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PubMedDate not supplied

Neurotransmitter control of growth hormone secretion in children after cranial radiation therapy.

Cranial radiation for childhood cancer can cause growth hormone deficiency (GHD), usually due to hypothalamic rather than pituitary dysfunction. To investigate whether this hypothalamic dysfunction is secondary to altered neurotransmitter input from other brain centers, we used neurotransmitter-excitatory substances to study the GH secretory response in 17 children who had received 12 to 60 Grey (Gy) to the cranium and 40 short children with normal endocrine function. As expected, the irradiated children had decreased mean GH secretion in response to insulin-induced hypoglycemia and arginine infusion, and decreased mean 24 hour GH concentrations, compared to the control group. In contrast, the two groups had similar GH secretory responses to GHRH stimulation and somatostatin suppression. Assessment of neurotransmitter pathways in the irradiated children revealed significantly lower mean peak GH concentrations in response to 5 of the 6 substances tested compared to control children: alpha-adrenergic stimulation (clonidine), beta-adrenergic blockade (propranolol), cholinergic stimulation, dopaminergic stimulation (L-dopa), and GABA-ergic stimulation (valproic acid). Results of serotonergic stimulation (L-tryptophan) were not statistically significant. Eleven patients who had abnormal GH secretion underwent 4 or more tests with neurotransmitter-stimulatory agents; 3 patients had peak GH concentrations of < 2.5 micrograms/l to all tests, whereas 4 patients had a peak GH concentration of > or = 7 micrograms/l to one or more tests but < 5 micrograms/l to one or more other tests. These observations suggest that radiation damage may sometimes spare growth hormone-releasing hormone (GHRH) and somatostatin secretion while affecting neurotransmitter pathways. We postulate that the hierarchy of sensitivity to radiation damage may be hypothalamic and extra-hypothalamic neurotransmitters > hypothalamic GHRH and/or somatostatin secretion > pituitary GH secretion.

Adolescent↗
PubMed1996

Immunophilin regulation of neurotransmitter release.

BACKGROUND: The immunophilins are proteins that mediate actions of immunosuppressant drugs such as FK506 and cyclosporin A by binding to calcineurin, inhibiting its phosphatase activity, and increasing the phosphorylation level of transcription factors required for interleukin 2 formation. Though concentrations in the brain greatly exceed levels in immune tissues, no function has been previously established for nervous system immunophilins. Nitric oxide (NO) has been implicated in neurotransmitter release. FK506 appears to inhibit NO production by maintaining NO synthase in a highly phosphorylated and thereby inactivated state. Accordingly, we examined effects of FK506 and cyclosporin A on neurotransmitter release in PC12 cells treated with nerve growth factor (NGF) and in rat brain striatal synaptosomes. MATERIALS AND METHODS: We monitored effects of immunophilin ligands on [3H]-neurotransmitter release from PC12 cells differentiated with NGF. Rat brain striatal synaptosomes were loaded with radiolabeled transmitters and treated with FK506 or cyclosporin A prior to initiating neurotransmitter release with N-methyl-D-aspartate (NMDA) or potassium depolarization. Striatal synaptosomes were also loaded with 32P-orthophosphate and treated with FK506. 32P-labeled synaptic vesicle proteins were isolated from these synaptosomes in an attempt to relate specific FK506-dependent phosphorylation of vesicle proteins with the effects of FK506 on neurotransmitter release. Identification of proteins targetted by FK506 was made by immunoblot analysis and immunoprecipitation. RESULTS: Low nanomolar concentrations of the immunosuppressant drugs FK506 and cyclosporin A (CsA) inhibit transmitter release from PC-12 cells and from NMDA-stimulated brain synaptosomes. By contrast, the immunosuppressants augment depolarization-induced transmitter release from synaptosomes. Synapsin I, a synaptic vesicle phosphoprotein, displays enhanced phosphorylation in the presence of FK506. CONCLUSIONS: Inhibition of transmitter release in PC-12 cells and NMDA-treated synaptosomes by immunosuppressants may reflect augmented phosphorylation of NO synthase, reducing its catalytic activity. This fits with the requirement of NO for transmitter release in PC12 cells and NMDA-treated synaptosomes. Stimulation by immunosuppressants of transmitter release in potassium depolarized synaptosomes may result from augmented phosphorylation of synapsin I, whose phosphorylation is known to facilitate transmitter release. Thus, immunophilins may modulate release of numerous neurotransmitters both by influencing NO formation and the phosphorylation state of synaptic vesicle-associated proteins.

