High potency of the orally-active NMDA-receptor antagonist CGP 40 116 in inhibiting excitatory postsynaptic potentials of rat basolateral amygdala neurones in vitro

Conventional intracellular recordings were used to monitor postsynaptic potentials of basolateral amygdala neurones (BLA) in brain slices comprising the BLA, the entorhinal cortex (EC) and the hippocampus, in which the EC-BLA connections were preserved. Stimulation of the BLA with a bipolar electrode elicited complex postsynaptic potentials consisting of alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid (AMPA) receptor-mediated fast excitatory postsynaptic potentials (fast EPSPs), gamma-amino-butyric acid [GABA(A)] receptor-mediated fast inhibitory postsynaptic potentials (fast IPSPs) and GABAB receptor-mediated slow IPSPs. Bath application of 10 microM of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and of 10 microM of the GABA(A) receptor antagonist bicuculline methiodide (BMI) revealed a N-methyl-D-aspartate (NMDA) receptor-mediated slow EPSPs, which was occasionally followed by a GABAB receptor-mediated slow IPSPs. Under these conditions, the log concentration-response curve for D-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 40 116), a newly developed drug with proposed NMDA-receptor antagonist properties, was compared to that obtained with the 'classic' antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) in inhibiting the NMDA-mediated postsynaptic potentials. CGP 40 116 (IC50: 130 nM) was over 30 times more potent than D-AP5 (IC50: 4100 nM) in reducing NMDA-mediated slow EPSP. In conclusion, the present study indicates that CGP 40 116, a new orally-active NMDA antagonist, shows a very high potency on NMDA receptors in the amygdala and may therefore be a valuable tool for studying the behavioural effect of NMDA-receptor mediated transmission in this structure.

Noradrenaline modulates glutamate-mediated neurotransmission in the rat basolateral amygdala in vitro

Pierre Magistretti, Emilie Pralong

The entorhinal cortex and the amygdala are interconnected structures of the limbic system in which paroxysmal activity occurs during temporal lobe epilepsy. Conflicting evidence shows that noradrenaline (i) inhibits the spreading to other parts of the limbic system of paroxysmal activity generated in the amygdala or the entorhinal cortex, but also (ii) increases glutamatergic transmission in the basolateral amygdala. Given our previous work on the inhibitory effect of noradrenaline on entorhinal cortex neurons, we developed an in vitro slice preparation to study the synaptic transmission in the basolateral amygdala and its modulation by noradrenaline. Noradrenaline reduced the fast excitatory postsynaptic potential (EPSP) by approximately 40% at 100 microM and the slow EPSP by approximately 50% at 50 microM. A similar effect was obtained with the alpha2-agonist UK 14304 at 100 and 50 microM respectively. In contrast, the beta-agonist isoproterenol increased the fast EPSP by approximately 40% at 100 microM and the slow EPSP by approximately 20% at 50 microM. Accordingly, the effect of noradrenaline on the EPSPs was blocked by the alpha2-antagonist yohimbine (10 microM) but not by the alpha1-antagonist prazosine (10 microM) and the beta-antagonist propranolol (10 microM). Noradrenaline (50-100 microM) was ineffective on most (14/16) of the isolated inhibitory postsynaptic potentials (IPSPs). These experiments provide evidence that noradrenaline inhibits the excitatory synaptic response of basolateral amygdala neurons. A pharmacological analysis revealed that the noradrenergic modulation of the excitatory transmission in the basolateral amygdala can be dissected into a predominant alpha2-adrenoreceptor-mediated inhibition and a beta-adrenoreceptor-mediated excitation.

1997

Noradrenaline increases K-conductance and reduces glutamatergic transmission in the mouse entorhinal cortex by activation of alpha 2-adrenoreceptors

Pierre Magistretti, Emilie Pralong

The entorhinal cortex is a gateway to the hippocampus; it receives inputs from several cortical associative areas as well as subcortical areas. Since there is evidence showing that noradrenaline reduces the epileptic activity generated in the entorhinal cortex, we have examined the action of noradrenaline in the superficial layer of the entorhinal cortex, which is the main source of afferents to the hippocampus. In a previous study we showed that noradrenaline hyperpolarized layer II entorhinal cortex neurons and reduced global synaptic transmission via alpha 2-adrenoreceptors. Here we present a detailed analysis of the effect of noradrenaline on membrane resistance and on the pharmacologically isolated postsynaptic potentials in layer II entorhinal cortex neurons of mice. Noradrenaline (50 microM) hyperpolarized most layer II entorhinal cortex neurons. This hyperpolarization corresponded to an outward current with a reversal potential following the Nernst equilibrium potential for potassium. The hyperpolarizing effect of noradrenaline was blocked by 10 microM yohimbine. These observations suggest that noradrenaline activates a potassium conductance via an alpha 2-adrenoreceptor. Noradrenaline (10-50 microM) reversibly reduced the amplitude of the pharmacologically isolated excitatory potentials mediated by both NMDA and alpha-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors, the former being more strongly affected. Again this effect was blocked by 10 microM yohimbine. In contrast, GABAA-mediated synaptic transmission was virtually unaffected by noradrenaline. Thus, noradrenaline appears to strongly inhibit the glutamate-mediated synaptic transmission in the entorhinal cortex without affecting inhibitory post-synaptic potentials. These observations suggest that alpha 2-adrenergic receptor agonists may exert a beneficial effect in the control of hyperexcitability in temporal lobe epilepsy.

1995

Noradrenaline reduces synaptic responses in normal and tottering mouse entorhinal cortex via alpha 2 receptors

Pierre Magistretti, Emilie Pralong

The effects of noradrenaline (NA) on synaptic responses in layer II of the entorhinal cortex (EC) were studied in normal and spontaneously epileptic mutant mice tottering using intracellular recording in a slice preparation. Neither the membrane properties of neurones nor the responses to NA differed between normal and tottering mice. NA (50 microM) hyperpolarized most (29/54) of the neurones via alpha 2 adrenergic receptors. Synaptic responses of EC neurones were complex. NA (10-100 microM) reduced all the components of the synaptic response in a concentration-dependent and reversible manner. The pharmacological properties of the inhibitory effect of NA were characterised and quantified on one component of the complex synaptic response, the fast excitatory postsynaptic potential. The effect of NA was mimicked by the alpha 2 agonist UK 14,304 and blocked by the alpha 2 antagonist yohimbine. It is concluded that NA can inhibit via an alpha 2 receptor-mediated action synaptic responses in the superficial layers of the EC.

1994

Noradrenaline increases K-conductance and reduces glutamatergic transmission in the mouse entorhinal cortex by activation of alpha 2-adrenoreceptors

Pierre Magistretti, Emilie Pralong

1995