperalgesia and temporal summation of second pain. Experimental data concerning the role of NMDA-mediated processes in central sensitization and the effects of NMDA receptor antagonists in different models of neuropathic pain are reviewed. In clinical trials ketamine and other NMDA receptor blocking agents caused a significant reduction of hypersensitive states of pain, but nearly all authors described psychomimetic and other side effects. Aminoadamantanes like memantine and amantadine also have NMDA blocking properties and are widely used in the treatment of Parkinson's disease. Further clinical studies may reveal whether these substances will play a role as adjuncts in future pain treatment. Improving the efficacy of opioids by blocking NMDA receptor-mediated activity constitutes another clinically relevant concept for pain management. Numerous experiments have shown synergistic effects of NMDA antagonists and opioids in analgesia, while the development of opioid tolerance was prevented.

Animals↗

[Pharmacotherapy of Alzheimer dementia: therapy of cognitive symptoms--new results of clinical studies].

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.

Aged↗

Conserved structural and functional control of N-methyl-D-aspartate receptor gating by transmembrane domain M3.

The molecular events controlling glutamate receptor ion channel gating are complex. The movement of transmembrane domain M3 within N-methyl-d-aspartate (NMDA) receptor subunits has been suggested to be one structural determinant linking agonist binding to channel gating. Here we report that covalent modification of NR1-A652C or the analogous mutation in NR2A, -2B, -2C, or -2D by methanethiosulfonate ethylammonium (MT-SEA) occurs only in the presence of glutamate and glycine, and that modification potentiates recombinant NMDA receptor currents. The modified channels remain open even after removing glutamate and glycine from the external solution. The degree of potentiation depends on the identity of the NR2 subunit (NR2A < NR2B < NR2C,D) inversely correlating with previous measurements of channel open probability. MTSEA-induced modification of channels is associated with increased glutamate potency, increased mean single-channel open time, and slightly decreased channel conductance. Modified channels are insensitive to the competitive antagonists D-2-amino-5-phosphonovaleric acid (APV) and 7-Cl-kynurenic acid, as well as allosteric modulators of gating (extracellular protons and Zn(2+)). However, channels remain fully sensitive to Mg(2+) blockade and partially sensitive to pore block by (+)MK-801, (-)MK-801, ketamine, memantine, amantadine, and dextrorphan. The partial sensitivity to (+)MK-801 may reflect its ability to stimulate agonist unbinding from MT-SEA-modified receptors. In summary, these data suggest that the SYTANLAAF motif within M3 is a conserved and critical determinant of channel gating in all NMDA receptors.

Allosteric Regulation↗

Two-year follow-up of amyloid deposition in patients with Alzheimer's disease.

Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.

Aged↗

Human brain N-methyl-D-aspartate receptors regulating noradrenaline release are positively modulated by HIV-1 coat protein gp120.

OBJECTIVE: To investigate the effect of HIV-1 gp120 on the function of glutamate receptors of the N-methyl-D-aspartate (NMDA) type in the human brain. DESIGN: The monitoring of neurotransmitter release from superfused isolated nerve endings is widely recognized as a technique appropriate for the study of neurotransmitter release and to attribute a precise localization to the site(s) of action of drugs able to modulate release. METHODS: Synaptosomes (pinched-off nerve endings) were prepared from fresh human brain tissue samples removed during neurosurgery, labelled with [3H]-noradrenaline and superfused at a rate of 0.5 ml/min with NMDA in the presence of gp41, gp160, gp120 or the V3 loop, with or without NMDA receptor antagonists. Fractions of superfusate were collected and measured for radioactivity. RESULTS: NMDA elicited a glycine-sensitive release of [3H]-noradrenaline from human brain synaptosomes. HIV-1 gp120 potentiated the NMDA (1 mM)-evoked [3H]-noradrenaline release (maximal effect approximately 110% at 1 nM). The release elicited by NMDA plus gp120 was prevented by the classical NMDA receptor antagonists dizocilpine or 7-chlorokynurenic acid, as well as by memantine. The potentiation by gp120 of the NMDA-evoked [3H]-noradrenaline release was mimicked by gp160 but not by gp41. The effect of gp120 was retained by the V3 loop. Finally, gp120 reversed (1 nM) and surmounted (10nM) the antagonism by 10 microM 7-chlorokynurenate of the NMDA-evoked [3H]-noradrenaline release. CONCLUSION: gp 120 binds directly through the V3 loop at noradrenergic axon terminals in human brain neocortex and may alter the function of presynaptic NMDA receptors mediating regulation of noradrenaline release.

Adult↗

The use of NMDA-receptor antagonists in the treatment of chronic pain.

Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and aspartate binding to the N-methyl-D-aspartate (NMDA) receptor. A number of antagonists to the NMDA receptor are antinociceptive in animal models but are associated with significant dose-limiting side effects. Commercially available NMDA-receptor antagonists include ketamine, dextromethorphan, memantine, and amantadine. The opioids methadone, dextropropoxyphene, and ketobemidone are also antagonists at the NMDA receptor. The NMDA-receptor antagonists have a significant impact on the development of tolerance to opioid analgesics. Consequently, NMDA-receptor antagonists may represent a new class of analgesics and may have potential as coanalgesics when used in combination with opioids.

Chronic Disease↗

A double-blind, cross-over comparison of the effects of amantadine or placebo on visuomotor and cognitive function in medicated schizophrenia patients.

The present study aimed to test the hypothesis that dopamine agonists may enhance cognitive function. The effect of amantadine on neuropsychological function in medicated schizophrenia patients was investigated. The study comprised an add-on, double-blind, placebo-controlled, cross-over 6-week trial. Participants comprised 29 inpatients at Sha'ar Menashe Mental Health Center who were diagnosed with chronic schizophrenia or schizoaffective disorder. Amantadine 200 mg/day or identical placebo was added to ongoing antipsychotic treatment for 3 weeks. Study medications were then switched for an additional 3 weeks. Assessments were performed at baseline, and weeks 3 and 6, including cognitive and visuomotor assessments. Clinical ratings included positive, negative and depressive symptoms and extrapyramidal side-effects. Blood prolactin levels were assayed. A mixed model was used to examine differences in the data at the three assessment points. Amantadine was associated with improved visuomotor coordination compared to placebo. No significant changes in cognitive functions were noted. Clinical symptoms, extrapyramidal side-effects and blood prolactin levels were not altered. Amantadine improved visuomotor coordination independently of extrapyramidal side-effects but not cognitive function. Because prolactin concentrations were unchanged, the mechanism is more likely to involve glutaminergic NMDA than dopaminergic mechanisms. Further studies of amantadine with different doses and treatment duration, as well as more glutamate selective agents such as memantine, are indicated.

Adult↗

New medical and surgical treatments for Parkinson's disease.

This article reviews new medical and surgical treatments for Parkinson's disease (PD). Catechol-O-methyl-transferase (COMT) inhibitors supplement the variety of antiparkinsonian drugs interacting with the dopaminergic system. Clinical studies show that COMT inhibitors prolong the action of levodopa in patients with the "wearing off" phenomenon. The atypical antipsychotic drug clozapine is the treatment of choice for the alleviation of levodopa-induced psychosis. Clozapine also has beneficial effects on tremor and levodopa-induced dyskinesias. Thus, COMT inhibitors and clozapine provide new opportunities for the treatment of patients with longstanding PD and fluctuating responses to levodopa. Experimental evidence in animals suggests that glutamate antagonists have symptomatic and neuroprotective actions in PD. At present, however, only weak antiglutamatergic drugs that have low specificity, such as memantine, amantadine, and budipine are available for clinical studies. Neurotrophic factors, in particular ciliary neurotrophic factor and glial cell line-derived neurotrophic factor, are among the most promising new approaches for neuroprotection in PD. Problems of bioavailability, however, thus far preclude their use in patients. An improved understanding of the pathophysiology of parkinsonism has led to a renaissance of stereotaxic surgery. The subthalamic nucleus is a potential new target for surgical intervention. Ventroposterior pallidotomy has been shown to improve not only rigidity and tremor, but also akinesia. The techniques for thalamic interventions have been refined by introducing chronic thalamic stimulation. Future transplantation approaches to PD will focus on the use of genetically modified cells carrying genes for dopamine-synthesizing enzymes or neurotrophic factors. Animal studies show the feasibility of in vivo gene transfer for the treatment of PD.

Animals↗

Nystagmus.

This article reviews some of the past year's important papers, with emphasis on early onset and acquired neurological nystagmus. Advances in understanding the mechanisms of suppression of oscillopsia, the evolution of nystagmus, and the treatment of periodic alternating nystagmus and of nystagmus in albinism have been made in early-onset nystagmus. Successful pharmacological treatment for acquired neurological nystagmus has been demonstrated with the gamma aminobutyric acid agonist gabapentin and with memantine, a glutamate antagonist.

Excitatory Amino Acid Antagonists↗

The cholinesterase inhibitors.

