European Journal of Neuroscience, 1991, Vol.3, No.11, pp.1104-1111
The metabotropic excitatory amino acid receptor agonist trans-(+)-1-amino-cyclopentane-1,3-dicarboxylate (t-ACDP) was applied to rat ventrobasal thalamic neurons by iontophoresis. This agonist typically evoked an excitatory response which was slower in onset and of longer duration than responses to the other excitatory amino acid agonists, N-methyl-aspartate, kainate or (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. Responses to t-ACPD were resistant to the excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline- 2,3-dione, 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid and kynurenate. These results suggest that t-ACPD may exert its effects via the so-called 'metabotropic' excitatory amino acid receptor. The putative antagonists at this receptor, D-2-amino-4-phosphono-butyrate (D-AP4), L-2-amino-4-phosphono-butyrate (L-AP4) and L-2-amino-3-phosphono-propionate (L-AP3), were able to reduce responses to t-ACPD under certain circumstances. However, such antagonism was always accompanied by similar reductions in excitatory responses to other agonists. These non-selective effects would appear to limit the usefulness of AP4 and AP3 as antagonists of t-ACPD.
Neuroscience, 1991, Vol.44, No.2, pp.277-286
The membrane potential responses and firing patterns of rat thalamic neurons evoked by iontophoretically applied excitatory amino acids were recorded in vivo. All excitatory amino acids, including N-methyl-D,L-aspartate, evoked a membrane depolarization and a repetitive, regular pattern of action potential firing in the thalamus. Both non-nociceptive and nociceptive thalamic neurons responded to all agonists tested. Iontophoretic application of magnesium ions selectively antagonized responses to N-methyl-D,L-aspartate but did not convert the repetitive firing pattern into a burst firing pattern. In contrast, in the hippocampus, N-methyl-D,L-aspartate evoked a burst pattern of action potential firing associated with rhythmic depolarizing membrane potential shifts, similar to those seen by other workers in the hippocampus and in other brain regions. These findings are discussed in relation to the possibility that the regular firing pattern of spikes evoked by excitatory amino acids in the thalamus is primarily determined by the intrinsic membrane properties of thalamic neurons.
European Journal of Neuroscience, 1991, Vol.3, No.3, pp.296-300
Excitatory amino acid neurotransmitters, such as L-glutamate, act at several receptors in the brain, which are sometimes referred to as N-methyl-D-aspartate (MDA) and non-NMDA receptors. Extensive in vitro work indicated that both NMDA receptors and non-NMDA receptors contribute to excitatory postsynaptic potentials (epsps). The contribution of NMDA receptors to epsps in vivo under physiological conditions is, however, almost unknown. The receptors that mediate the epsps evoked in thalamic relay cell by natural stimulation of sensory afferents have been investigated in anaesthetized rats, and we report the first pharmacological characterization of an excitatory amino acid receptor-mediated epsp in vivo involving both non-NMDA receptors and, in particular, NMDA receptors.
Neuroscience, 1990, Vol.34, No.2, pp.273-280
The N-methyl-D-aspartate receptor antagonist 3-((+)2- carboxypiperazin-4-yl)-propyl-1-phosphonic acid and the non-N- methyl-D-aspartate receptor antagonist, 6-cyano-7- nitroquinoxaline-2,3-dione have been iontophoretically applied to cells in the cat dorsal lateral geniculate nucleus and their effects on the visual response compared. The objective was to examine the possibility of both N-methyl-D-aspartate and non-N- methyl-D-aspartate receptors being involved in the transfer of the retinal input to X and Y cells in the dorsal lateral geniculate nucleus. The results show that selective blockade of either N-methyl-D-aspartate receptors or non-N-methyl-D- aspartate receptors can block the visual response of both X and Y cells. Overall, the most potent reduction of visual responses across the population of cells studied were obtained with the N-methyl-D-aspartate receptor antagonist with X cells showing a slightly greater reduction on average (80%) than Y cells (66%). The relatively smaller overall reductions in visual responses obtained with the non-N-methyl-D-aspartate receptor blockade reflected the lower levels of blockade that were compatible with selectivity using iontophoretic applications of 6-cyano-7- nitroquinoxaline-2,3-dione. It is concluded that N-methyl-D- aspartate and non-N-methyl-D-aspartate receptors are critically involved in the visual response of both 'on' and 'off' centre X and Y cells.
Neuroscience Letters, 1990, Vol.110, No.3, pp.297-302
The responses of single thalamic neurones to noxious thermal stimulation were recorded in anaesthetized rats. The selective N-methyl-D-aspartate (NMDA) receptor antagonist, 3-((+/-)-2- carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), antagonised nociceptive responses when ejected iontophoretically with currents which produced selective antagonism at NMDA receptors. In contrast, the non-NMDA excitatory amino acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) had little or no effect on nociceptive responses, although it was able to reduce responses to non-nociceptive mechanoreceptor input. These results show that there is substantial NMDA receptor involvement in thalamic nociceptive responses, and that the contribution of CNQX-sensitive non-NMDA receptors to these responses is not extensive. Furthermore, it appears that nociceptive and non-nociceptive input to the thalamus have distinct synaptic pharmacologies.
