Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pont... more Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pontine reticular formation (PRF) is implicated in the propagation pathway for AGS during ETX. The present study examined the changes in single PRF neuronal firing patterns produced by ethanol and during ETX following repeated intragastrically administered ethanol. Microwire electrode bundles were implanted into PRF and single neuronal responses in freely moving rats were examined. During initial ethanol administration the animals were stuporous, and spontaneous and acoustically-evoked PRF neuronal firing were reduced significantly. During ETX the animals were susceptible to AGS and displayed agitated and irritable behavior. At this time a significant increase in spontaneous and acoustically-evoked PRF neuronal firing was observed. Repetition-induced response attenuation (habituation) of PRF neuronal responses was significantly diminished during ETX, leading to an exaggerated acoustic startle response, which may be a physiological basis for AGS. Previous reports indicate that ethanol enhances the effects of GABA and decreases the effects of glutamate. The PRF neuronal firing increases during ETX in the present study may involve the down-regulation of GABA A receptors and supersensitivity of glutamate receptors reported to occur during ETX, which could contribute to AGS susceptibility. The PRF neuronal firing increases observed in the present study in concord with previous observation of AGS blockade by PRF microinjections during ETX further support an important role of this brain region in the propagation of AGS during ethanol withdrawal.
Alcoholism: Clinical and Experimental Research, 1994
Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In... more 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 eudiogenic 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-((.C) -2-carboxypiperazin-4-yl) -propyl-1phosphonic 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-nitroquinoxalined,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 subsewing AGS susceptibility during ethanol withdrawal.
Alterations of excitant amino acid (EAA) action are implicated in seizure susceptibility in the g... more Alterations of excitant amino acid (EAA) action are implicated in seizure susceptibility in the genetically epilepsy-prone rat (GEPR). The inferior colliculus (IC) is critical for audiogenic seizure (AGS) initiation in the GEPR. The present study observed that bilateral microinjection into the IC of L-canaline, a glutamate synthesis inhibitor, decreased AGS severity in the GEPR and also decreased potassium-evoked release of glutamate from IC slices. Bilateral microinjection of NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (AP7) or 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) into IC blocked AGS, and an antagonist at non-NMDA EAA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), also blocked AGS. NMDA receptor antagonists were 5-200 times more effective than CNQX. Microinjection of a non-competitive NMDA receptor antagonist, dizocilpine (MK-801), into IC had little effect except with very high doses. Microinjection of CPP or AP7 into the IC blocked AGS at considerably lower doses as compared to pontine reticular formation (PRF). However, MK-801 attenuated AGS when microinjected into PRF at doses that were ineffective in IC. Systemically administered CPP blocked AGS and significantly reduced IC neuronal firing in the behaving GEPR, suggesting an important action of systemically administered NMDA receptor antagonists on brainstem auditory nuclei critical to AGS. The present results support a critical role for glutamate acting, in part, through NMDA receptors in IC in initiation of AGS.
Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pont... more Susceptibility to audiogenic seizures (AGS) is observed during ethanol withdrawal (ETX). The pontine reticular formation (PRF) is implicated in the propagation pathway for AGS during ETX. The present study examined the changes in single PRF neuronal firing patterns produced by ethanol and during ETX following repeated intragastrically administered ethanol. Microwire electrode bundles were implanted into PRF and single neuronal responses in freely moving rats were examined. During initial ethanol administration the animals were stuporous, and spontaneous and acoustically-evoked PRF neuronal firing were reduced significantly. During ETX the animals were susceptible to AGS and displayed agitated and irritable behavior. At this time a significant increase in spontaneous and acoustically-evoked PRF neuronal firing was observed. Repetition-induced response attenuation (habituation) of PRF neuronal responses was significantly diminished during ETX, leading to an exaggerated acoustic startle response, which may be a physiological basis for AGS. Previous reports indicate that ethanol enhances the effects of GABA and decreases the effects of glutamate. The PRF neuronal firing increases during ETX in the present study may involve the down-regulation of GABA A receptors and supersensitivity of glutamate receptors reported to occur during ETX, which could contribute to AGS susceptibility. The PRF neuronal firing increases observed in the present study in concord with previous observation of AGS blockade by PRF microinjections during ETX further support an important role of this brain region in the propagation of AGS during ethanol withdrawal.
Alcoholism: Clinical and Experimental Research, 1994
Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In... more 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 eudiogenic 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-((.C) -2-carboxypiperazin-4-yl) -propyl-1phosphonic 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-nitroquinoxalined,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 subsewing AGS susceptibility during ethanol withdrawal.
Alterations of excitant amino acid (EAA) action are implicated in seizure susceptibility in the g... more Alterations of excitant amino acid (EAA) action are implicated in seizure susceptibility in the genetically epilepsy-prone rat (GEPR). The inferior colliculus (IC) is critical for audiogenic seizure (AGS) initiation in the GEPR. The present study observed that bilateral microinjection into the IC of L-canaline, a glutamate synthesis inhibitor, decreased AGS severity in the GEPR and also decreased potassium-evoked release of glutamate from IC slices. Bilateral microinjection of NMDA receptor antagonists, 2-amino-7-phosphonoheptanoate (AP7) or 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) into IC blocked AGS, and an antagonist at non-NMDA EAA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), also blocked AGS. NMDA receptor antagonists were 5-200 times more effective than CNQX. Microinjection of a non-competitive NMDA receptor antagonist, dizocilpine (MK-801), into IC had little effect except with very high doses. Microinjection of CPP or AP7 into the IC blocked AGS at considerably lower doses as compared to pontine reticular formation (PRF). However, MK-801 attenuated AGS when microinjected into PRF at doses that were ineffective in IC. Systemically administered CPP blocked AGS and significantly reduced IC neuronal firing in the behaving GEPR, suggesting an important action of systemically administered NMDA receptor antagonists on brainstem auditory nuclei critical to AGS. The present results support a critical role for glutamate acting, in part, through NMDA receptors in IC in initiation of AGS.
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