Acetylcholine↗
PubMed1993

Clinical investigation of monoamine neurotransmitter interactions.

Monoamine neurotransmitter systems are widely thought to be involved in the pathophysiology of affective disorders and schizophrenia and the mechanism of action of antidepressant and antipsychotic drugs. Previous clinical studies have focused on individual monoamine function in isolation, even though a large number of preclinical studies have demonstrated that monoamine neurotransmitter systems interact with one another. In the present paper, preclinical data on monoamine neurotransmitter interactions are reviewed, and two methods for examining monoamine neurotransmitter system interactions in clinical data are presented. One of the best replicated findings in biological psychiatry is that monoamine metabolites in CSF correlate with one another. The degree of correlation may be in part a measure of the degree of interaction between the parent monoamine neurotransmitter systems. Another approach to studying interactions is the use of HVA/5HIAA and HVA/MHPG ratios as an index of interactions between 5HT-DA and NE-DA. When these methods are applied in schizophrenia, patients are found to have decreased monoamine metabolite correlations compared to normal controls. Metabolite correlations increase significantly after antipsychotic treatment, and the HVA/5HIAA and HVA/MPHG ratios also increase, suggesting that neuroleptics may act in part by strengthening interactions between monoamines. BPRS ratings are negatively correlated with HVA/5HIAA and HVA/MHPG so that patients with higher ratios have fewer symptoms, particularly after treatment. These results provide direct experimental support for hypotheses suggesting that interactions between monoamine neurotransmitters are important in schizophrenia. Some of the effects of the atypical neuroleptic, clozapine, on metabolite correlations and ratios are also discussed.

Animals↗
PubMed2005

Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization.

Neurotransmitter transporters are critical for synaptic neurotransmitter inactivation. Transporter inhibitors markedly increase the duration and magnitude of synaptic transmission, underscoring the importance of transporter activity in neurotransmission. Recent studies indicate that membrane trafficking dynamically governs neuronal transporter cell-surface presentation in a protein kinase C-regulated manner, suggesting that transporter trafficking profoundly affects synaptic signaling. However, the molecular architecture coupling neurotransmitter transporters to the endocytic machinery is not defined. Here, we identify nonclassical, distinct endocytic signals in the dopamine transporter (DAT) that are necessary and sufficient to drive constitutive and protein kinase C-regulated DAT internalization. The DAT internalization signal is conserved across SLC6 neurotransmitter carriers and is functional in the homologous norepinephrine transporter, suggesting that this region is likely to be the endocytic signal for all SLC6 neurotransmitter transporters. The DAT endocytic signal does not conform to classic internalization motifs, suggesting that SLC6 neurotransmitter transporters may have evolved unique endocytic mechanisms.

Amino Acid Sequence↗
PubMed1997

Alcohols and neurotransmitter gated ion channels: past, present and future.

The neurotransmitter-gated ion channels form a superfamily of neurotransmitter receptors specialized for recognizing transmitters and rapidly gating ion channels that are contained within the same holoprotein complex. A large body of research indicates that alcohols alter the function of this class of receptor at concentrations relevant to the intoxicating and anesthetic effects of the alcohols. In addition, studies have implicated several types of neurotransmitter-gated channels in intoxicating and anesthetic alcohol actions. All of the neurotransmitter-gated ion channels contain conserved features such as N-terminal ligand binding domains, hydrophobic membrane spanning domains and charged pore-lining domains. However, at least two, and possibly three families of receptors have been identified within the superfamily, including the nicotinic ACh-like receptors, the ionotropic glutamate receptors and the ATP-gated ion channels. This review will begin with a brief overview of the structural features of the different receptors, with an emphasis on comparing and contrasting features of the different families of neurotransmitter-gated channels. The emphasis will be mostly on the nicotinic-like receptors and the iGluRs, since more is known about these receptors than about other types of ligand-activated cation channels. The remainder of the review focuses on the latest studies aimed at determining the mechanism of alcohol actions on this superfamily of receptor-channels as well as the relationship between the molecular structure of these channels and the effects of alcohols on channel function. In addition, emerging directions for future study of these effects of alcohols and possible regions of the protein that may be altered during alcohol exposure are discussed.