Experimental Brain Research, 1989, Vol.77, No.3, pp.646-652
Sensory synaptic responses of rat ventrobasal thalamus neurones were challenged with iontophoretic applications of the excitatory amino acid antagonists CNQX and CPP. CNQX, applied with currents which were selective for non-NMDA receptors, antagonised responses of VB neurones to both 10 ms and 2000 ms air jet stimulation of the peripheral receptive field. In contrast, CPP only antagonised the latter type of response. These results suggest a differential involvement of excitatory amino acid receptors in sensory synaptic transmission to the ventrobasal thalamus, with an initial synaptic component being mediated by non-NMDA receptors (including kainate receptors), and a further NMDA receptor-mediated component being manifested upon maintained sensory stimulation. The expression of this latter component appears to be largely dependent upon the integrity of the non-NMDA receptor-mediated component.
Brain Research, 1989, Vol.481, No.2, pp.403-406
The effects of iontophoretically applied glycine and D-serine upon responses of rat ventrobasal thalamus neurones to excitatory amino acids and sensory stimulation were investigated. Glycine inhibited excitatory responses to kainate, quisqualate and N-methyl-aspartate (NMA). Strychnine antagonised inhibitory responses to glycine, but in only a small number (2/7) of cases did such an antagonism reveal a facilitatory action of glycine on NMA responses. D-serine inhibited responses of almost all neurones to either kainate or quisqualate, but enhanced responses to NMA on nearly half of the tested neurones, whilst having a weaker inhibitory action on the remainder. It is thus possible that D-serine has a dual action: (i) a facilitation of N-methyl-D-aspartate (NMDA) receptor-mediated responses and (ii) a non-selective inhibitory action.
Neuroscience, 1989, Vol.28, No.1, pp.17-26
Extracellular single neuron recordings were made in the ventrobasal thalami of anaesthetized rats and cats. Physiological stimulation of vibrissa and hair follicle afferents was performed with an air jet (10-20 ms duration) directed at a single vibrissa or small area of hairy skin. Paired conditioning and test air jets delivered to the excitatory portion of receptive fields revealed inhibition of the response of ventrobasal thalamic neurons to test stimuli following the excitatory response to the conditioning stimulus. Such inhibitions could last up to 500 ms. An increase in neuronal excitability was sometimes observed following this inhibitory period. In addition, it was possible to produce inhibition without an excitatory response using conditioning stimuli delivered adjacent to the excitatory receptive field. Iontophoretic application of bicuculline methochloride, with currents that were adequate to antagonize iontophoretically applied GABA, was found to reduce the inhibition of test responses evoked by conditioning stimuli in almost all of the neurons studied. In most cases, no excitatory responses to conditioning stimuli directed outside the original excitatory receptive field were revealed by application of the GABA antagonist. In rats, bicuculline also led to a decrease in the post-inhibitory excitation, whereas in cats the converse appeared to be the case. These results suggest that GABAergic transmission may underlie inhibitory responses of cat and rat ventrobasal thalamus neurons to physiological stimulation of somatosensory afferents. Furthermore, removal of such inhibition does not appear to reveal excitatory inputs from outside of the original excitatory receptive field.
Journal of Physiology, 1987, Vol.391, pp.499-510
1. Extracellular single-neurone recordings were made in the ventrobasal thalamus (v.b.t.) of urethane-anaesthetized rats with multi-barrel ionophoretic electrodes in order to test the hypothesis that excitatory amino acid receptors are involved in the responses of these neurones to stimulation of sensory afferents. 2. Responses of neurones to either physiological stimulation of hair and vibrissa follicle sensory afferents and to ionophoretically applied excitatory amino acids were challenged with the antagonists D-2-amino-5-phosphonovalerate (APV), kynurenate and gamma-D-glutamylaminomethyl sulphonate (GAMS). 3. In agreement with previous findings in other brain areas, ionophoretically applied APV was found to selectively antagonize responses of v.b.t. neurones to N-methylaspartate (NMA), whereas GAMS was found to be moderately kainate selective. Kynurenate was found to be relatively non-selective. 4. Responses of neurones to short-duration (10-20 ms) physiological stimulation of afferents were resistant to APV when this antagonist was applied with NMA-selective ionophoretic currents. In contrast, these APV currents were adequate to antagonize responses to maintained physiological stimulation. 5. The broad spectrum excitatory amino acid antagonist kynurenate was found to block synaptic responses of v.b.t. neurones to both short-duration and maintained stimuli when it was applied with currents which were sufficient to reduce responses to ionophoretic quisqualate. 6. GAMS was found to selectively block kainate responses in a proportion of the neurones tested. In such cases, there was little effect of the antagonist on the responses evoked by either short-duration or maintained sensory stimuli. 7. It is concluded that excitatory amino acid receptors of both the NMDA and non-NMDA type are involved in the synaptic responses of v.b.t. neurones to sensory afferent stimulation, and that the apparent synaptic pharmacology depends on the mode of stimulation of the afferent pathway.
Nature, 1986, Vol.322, No.6076, pp.263-265
Excitatory amino acids such as L-glutamate and L-aspartate are well established as neurotransmitter candidates in the mammalian central nervous system, and three types of receptor for these substances have been proposed, characterized by the agonists N-methyl-D-aspartate (NMDA), kainate and quisqualate. All these receptors have been suggested to have synaptic roles in excitatory transmission in the brain. Here I demonstrate that NMDA receptors play a crucial role in the observed response of ventrobasal thalamus (VB) neurones to natural stimulation of somatosensory afferents, but do not appear to be responsible for the short-latency excitation seen on electrical stimulation of the afferents, which is apparently mediated by excitatory amino-acid receptors of the non-NMDA type. This result indicates an involvement of both NMDA and non-NMDA receptors in the responses of VB neurones to stimulation of somatosensory afferents, depending on the mode of stimulation of the pathway.
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