Effects of ethylenediamine--a putative GABA-releasing agent--on rat hippocampal slices and neocortical activity in vivo

The simple diamine diaminoethane (ethylenediamine, EDA) has been shown to activate GABA receptors in the central and peripheral nervous systems, partly by a direct action and partly by releasing endogenous GABA. These effects have been shown to be produced by the complexation of EDA with bicarbonate to form a carbamate. The present work has compared EDA, GABA and β-alanine responses in rat CA1 neurons using extracellular and intracellular recordings, as well as neocortical evoked potentials in vivo. Superfusion of GABA onto hippocampal slices produced depolarisation and a decrease of field epsps, both effects fading rapidly, but showing sensitivity to blockade by bicuculline. EDA produced an initial hyperpolarisation and increase of extracellular field epsp size with no fade and only partial sensitivity to bicuculline, with subsequent depolarisation, while β-alanine produces a much larger underlying hyperpolarisation and increase in fepsps, followed by depolarisation and inhibition of fepsps. The responses to β-alanine, but not GABA or EDA, were blocked by strychnine. In vivo experiments, recording somatosensory evoked potentials, confirmed that EDA produced an initial increase followed by depression, and that this effect was not fully blocked by bicuculline. Overall the results indicate that EDA has actions in addition to the activation of GABA receptors. These actions are not attributable to activation of β-alanine-sensitive glycine receptors, but may involve the activation of sites sensitive to adipic acid, which is structurally equivalent to the dicarbamate of EDA. The results emphasise the complex pharmacology of simple amines in bicarbonate-containing solutions.

Interactions of glutamate receptor agonists with long-term potentiation in the rat hippocampal slice

Previous work has described the apparent desensitisation of neuronal networks in the rat neocortex to amino acid agonists, following prior exposure several minutes earlier. Since long-term potentiation is believed to involve activation of amino acid receptors, we have now sought to determine whether long-term potentiation can modify the sensitivity of neurones to glutamate receptor agonists in rat hippocampal slices. Responses were measured as the change in population spike or postsynaptic potential (e.p.s.p) size. Two applications of N-methyl-D-aspartate (NMDA), quinolinic acid, teta-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) or kainate, 45 min apart, did not exhibit any apparent desensitisation. However, the induction of long-term potentiation produced a marked loss of sensitivity to quinolinic acid, with smaller effects on NMDA,AMPA and kainate responses. No marked changes were obtained of e.p.s.p. size. In order to localise the cellular sites of these changes, agonist were also applied by microiontophoresis to the cell bodies or dendritic regions of CA1 neurones. Responses to quinolinic acid showed apparent desensitisation at both sites, whereas no decrease was observed in the responses to NMDA and AMPA application. THe induction of long-term potentiation again produced a decrease in the size of responses to NMDA and AMPA. Inhibition of nitric oxide (NO) synthase prevented the long-term potentiation-induced loss of responsiveness to NMDA, but not AMPA, implying a role for NO in the loss of NMDA sensitivity. Recordings of single cell activity during the iontophoretic application of agonists and induction of long-term potentiation showed that responses to NMDA were often suppressed to a greater extent that to quinolinic acid. The results indicate that long-term potentiation showed that responses to NMDA were often suppressed to a greater extent than to quinolinic acid. The results indicate that long-term potentiation can modify the sensitivity of hippocampal neurones to glutamate receptor agonists, and that differences exist in the pharmacology of NMDA and quinolinic acid (AU)

The ¢ ligand 1, 3-di-o-tolylguanidine depresses amino acid-induced exitation non-selectively in rat brain

The ¢ ligand 1, 3-di-o-tolylguanidine (DTG) has been applied by microiontophoresis to neurones in the rat hippocampal slice and to neurones in the neocortex and hippocampus of rats anaesthetised with urethane. DTG depressed the excitatory responses of cells to both N-methyl-D-aspartate (NMDA) and quisqualate on a majority of the units tested, in no case causing an enhancement. Haloperidol had no consistent effect of its own and did not prevent the depressant effects of DTG. It is concluded that in the preparations used, DTG did not selectively modify neuronal sensitivity to NMDA (AU)