Animals↗
PubMed1993

Neurotransmitters as growth regulatory signals: role of receptors and second messengers.

In the adult nervous system, neurotransmitters act as chemical mediators of intercellular communication by the activation of specific receptors and second messengers in postsynaptic cells. This specialized role may have evolved from more primitive functions in lower organisms where these substances were used as both intra- and intercellular signalling devices. This view derives from the finding that a number of 'classical' neurotransmitters are present in primitive organisms and early embryos in the absence of a nervous system, and pharmacological evidence that these substances regulate morphogenetic activities such as proliferation, differentiation, cell motility and metamorphosis. These phylogenetically old functions may be reiterated in the developing nervous system and in the humoral functions of neurotransmitters outside the nervous system. This review will provide evidence for this hypothesis based on the commonality of signal transduction mechanisms used in primitive organisms, early embryos and non-neuronal cells, and relate these relationships to the functions of neurotransmitters in the developing nervous system. This discussion has generally been limited to neurotransmitters where non-neuronal functions have been studied and information regarding the involvement of receptors and second messenger pathways is available.

Animals↗
PubMed1990

Alteration in the function of cerebral neurotransmitter receptors during the establishment of alcohol dependence: neurochemical aspects.

Chronic alcohol treatment induces a variety of effects on the metabolism of neurotransmitters and the function of their receptors. Recent studies on alcohol dependence and/or functional tolerance to alcohol have clearly demonstrated that neurotransmitter-gated and receptor-coupled ion channels, as well as neurotransmitter receptor coupled with intracellular mediator systems, such as phosphatidylinositides and cyclic nucleotide-generating systems, are invariably suppressed during alcohol dependence. Future studies on the central actions of alcohol and on alcohol dependence should therefore be directed at the molecular changes in synaptic membrane-bound components such as neurotransmitter receptors, as well as on neurotransmitter release and relevant membrane-bound enzymes.

Alcoholism↗
PubMed1989

Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain.

THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects. Results from these experiments suggest that chronic exposure to THC does not produce significant alterations in catecholamine or indoleamine neurotransmitter systems or in opiate or GABA receptor systems in the rat brain.

Animals↗
PubMed1984

[Possible functional significance of the simultaneous release of several putative neurotransmitters by the same neuron].

At least three criteria should be fulfilled before it can be concluded that one neurone may use more than one neurotransmitter (or neuromodulator) for synaptic transmission: Such putative neurotransmitters must be located in this particular neurone: They must be released from the neurone under physiological conditions, and: They must exert separately or together pre- and/or post-synaptic effects. Critical analysis of the literature reveals that the coexistence and corelease of neuroactive substances are rarely firmly established. However, more convincing data have been reported on the interaction at the pre- and/or post-synaptic levels between neurotransmitters possibly located in the same neuronal population. Thus, it has been shown that VIP coreleased with acetylcholine from the same parasympathetic fibres can facilitate the interaction of this neurotransmitter with muscarinic receptors on target cells. In contrast, substance P coreleased with serotonin from bulbo-spinal fibres can reduce the effect of the amine on specific presynaptic autoreceptors. The functional significance of such interactions between neurotransmitters coexisting in the same neurone seems extremely important. In particular, they might well be involved in the physiological control of hormone release from the adenohypophysis.

Animals↗
PubMed1993

[Involuntary movement and neurotransmitter systems].

The brain is composed of numerous neurons, and information is chemically transmitted between neurons by neurotransmitters. In other words, the function of the brain is the sum of synaptic transmission phenomena. Therefore, to clarify physiological brain function and pathophysiology of involuntary movements, quantification of both neurotransmitters and receptors are indispensable. In the present paper, changes in neurotransmitters and receptors in the brain of various type of involuntary movements are reviewed. In spite of the fact that changes in neurotransmitter systems are the cardinal pathological lesions in involuntary movements, there is little evidence to support the view that these changes are actually related to the generation of involuntary movements. It is required to summarize all informations from neurotransmitter system analysis, behavioral pharmacology, clinical observations and animal models for clarifying the pathophysiology and developing a better therapeutic strategy against various involuntary movements.

