Seizures during Ethanol Withdrawal Are Blocked by Focal Microinjection of Excitant Amino Acid Antagonists into the Inferior Colliculus and Pontine Reticular Formation

Abstract

Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In rats, generalized tonic-clonic seizures are precipitated by auditory stimulation during the ethanol withdrawal syndrome. Excitant amino acids (EAAs) are implicated as neurotransmitters in the inferior colliculus and the brain stem reticular formation, which play important roles in the neuronal network for genetic models of audiogenic seizures (AGSs). Ethanol blocks the actions of EAAs in various brain regions, including the inferior colliculus. In this study, dependence was produced by intragastric administration of ethanol for 4 days. During ethanol withdrawal, AGSs were blocked by systemic administration of competitive or noncompetitive NMDA antagonists 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or dizocilpine (MK-801). Focal microinjections of NMDA or non-NMDA antagonists into the inferior colliculus or the pontine reticular formation also inhibited AGSs. MK-801 was the most potent anticonvulsant systemically. When injected into the inferior colliculus, CPP had a more potent anticonvulsant effect than either MK-801 or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The inferior colliculus was more sensitive than the pontine reticular formation to the anticonvulsant effects of both competitive NMDA and non-NMDA antagonists. The results of the present support the idea that continued ethanol administration may lead to development of supersensitivity to the action of EAAs in inferior colliculus and pontine reticular formation neurons. This may be a critical mechanism subserving AGS susceptibility during ethanol withdrawal.

In Vitro Effects of Ethanol Withdrawal and Spermidine on Viability of Hippocampus From Male and Female Rat

“…One consequence of these effects is overactivation of NMDA receptors during acute withdrawal from ethanol that contributes to CNS seizure activity (Danysz et al, 1992;Riaz and Faingold, 1994) and delayed neuronal cell death (Rudolph et al, 1997;Thomas and Morrisett, 2000). These effects of ethanol exposure and withdrawal are postulated to influence, in part, the development of neuropathology and neurological symptoms during the course of long-term alcoholism (for review, see .…”

Glutamatergic Neurotransmission in Alcoholism

“…At this time, a significant increase in pontine reticular formation neuronal firing was also observed, consistent of upregulation of NMDA receptor. In addition, repetition-induced response attenuation of pontine reticular formation neuronal responses (tolerance) was significantly diminished during ethanol withdrawal, leading to an exaggerated acoustic startle response, which may be a physiological basis for audiogenic seizure and autonomic hyperactivity [28], whereas microinjection of NMDA antagonists into the pontine reticular formation block the seizure susceptibility [106]. The long-lasting memory deficit in Wenicke's encephalopathy, cerebral atrophy, and cerebellar degeneration can be the result of neuronal degeneration that is mediated by ethanol-induced neurotoxicity.…”

Glutamatergic-cholinergic synergistic interaction in the pontine reticular formation. Effects on catalepsy

“…They were effective in producing pressor or depressor responses (Chen et al 1997), respiratory responses (Chamberlin and Saper 1994), locomotion or tone suppression Siegel 1990, 1991). EAA receptor antagonists inhibited seizures produced by auditory stimulation (Riaz and Faingold 1994) and electroshock (Peterson 1995). A number of studies have been concerned with the role of EAA receptors in the generation of REM sleep.…”