Dementia is a serious and growing problem that presents enormous burdens to patients, their families, and national healthcare systems throughout the world. In the United States, there are currently two classes of psychopharmacologic agents approved for the treatment of Alzheimer's disease: the cholinesterase inhibitors, which are approved for use in patients with mild to moderate disease, and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which is approved for treatment of moderate to severe illness. Three cholinesterase inhibitors are in general clinical use, each of which has a distinct pharmacokinetic, pharmacodynamic, and side-effect profile. In addition, there is growing research and clinical evidence of the effectiveness of the cholinesterase inhibitors in patients who are in the more advanced stages of Alzheimer's dementia as well as in patients with other forms of dementia.

Journal Article↗

Vascular cognitive impairment.

Cerebrovascular disease is increasingly recognized as a common cause of cognitive impairment and dementia in later life either alone or in conjunction with other pathologies, most often Alzheimer disease (AD). Progress in the field has been limited by difficulties in terminology; for example, use of the term dementia necessitates the presence of memory impairment, which is the norm in AD, but not in cognitive disorders associated with cerebrovascular disease. The term vascular cognitive impairment (VCI) has been proposed as an umbrella term to recognize the broad spectrum of cognitive, and indeed behavioral, changes associated with vascular pathology. It is characterized by a specific cognitive profile with predominantly attentional and executive impairments together with particular noncognitive features (especially depression) and a relatively stable course, at least in clinical trial populations. Subtypes of VCI have been proposed based on clinical and pathologic differences, including cortical, subcortical, strategic infarct, hypoperfusion, hemorrhagic, and mixed (with AD) type. Diagnostic criteria are emerging but require refinement and validation, especially for mixed dementias. There remain fundamental gaps in our understanding of pathophysiology, predicting prognosis and outcome, and in therapeutics. Clinical trials to date, mainly in populations selected using currently accepted criteria for vascular dementia, have generally been disappointing. A relatively modest cognitive benefit of agents such as nimodipine, memantine, and cholinesterase inhibitors has been reported, although the clinical significance of these improvements remains to be established. Further studies, focusing on particular subtypes of VCI and involving subjects at earlier stages of the disease, are required. The aim of this article is to review the concept of VCI in terms of the evidence base surrounding diagnosis, clinical features, pathophysiology, and management and to make some recommendations regarding further research in the area. It begins with a discussion on the historical background, which is important to understand the different and somewhat confusing terminology that currently exists in the field.

Aged↗

Pharmacological advances in the treatment of neuro-otological and eye movement disorders.

PURPOSE OF REVIEW: First, to describe the current pharmacological treatment options for peripheral and central vestibular, cerebellar, and ocular motor disorders. Second, to identify vestibular and ocular motor disorders in which treatment trials are warranted. RECENT FINDINGS: Peripheral vestibular disorders: In vestibular neuritis recovery of the peripheral vestibular function can be improved by treatment with oral corticosteroids. In Ménière's disease treatment strategies range from low-salt diet, diuretics, and betahistine, to intratympanic injection of corticosteroids or gentamicin. Unfortunately most of the trials on Ménière's disease do not have an up-to-date design. In bilateral vestibulopathy steroids do not seem to improve vestibular function.Central vestibular, cerebellar, and ocular motor disorders: The use of aminopyridines introduced a new therapeutic principle in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA2). These potassium channel blockers presumably increase the activity and excitability of cerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells on vestibular and cerebellar nuclei. A few studies showed that baclofen improves periodic alternating nystagmus, and gabapentin and memantine, pendular nystagmus. Many other eye movement disorders, however, such as ocular flutter, opsoclonus, central positioning, or see-saw nystagmus are still difficult to treat. SUMMARY: Although progress has been made in the treatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA2, state-of-the-art trials must still be performed on many vestibular and ocular motor disorders, namely Ménière's disease, bilateral vestibulopathy, vestibular paroxysmia, vestibular migraine, and many forms of central eye movement disorders.

Animals↗

Anticholinesterase toxicity and oxidative stress.

Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.

Animals↗

HIV-1 envelope protein gp120 potentiates NMDA-evoked noradrenaline release by a direct action at rat hippocampal and cortical noradrenergic nerve endings.