Humans↗
PubMed2002

Forty years of neurotransmitters: a personal account.

All drugs in psychiatry act by influences on neurotransmitter systems. Hence, an appreciation of neurotransmitter disposition helps clarify our understanding of therapeutic actions as well as adverse effects of psychotropic drugs. Moreover, understanding the nuances of neurotransmitters facilitates efforts to develop novel agents. Currently available psychoactive drugs exert their effects through 3 or 4 of the longest-known neurotransmitters. Over the past few decades, up to 100 novel neurotransmitter candidates have been identified, each of them as interesting as traditional biogenic amines. It is likely that totally new classes of therapeutic agents will emerge based on these transmitter molecules.

Animals↗
PubMed1997

Localisation of amino acid neurotransmitters during postnatal development of the rat retina.

We used postembedding immunocytochemistry to determine the localisation of the amino acid neurotransmitters glutamate, gamma-aminobutyrate (GABA), and glycine, potential neurotransmitter precursors (aspartate and glutamine), and taurine in the rat retina during postnatal development. All amino acids investigated were present at birth; however, only the inhibitory neurotransmitters GABA and glycine displayed neuronal localisation. GABA was localised in a sparse population of amacrine cells, and glycine immunoreactivity was found in cells within the ventricular zone that appeared to migrate through the neuroblastic layer. Glutamate labelling was diffuse across the retina until postnatal day (PND) 8. Localisation of glutamine was evident within Müller's cells by PND 6, in agreement with the known age of onset of glutamine synthetase activity. Based on the findings of uptake of radiolabelled glutamate and GABA by PND 8 and changes in immunoreactivity, we propose that Müller's cells evolve at PND 6-8 from their precursor cells, the radial glial cells. Evidence for differences in glutamate turnover in the infant retina was seen on examination of aspartate and glutamine immunoreactivity. Aspartate labelling was weak until PND 11, when ganglion cells and some amacrine cells were labelled. Unlike the mature retina, a large number of amacrine cells were glutamine immunoreactive in the PND 6 retina. One reason for the observed differences in precursor pooling may be a lack of neuronal neurotransmitter release and overall low metabolic activity. We also investigated the response of the developing retina to ischaemic insult to test the physiological hypoxia model of vascular development. Our findings are consistent with the hypothesis that the developing retina has increased tolerance to ischaemic insult. Our findings suggest that, although the retina is morphologically adult like by PND 8, there are differences in neurotransmitter turnover in the immature rat retina.

Amino Acids↗
PubMed1997

Effects of excitatory amino acid antagonists on dendrotoxin-induced increases in neurotransmitter release and epileptiform bursting in rat hippocampus in vitro.

Alpha-dendrotoxin (alpha-DTx), a snake venom toxin which blocks several types of fast-activating voltage-dependent potassium channels, induces limbic seizures and neuronal damage when injected into the brain. The mechanisms underlying these convulsant and neuropathological actions are not fully understood. We have studied the effects of alpha-DTx on neurotransmitter release and electrical activity in rat hippocampal brain slices and the role of excitatory amino acid receptors in mediating these actions of the toxin. alpha-DTx increased the basal release of acetylcholine, glutamate, aspartate, and GABA in a concentration-dependent manner and induced epileptiform bursting in the CA1 and CA3 regions of the slice. The increase in neurotransmitter release was evident during the first 4 min after toxin addition, whereas the bursting appeared after a concentration-dependent delay (20-40 min with 250 nM toxin). The N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and MK-801 had no effect on the frequency or amplitude of dendrotoxin-induced epileptiform bursts, but the non-NMDA antagonists CNQX and DNQX abolished bursting in both CA1 and CA3 within 4-6 min. In contrast, the toxin-induced increases in neurotransmitter release were not blocked by DNQX. This study has demonstrated that, following exposure to alpha-DTx, there is a rapid increase in the release of neurotransmitters which precedes the onset of epileptiform bursting in the hippocampus. Since DNQX abolished the bursting but had no effect on the increase in neurotransmitter release, these results suggest that DNQX blocks alpha-DTx-induced epileptiform activity by antagonism of postsynaptic non-NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed2003

Magnetic resonance spectroscopy of neurotransmitters in human brain.

