Comparison of paired-pulse facilitation of AMPA and NMDA synaptic currents in the lateral amygdala.

Stimulating thalamic fibers exiting from the internal capsule evokes a glutamatergic excitatory postsynaptic current (EPSC) recorded in vitro with patch electrodes in neurons of the rat lateral amygdala (LA). The purpose of this study is to compare paired-pulse facilitation (PPF), a form of short-term synaptic plasticity, of AMPA and NMDA receptor-mediated EPSCs. Analysis of PPF at this synapse is important since, in fear-conditioned animals, PPF reflects an enhanced transmitter release but the amplitude of only AMPA EPSCs is facilitated. PPF magnitude of the composite EPSC is a result of both AMPA and NMDA receptor activation; however, the characteristics of AMPA and NMDA PPF are dissimilar. Specifically, the NMDA EPSC shows greater PPF (NMDA PPF) than does the AMPA EPSC whether measuring the NMDA PPF magnitude in an AMPA antagonist/Mg(2+)-free solution or by subtracting the AMPA EPSC from the composite EPSC in normal Mg(2+). Presynaptic NMDA receptors neither influence AMPA PPF nor account for the difference between the NMDA and AMPA PPF. Another difference was that removal of inhibitory tone enhanced AMPA PPF, while it had mixed effects on NMDA PPF. Furthermore, AMPA PPF was independent of stimulus intensity and postsynaptic voltage, unlike the NMDA PPF. Another dissimilarity was that the amplitudes of pairs of AMPA EPSCs were not correlated, suggesting presynaptic mechanisms. In contrast, NMDA PPF was dependent on stimulus intensity and postsynaptic voltage and the amplitudes of paired NMDA EPSCs had a positive correlation, suggesting a postsynaptic influence. Both AMPA and NMDA PPF were influenced by GABA inhibition and this could be a factor in the magnitude disparity. These data show that AMPA and NMDA PPF have different characteristics and contribute to the composite PPF in the thalamic to lateral amygdala pathway.

Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala.

G-protein-coupled metabotropic glutamate receptors (mGluRs) are being implicated in various forms of neuroplasticity and CNS disorders. This study examined whether the sensitivities of mGluR agonists are modulated in a distinct fashion in different models of synaptic plasticity, specifically, kindling and chronic cocaine treatment. The influence of kindling and chronic cocaine exposure in vivo was examined in vitro on the modulation of synaptic transmission by group II and III metabotropic glutamate receptors using whole cell voltage-clamp recordings of central amygdala (CeA) neurons. Synaptic transmission was evoked by electrical stimulation of the basolateral amygdala (BLA) and ventral amygdaloid pathway (VAP) afferents in brain slices from control rats and from rats treated with cocaine or exposed to three to five stage-five kindled seizures. This study shows that after chemical stimulation with chronic cocaine exposure or after electrical stimulation with kindling the receptor sensitivities for mGluR agonists are altered in opposite ways. In slices from control rats, group II agonists, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1) and (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), depressed neurotransmission more potently at the BLA-CeA than at the VAP-CeA synapse while group III agonist, L(+)-2-amino-4-phosphonobutyrate (LAP4), depressed neurotransmission more potently at the VAP-CeA synapse than at the BLA-CeA. These agonist actions were not seen (were absent) in amygdala neurons from chronic cocaine-treated animals. In contrast, after kindling, concentration response relationships for LCCG1 and LAP4 were shifted to the left, suggesting that sensitivity to these agonists is increased. Except at high concentrations, LCCG1, LY354740, and LAP4 neither induced membrane currents nor changed current-voltage relationships. Loss of mGluR inhibition with chronic cocaine treatment may contribute to counter-adaptive changes including anxiety and depression in cocaine withdrawal. Drugs that restore the inhibitory effects of group II and III mGluRs may be novel tools in the treatment of cocaine dependence. The enhanced sensitivity to group II and III mGluR agonists in kindling is similar to that recorded at the lateral to BLA synapse in the amygdala where they reduce epileptiform bursting. These findings suggest that drugs modifying mGluRs may prove useful in the treatment of cocaine withdrawal or epilepsy.

Epileptogenesis up-regulates metabotropic glutamate receptor activation of sodium-calcium exchange current in the amygdala.

Postsynaptic metabotropic glutamate (mGlu) receptor-activated inward current mediated by Na(+)-Ca(2+) exchange was compared in basolateral amygdala (BLA) neurons from brain slices of control (naïve and sham-operated) and amygdala-kindled rats. In control neurons, the mGlu agonist, quisqualate (QUIS; 1-100 microM), evoked an inward current not associated with a significant change in membrane slope conductance, measured from current-voltage relationships between -110 and -60 mV, consistent with activation of the Na(+)-Ca(2+) exchanger. Application of the group I selective mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine [(S)-DHPG; 10-1000 microM] or the endogenous agonist, glutamate (10-1000 microM), elicited the exchange current. QUIS was more potent than either (S)-DHPG or glutamate (apparent EC(50) = 19 microM, 57 microM, and 0.6 mM, respectively) in activating the Na(+)-Ca(2+) exchange current. The selective mGlu5 agonist, (R, S)-2-chloro-5-hydroxyphenylglycine [(R,S)-CHPG; apparent EC(50) = 2. 6 mM] also induced the exchange current. The maximum response to (R, S)-DHPG was about half of that of the other agonists suggesting partial agonist action. Concentration-response relationships of agonist-evoked inward currents were compared in control neurons and in neurons from kindled animals. The maximum value for the concentration-response relationship of the partial agonist (S)-DHPG- (but not the full agonist- [QUIS or (R,S)-CHPG]) induced inward current was shifted upward suggesting enhanced efficacy of this agonist in kindled neurons. Altogether, these data are consistent with a kindling-induced up-regulation of a group I mGlu-, possibly mGlu5-, mediated responses coupled to Na(+)-Ca(2+) exchange in BLA neurons.

