Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons

Abstract

Kainate receptors (KA-Rs) are members of the glutamate-gated family of ionotropic receptors, which also includes N-methyl-Daspartate (NMDA) and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. KA-Rs are important modulators of interneuron excitability in the CA1 region of the hippocampus. Activation of these receptors enhances interneuron firing, which robustly increases spontaneous inhibitory postsynaptic currents in pyramidal neurons. We report here that ethanol (EtOH) potently inhibits this KA-R-mediated effect at concentrations as low as those that can be achieved in blood after the ingestion of just 1-2 drinks (5-10 mM). Pressure application of kainate, in the presence of AMPA and NMDA receptor antagonists, evoked depolarizing responses in interneurons that triggered repetitive action potential firing. EtOH potently inhibited these responses to a degree that was sufficient to abolish action potential firing. This effect appears to be specific for KA-Rs, as EtOH did not affect action potential firing triggered by AMPA receptor-mediated depolarizing responses. Importantly, EtOH inhibited interneuron action potential firing in response to KA-R activation by synaptically released glutamate, suggesting that our findings are physiologically relevant. KA-R-dependent modulation of glutamate release onto pyramidal neurons was not affected by EtOH. Thus, EtOH increases excitability of pyramidal neurons indirectly by inhibiting the KA-R-dependent drive of ␥-aminobutyric acid (GABA)ergic interneurons. We postulate that this effect may explain, in part, some of the paradoxical excitatory actions of this widely abused substance. The excitatory actions of EtOH may be perceived as positive by some individuals, which could contribute to the development of alcoholism.K ainate receptors (KA-Rs) are glutamate-gated ion channels that play important roles in the regulation of hippocampal excitability. In mossy fiber-to-CA3 pyramidal neuron synapses, KA-Rs mediate synaptic currents and plasticity and modulate glutamate release presynaptically (reviewed in refs. 1 and 2). Although KA-Rs are also present in CA1 pyramidal neurons, these receptors are not activated synaptically (3, 4). In the CA1 region, however, KA-Rs inhibit glutamate release presynaptically (5-7) and also regulate action potential (AP)-dependent GABA release from interneurons; studies have shown that the frequency of AP-independent GABA release is either unaffected (8-10) or inhibited by KA-R activation (11). Activation of KA-Rs by micromolar concentrations of KA inhibits evoked ␥-aminobutyric acid type A (GABA A ) receptor (GABA A -R)-mediated inhibitory postsynaptic currents (eIPSCs) in CA1 pyramidal neurons (8,9,(12)(13)(14)(15). However, the precise mechanism and the physiological importance of this effect are a matter of controversy (reviewed in refs. 1 and 16). This effect was initially interpreted to indicate that activation of interneuronal KA-Rs exerts a disinhibitory effect on CA1 pyramidal neurons, but subsequent studies have challenge...

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

“…In contrast, higher concentrations of ethanol reduce the inhibitory effect of KA receptors on GABAergic transmission, 41 inhibit KA-receptor-mediated synaptic currents in hippocampal CA3 pyramidal neurons 42 and modulate the function of other neuronal proteins, including GABA-A and NMDA-receptors. 15 The end results of the combined action of ethanol on all these effects is believed to cause neuronal depression, 43 which may also be a result of chronic alcohol intake. During withdrawal, however, upregulated NMDA-receptors are no longer blocked by chronic alcohol intake, and the decreased number or impaired function of GABA-A receptors may be too low to compensate for excessive glutamatergic excitation.…”

“…During withdrawal, however, upregulated NMDA-receptors are no longer blocked by chronic alcohol intake, and the decreased number or impaired function of GABA-A receptors may be too low to compensate for excessive glutamatergic excitation. 44 Concerning the potential role of hippocampal KA receptors during withdrawal, while previous research reported significant acute effects of alcohol intake on KA receptor expression and function, 15,16 chronic and high-dose alcohol consumption may lead to upregulation of KA receptors, as well as NMDA receptors, in particular in hippocampal regions and subsequently resulting in stronger GABAergic transmission and neuronal depression. During withdrawal from chronic alcohol intake, higher expression of KA receptors may eventually amplify low GABAergic transmission, beside the direct effects of chronic alcohol ingestion on GABA-receptors.…”

“…13,14 While little was known about adaptations in KA receptors after chronic ethanol intake, in recent years KA receptors have emerged as important targets of alcohol's action in the central nervous system. 15 Exposure to ethanol for 1-5 days selectively decreased the sensitivity of KA receptor responses to low KA concentrations. 16 Furthermore, an upregulation of these receptors under chronic administration of alcohol in hippocampal regions has been reported.…”

Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala

“…For example, KA-Rs contribute to postsynaptic glutamatergic excitatory responses in the BLA (Li and Rogawski, 1998) and also mediate a form of long-lasting heterosynaptic facilitation in this brain region (Li et al, 2001). We have previously demonstrated that KA-Rs in the rat hippocampus are potently inhibited by acute ethanol (Carta et al, 2003;Weiner et al, 1999). In fact, the potency of these effects was, in some cases, fourfold greater than that of the well-characterized ethanol inhibition of NMDA receptors.…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…This action of ethanol to release GABA can apparently be modified at presynaptic sites (see designation in Figure 4), by GABA B (Ariwodola and Weiner, 2004;Wan et al, 1996) and corticotrophin releasing factor (CRF; Nie et al, 2004) receptors. Additionally, other neurotransmitter receptors affected by ethanol can influence neural circuits that influence GABA transmission (Carta et al, 2003(Carta et al, , 2004; Figure 3 Effect of ethanol on neural rate from cerebellar Purkinje neurons. This figure illustrates the effect of GABA (top), ethanol (middle; 50 mM) and the combination of GABA and ethanol (bottom) on extracellularly recorded action potentials from a cerebellar Purkinje neuron in a slice preparation.…”