Magnetic resonance spectroscopy (MRS) is a noninvasive method that permits measurement of the concentration of specific biochemical compounds in the brain and other organ systems in precisely defined regions guided by MR imaging (MRI). Recently, MRS methods have been developed to measure specific neurotransmitters in the brain. More advanced MRS methods have been developed to measure the synthesis rates and turnover of specific neurotransmitters. These turnover rates can provide measures of brain metabolism similar to radioisotope techniques. Also, investigations of the relationship of brain metabolism and specific neurotransmitter systems are now possible using MRS. Here, we review the MRS techniques and studies of neurotransmitters in the human brain. A discussion of the potential use of these techniques in the context of certain pediatric neurotransmitter disorders will be presented.

Brain Chemistry↗
PubMed1985

Coexistence of high-affinity uptake mechanisms for putative neurotransmitter molecules in chick embryo retinal neurons in purified culture.

We report here that high-affinity uptake mechanisms for two or three putative neurotransmitter molecules coexist in many of the neurons present in glia-free, purified neuronal monolayers from chick embryo retina. Replicate cultures were incubated with the tritiated forms of the amino acids gamma-aminobutyric acid (GABA), taurine (TAU) and aspartate (ASP) either individually or in binary or tertiary combinations. Incubation conditions were those typically used to analyze high-affinity uptake mechanisms. At the end of the incubation period the cultures were either lysed in water for measurement of intracellular radioactivity by liquid scintillation counting, or fixed in glutaraldehyde and prepared for autoradiography. Our results indicate that there is coexistence of uptake mechanisms for putative neurotransmitters in retinal cells. Biochemical measurements showed that, at the concentrations used in these experiments, two or more radioactive amino acids could be taken up simultaneously by the cultured populations without extensive inhibition. Moreover, the percentage of cells that appeared autoradiographically labeled in cultures exposed to two or more radioactive amino acid was less than the sum of the percentages of labeled cells when each amino acid was applied individually. Numerical analysis of the autoradiographs was carried out to determine the percentage of cells that could take up only one, only two, or the three putative amino acid neurotransmitters under investigation. This analysis showed that approximately 20% of the neurons have only the mechanism for TAU, whereas very few if any neurons have high-affinity uptake mechanisms for GABA alone or ASP alone. Our experiments have identified populations of cells that take up GABA and TAU (but not ASP) or ASP and TAU (but not GABA). Interestingly, we have not seen any neurons that can take up ASP and GABA and cannot take up TAU, although as many as 50% of the neurons can take up ASP, GABA, and TAU simultaneously. By showing simultaneous uptake of different putative neurotransmitters within individual neurons, our results emphasize the concept that the presence in a given neuron of a high-affinity uptake mechanism for a particular molecule is not a sufficient criterion to assign a neurotransmitter function to that molecule in that neuron.

Absorption↗
PubMed1993

mRNAs coding for neurotransmitter receptors in rabbit and rat visual areas.

Levels of mRNAs encoding neurotransmitter receptors in the visual cortex, lateral geniculate nucleus, and superior colliculus of the rabbit and rat, and properties of the receptors expressed, were studied using Xenopus laevis oocytes. mRNA extracted from these areas was injected into the oocytes, which then acquired functional receptors. Electrical recordings of neurotransmitter-induced membrane currents reflect the relative amounts of mRNAs encoding the corresponding receptors. Receptors to gamma aminobutyric acid (GABA), kainate, glutamate, and serotonin exhibited uniformly high levels of expression, whereas expression of receptors to glycine and N-methyl-D-aspartate was uniformly low. In contrast, the expression of receptors to acetylcholine and substance P was highly non-uniform. Expression of acetylcholine receptors was high in oocytes injected with mRNA from the visual cortex, low for the lateral geniculate nucleus, and very low or absent for the superior colliculus. Conversely, the currents elicited by substance P were large in oocytes injected with superior colliculus mRNA, but were small or absent in oocytes injected with mRNAs from the other regions. Immunohistochemical analysis, at the light and electron microscopic levels, was used to localize choline acetyltransferase, the acetylcholine-synthesizing enzyme, and substance P-containing synaptic boutons in the three visual areas. Their presence closely paralleled the potency of mRNAs coding for acetylcholine and substance P receptors. The ability of rat mRNA, from each visual area, to induce neurotransmitter receptors was similar to that observed in the corresponding rabbit mRNAs. In addition to the marked differential distribution of mRNA encoding neurotransmitter receptors in the visual system, our findings reveal the probable existence of as yet uncharacterized receptors, whose new molecular forms may be revealed by further study. Our results also provide the basic information required for subsequent studies on the effect of monocular deprivation on the expression of neurotransmitter receptors in the visual system.