Exposure of rat or human neocortical or hippocampal tissue to glutamate receptor agonists elicits as Ca(2+)-dependent, exocytotic-like release of previously accumulated [3H]noradrenaline through activation of both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors colocalized on the noradrenergic axon terminals. Here we show that the NMDA (100 microM)-evoked release of [3H]noradrenaline from superfused thin layers of isolated rat hippocampal or cortical nerve endings was potentiated when the human immunodeficiency virus type 1 coat protein gp120 was added to the superfusion medium concomitantly with NMDA. The effect of gp120 (10 pM to 3 nM) on the 100 microM NMDA-evoked release of [3H]noradrenaline was concentration-dependent; the maximal effect (approximately 140% potentiation) was reached at 100 pM of gp120. The protein was inactive on its own. The [3H]noradrenaline release evoked by NMDA (100 microM)+gp120 (100 pM) was prevented by classical NMDA receptor antagonists, as well as by 10 microM memantine. Neither the release evoked by NMDA nor that elicited by NMDA+gp120 was sensitive to the nitric oxide synthase inhibitor NG-nitro-L-arginine, suggesting no involvement of nitric oxide. The [3H]noradrenaline release elicited by 100 microM AMPA was unaffected by gp120. The protein potentiated the release evoked by 100 microM glutamate; the effect of 100 pM gp120 was quantitatively identical to that of 1 microM glycine, with no apparent additivity between gp120 and glycine. The antagonism by 1 microM 7-chloro-kynurenic acid of the NMDA-induced [3H]noradrenaline release was reversed by glycine or gp120.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Pain in diabetic neuropathy case study: whole patient management.

Painful diabetic peripheral neuropathy (DPN) is described as a superficial burning pain associated with other positive and/or negative sensory systems affecting the feet and lower extremities. It is one of the most commonly encountered neuropathic pain syndromes in clinical practice. Presentation may be complicated by multiple symptoms, including allodynia, hyperalgesia, other less well characterized dysesthesias, and serious disruption of social functioning and mood. Peripheral nerve function may deteriorate, which can account for patient reports of diminution of pain after several years of follow-up. Although current understanding holds that the pathogenesis of DPN is multifactorial in nature, long-term studies have shown that rigorous glycemic control is the most relevant factor in clinical intervention and can delay the onset and slow the progression of neuropathy. In addition to glycemic control, other treatment approaches must be examined in order to restore quality of life for patients experiencing painful DPN. Differential diagnosis is required to isolate DPN from other unexplained chronic pain. Neurologic testing in painful DPN is an area of active research and is used to assess the neurologic pathways giving rise to the pain, the degree of neural damage and the degree of subclinical damage. Current treatment options for DPN include mainly antidepressants and anticonvulsants, with other agents such as tramadol, dextromethorphan and memantine being employed or studied. This review article includes a case study of a patient with painful DPN to demonstrate the current management strategies for this neuropathic pain syndrome.

Adult↗

Characteristics of [14C]guanidinium accumulation in NG 108-15 cells exposed to serotonin 5-HT3 receptor ligands and substance P.

In the presence of substance P (SP; 10 microM), serotonin (5-HT; 1 microM) triggered a cation permeability in cells of the hybridoma (mouse neuroblastoma x rat glioma) clone NG 108-15 that could be assessed by measuring the cell capacity to accumulate [14C]guanidinium for 10-15 min at 37 degrees C. In addition to 5-HT (EC50 0.33 microM), the potent 5-HT3 receptor agonists 2-methyl-serotonin, phenylbiguanide, and m-chlorophenylbiguanide, and quipazine, markedly increased [14C]guanidinium uptake in NG 108-15 cells exposed to 10 microM SP. In contrast, 5-HT3 receptor antagonists prevented the effect of 5-HT. The correlation (r = 0.97) between the potencies of 16 different ligands to mimic or prevent the effects of 5-HT on [14C]guanidinium uptake, on the one hand, and to displace [3H]zacopride specifically bound to 5-HT3 receptors on NG 108-15 cells, on the other hand, clearly demonstrated that [14C]guanidinium uptake was directly controlled by 5-HT3 receptors. Various compounds such as inorganic cations (La3+, Mn2+, Ba2+, Ni2+, and Zn2+), D-tubocurarine, and memantine inhibited [14C]guanidinium uptake in NG 108-15 cells exposed to 5-HT and SP, as expected from their noncompetitive antagonistic properties at 5-HT3 receptors. However, ethanol (100 nM), which has been reported to potentiate the electrophysiological response to 5-HT3 receptor stimulation, prevented the effects of 5-HT plus SP on [14C]guanidinium uptake. The cooperative effect of SP on this 5-HT3-evoked response resulted neither from an interaction of the peptide with the 5-HT3 receptor binding site nor from a possible direct activation of G proteins in NG 108-15 cells. Among SP derivatives, [D-Pro9]SP, a compound inactive at the various neurokinin receptor classes, was the most potent to mimic the stimulatory effect of SP on [14C]guanidinium uptake in NG 108-15 cells exposed to 5-HT. Although the cellular mechanisms involved deserve further investigations, the 5-HT-evoked [14C]guanidinium uptake appears to be a rapid and reliable response for assessing the functional state of 5-HT3 receptors in NG 108-15 cells.

Animals↗