Excitatory and inhibitory amino acids involved in the high pressure nervous syndrome: Epileptic activity and hyperexcitability.

Epileptic-like activities are observed in mammals exposed to ambient pressures higher than 20 atm. These symptoms are part of the so called "high pressure nervous syndrome". In the search of the cellular mechanisms of this syndrome, we examined synaptic and intrinsic pressure-induced changes in the in vitro hippocampal slice preparation in the rat. We found that pressure (80 atm) depresses the efficiency of excitatory amino acidergic and inhibitory GABA synaptic transmissions, while it increases the intrinsic excitability of the CA1 pyramidal cells and induced multiple population spikes. The changes were associated with a selective increase in the effects of NMDA andL-homocysteate, while the postsynaptic effects of GABA was unchanged. NMDA antagonists and GABA synergistic drugs antagonized the pressure-induced hyperexcitability and multiple population spikes. These results suggest that pressure would decrease transmitter release at the tested excitatory and inhibitory synapses and would facilitate NMDA postsynaptic mechanisms. Thus, changes in both NMDA and GABA processes might be involved in the development of the high pressure nervous syndrome.

Excitatory and inhibitory amino-acidergic determinants of the pressure-induced neuronal hyperexcitability in rat hippocampal slices.

In a previous study we found that the intrinsic excitability of the hippocampal CA1 pyramidal cells increased under helium pressure (80 bar). We presently show that drugs inhibiting gamma-aminobutyric acid (GABA) uptake or facilitating GABA binding partially reversed the pressure-induced hyperexcitability of the CA1 pyramidal cells. When these drugs were simultaneously applied with 2-D,L-aminophosphonovaleric acid, a specific antagonist of N-methyl-D-aspartate (NMDA) receptors, the effect of pressure on the neuronal excitability was nearly abolished. These results suggested that the observed pressure-induced hyperexcitability of pyramidal cells resulted from reduced efficiency of GABA transmission and facilitated excitation mediated by NMDA receptors.

Decrease of recurrent and feed-forward inhibitions under high pressure of helium in rat hippocampal slices.

The effect of high helium pressure on inhibitory synaptic transmission was studied in rat hippocampal slices with extracellular recordings. Both feed-forward and recurrent GABAergic inhibition were tested in the CA1 region with paired-pulse stimulation paradigms. The efficiency of both types of inhibition decreased under high pressure (80 atm). However, the depression of synaptic and antidromic field potentials induced by perfusion of GABA or muscimol were not significantly affected by pressure. High pressure induced hyperexcitability of CA1 pyramidal cells. This effect was reduced by the application of 2-aminophosphonovalerate or GABA. The present results suggest that: (1) high pressure reduces the efficiency of the GABAergic inhibitory transmission but does not affect the sensitivity of GABAA receptors; (2) two different processes (reduction of GABAergic inhibition and facilitation of N-methyl-D-aspartate-mediated excitation) might be a direct consequence of the change in the voltage-sensitive ion channels under high pressure and might be involved in the development of the pressure-induced hyperexcitability of CA1 pyramidal cells.

The influence of helium pressure on the reduction induced in field potentials by various amino acids and on the GABA-mediated inhibition in the CA1 region of hippocampal slices in the rat.

In a previous study, it was shown that helium pressure depressed excitatory synaptic transmission mediated by the Schaffer-commissural afferents and increased the intrinsic excitability of pyramidal cells, in the CA1 region of hippocampal slices in the rat. In the present study, the neurochemical bases of these changes was investigated. Various excitatory amino acids were studied under normal and up to 80 atm of helium. At normal pressure, the amino acids tested induced a decrease in the field excitatory postsynaptic potential (EPSP) and antidromic field potential of CA1 pyramidal cells. These changes probably resulted from the well known depolarizing effect of the compounds. Quisqualate is supposed to activate the synaptic receptors of the pathway tested. Since the effect of this amino acid and other agonists were not significantly affected by helium pressure, it is suggested that the depressed hippocampal synaptic potentials under pressure did not result from reduced sensitivity of synaptic receptors. On the other hand, helium pressure enhanced the action of N-methyl-D-aspartate (NMDA) and depressed the GABA-mediated inhibition of CA1 pyramidal cells. Given that the excitability of these neurones is modulated by NMDA-related events and GABA inhibition, these results indicate that both neurochemical systems were probably involved in the helium pressure-induced hyperexcitability of the cells studied.

Helium pressure potentiates the N-methyl-D-aspartate- and D,L-homocysteate-induced decreases of field potentials in the rat hippocampal slice preparation.

We examined the influence of helium pressure on the depression induced by various excitatory amino acids in CA1 hippocampal field potentials. The effects of quisqualate, L-glutamate, L-aspartate and kainate were not significantly affected by helium pressure, while those of N-methyl-D-aspartate and D,L-homocysteate were enhanced. These findings suggest that helium pressure specifically increased the sensitivity of the N-methyl-D-aspartate receptor type in the hippocampus. Other hypotheses are discussed.

Evoked potential changes in rat hippocampal slices under helium pressure.

High pressures of helium affect the physiology of the central nervous system in animals and humans. We examined these effects in rat hippocampal slices. The in vitro preparation displayed a reversible reduction in postsynaptic and antidromic field potentials of CA1 pyramidal cells, but no significant change in the amplitude of the afferent volley. Although the subliminal synaptic response of CA1 neurons was depressed, the ability of these cells to produce population spikes was enhanced. These changes resembled those previously found in vivo in the rat hippocampus. The present results support the hypothesis of a helium pressure-induced depolarization of hippocampal neurons. Other possible mechanisms are discussed.