Animals↗
PubMed1992

Interrelationship between retinal ischaemic damage and turnover and metabolism of putative amino acid neurotransmitters, glutamate and GABA.

Conditions causing a reduction of oxygen availability (anoxia), such as stroke or diabetes, result in drastic changes in ion movements, levels of neurotransmitters and metabolites and subsequent neural death. Currently, there is no clinically available treatment for anoxia induced neural cell death resulting in drastic and permanent central nervous system dysfunction. However, there have been some exciting developments in experimentally induced anoxic conditions where several classes of drugs appear to significantly reduce neural cell death. This report aims to provide the foundations for understanding both the basic mechanisms involved in retinal ischaemic damage and experimental treatments used to prevent such damage. We discuss the normal release, actions and uptake of the fast retinal neurotransmitters, glutamate and GABA, in the vertebrate retina. Immunocytochemistry is used to demonstrate that both glutamate and GABA are found in the macaque retina. Following this is a discussion on how ischaemia may enhance neurotransmitter release or disrupt its uptake, thus causing an increase in extracellular concentration of these neurotransmitters and subsequent neuronal damage. The mechanisms involved in glutamate neurotoxicity are reviewed, because excess glutamate is the likely cause of retinal ischaemic damage. Finally, the mechanisms behind four possible modes of treatment of neurotransmitter toxicity and their advantages and disadvantages are discussed. Hopefully, further research in this area will lead to the development of a rational therapy for retinal, as well as cerebral ischaemia.

Amino Acids↗
PubMedDate not supplied

Both ethanol and ifenprodil inhibit NMDA-evoked release of various neurotransmitters at different, yet proportional potency: potential relation to NMDA receptor subunit composition.

Superfused slices of the rat cerebral cortex and corpus striatum were used to investigate the effect of ethanol on the N-methyl-D-aspartate (NMDA)-evoked release of various [3H]neurotransmitters. To obtain information on the subunit composition of the NMDA receptors involved, the influence of ifenprodil (a drug which preferentially inhibits NMDA receptors containing the NMDAR2B subunit) on the NMDA-evoked [3H]neurotransmitter release was also determined. Ethanol inhibited the NMDA-evoked release of all neurotransmitters investigated in a concentration-dependent manner. Irrespective of the brain region, ethanol was 2.6-5.1 times more potent in inhibiting the release of [3H]noradrenaline, [3H]5-hydroxytryptamine and [3H]GABA than the release of [3H]acetylcholine and [3H]dopamine. Ifenprodil inhibited the NMDA-evoked release of these [3H]neurotransmitters in both brain regions at virtually the same potency order as ethanol. Comparison of the potencies of ethanol and ifenprodil in inhibiting NMDA-evoked [3H]neurotransmitter release revealed an excellent correlation (r = 0.96; P < 0.001). After blockade of the highly ifenprodil-sensitive fraction of the NMDA receptors by 100 nM ifenprodil, the potency of ethanol in inhibiting NMDA-evoked [3H]noradrenaline release in the cerebral cortex was decreased by a factor of 6. In contrast, 100 nM ifenprodil did not affect the potency of ethanol in inhibiting [3H]dopamine and [3H]acetylcholine release in the corpus striatum. It is concluded that ethanol predominantly inhibits NMDA receptors containing a high proportion of the NMDAR2B subunit (as reflected by high sensitivity to ifenprodil), i.e. the NMDA receptors involved in stimulation of noradrenaline, 5-hydroxytryptamine and GABA release. In view of the ability of ifenprodil to interact with ethanol at NMDA receptors, which are important sites of action of ethanol, ifenprodil may be assumed to influence neuronal effects of ethanol in vivo.

Analysis of Variance↗