A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices

Whittington, Miles A.; Little, H.J.

doi:10.1111/j.1476-5381.1991.tb09786.x

Cited by 53 publications

(15 citation statements)

References 29 publications

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“…Intracellular calcium concentration is significantly enhanced after chronic in vitro exposure to ethanol. The enhancement is consistent with an increased number of NMDA receptors through which calcium can enter neurons, whereas calcium channel antagonist can attenuate the ethanol withdrawal hyperexcitability in hippocampus [143]. During the chronic dependent state, glutamate release is decreased; conversely, uptake and tissue concentration of glutamate are increased [54,79].…”

Section: Neurochemical Effects Of Alcohol On Glutamatergic Transmissionmentioning

confidence: 64%

Glutamatergic Neurotransmission in Alcoholism

Tsai¹

1998

J Biomed Sci

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Substance abuse and dependence is the most common psychiatric problem. Alcohol is the most commonly abused substance and most people who abuse other substance(s) abuse alcohol at the same time. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent via the glutamatergic system. Ethanol disrupts glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor and by promoting neuronal toxicity through upregulation of the NMDA receptor density. Therefore, short-term/acute ethanol treatment results in a blockade of NMDA receptor-mediated neurotransmission and apoptotic cell death by inhibiting the trophic effect mediated by the NMDA receptor whereas chronic ethanol treatment and withdrawal results in an enhanced toxic response toward glutamate. The neurobiology of human alcoholism such as ethanol intoxication, dependence, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome can be better understood as a spectrum of consequences of ethanol’s effect on the NMDA glutamatergic system.

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Section: Neurochemical Effects Of Alcohol On Glutamatergic Transmissionmentioning

confidence: 64%

Glutamatergic Neurotransmission in Alcoholism

Tsai¹

1998

J Biomed Sci

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“…The neuronal mechanisms are likely to be complex given the multiple actions of ethanol in the central nervous system and the fact that these systems may be (and often are) altered by the history of ethanol exposure. For example, chronic exposure to ethanol results in an upregulation of NMDA receptors (Grant, 1990;Liljequist, 1991;Hoffman and Tabakoff, 1994) and an upregulation in the density of voltage-dependent calcium channels (Messing et al, 1986;Dolin et al, 1987;Dolin and Little, 1989;Whittington and Little, 1991). More recently, Rasmussen et al (2002) has reported that mediobasal hypothalamus pro-opiomelanocortin (POMC) mRNA concentrations were decreased after chronic ethanol consumption.…”

Section: Discussionmentioning

confidence: 99%

“…Their work suggests that acamprosate acts as a 'partial coagonist' at the NMDA receptor, such that low concentrations enhance activation when receptor activity is low, and high concentrations inhibit activation when receptor activity is high. This may be particularly relevant to the success of acamprosate as a pharmacotherapy given that chronic exposure to ethanol results in an upregulation of NMDA receptors (Grant, 1990;Liljequist, 1991;Hoffman and Tabakoff, 1994) and an upregulation in the density of voltage-dependent calcium channels (Messing et al, 1986;Dolin et al, 1987;Dolin and Little, 1989;Whittington and Little, 1991). Acamprosate also promotes the release of taurine in the brain (Dahchour and de Witte, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Heyser

Moc

Koob

2003

Neuropsychopharmacol

101

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Previous research in our laboratory has shown that responding for ethanol increases after a period of imposed deprivation during which no ethanol is available (the alcohol deprivation effect). This selective increase in responding for ethanol was blocked by chronic administration of acamprosate. In the present study the effects of naltrexone and the combination of naltrexone+acamprosate on oral ethanol self-administration were examined following an imposed period of abstinence. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice condition. After training, separate groups of rats received chronic injections (2 Â /day) of saline, naltrexone, or naltrexone+acamprosate during a 5-day period of abstinence. Ethanol self-administration was tested in all groups of rats on the last day of abstinence, 30 min after the last drug injection. Responding for ethanol increased significantly following the deprivation period in animals treated with saline. Chronic administration of naltrexone and the combination naltrexone+acamprosate blocked the increased ethanol consumption following the imposed abstinence period on post-deprivation Day 1. On post-deprivation Day 2, the combination of acamprosate with naltrexone blocked the rebound increase in ethanol consumption observed in animals treated with a low dose of naltrexone. These results support the hypothesis that naltrexone and acamprosate are effective in modulating aspects of alcohol-seeking behavior, and under certain situations may be more effective in combination.

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“…This effect was stereoselective and was seen with the doses of drug that were required to displace radiolabelled dihydropyridines from CNS binding sites in vivo (Supervilai & Karobath, 1984). We have demonstrated that ethanol withdrawal hyperexcitability occurs in the isolated hippocampal slices in vitro ; this was prevented by the dihydropyridine calcium channel antagonist, PN 200-1 10, in a selective and stereospecific manner (Whittington & Little, 1991).…”

Section: Introductionmentioning

confidence: 99%

Changes in voltage‐operated calcium channels modify ethanol withdrawal hyperexcitability in mouse hippocampal slices

Whittington¹,

Little²

1993

Experimental Physiology

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SUMMARYMeasurements of hippocampal excitability were made from area CAl of isolated mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, and the effects of the stereoisomers of the dihydropyridine Bay K 8644, that act at calcium channels, were investigated. The decrease in the threshold stimulation required to produce a single population spike, the leftward shift in the population spike input-output curves, and the increase in population spike amplitude, that were seen during ethanol withdrawal, were all increased by the (-) isomer of Bay K 8644. This isomer has been shown to increase opening of calcium channels. These effects of ethanol withdrawal were decreased by the (+) isomer of Bay K 8644, that is a calcium channel blocker. In contrast, the increase in paired-pulse potentiation of the population spike, seen during the initial phase of ethanol withdrawal, was significantly decreased by both isomers of Bay K 8644. After the chronic ethanol treatment, single orthodromic stimuli produced epileptiform field potentials, consisting of two independent phases, a short latency series of multiple population spikes, superimposed upon the initial observed EPSP, and a longer latency train of spikes, occurring on a second EPSP, temporally distinct from the first. The (-) isomer of Bay K 8644 increased both these phases of epileptiform activity during ethanol withdrawal in a dose-dependent manner, while (+)-Bay K 8644 reduced the initial phase of multiple spiking and abolished the later phase. In slices from control animals, the higher concentration of (-)-Bay K 8644 (2 /sM), but not the lower concentration (500 nM) decreased the stimulation required to produce multiple population spikes. Neither produced the long latency epileptiform activity. The (+) isomer of Bay K 8644 had no effect on control recordings. Lesioning the Schaffer collateral-commissural fibre pathway, or removing area CA3, in slices from ethanol-treated animals, abolished the later phase of epileptiform activity without affecting the initial multiple spiking. Intracellular recordings from area CAl showed both the short latency and the longer latency epileptiform activities in slices from ethanol-treated mice and in control hippocampal slices after application of the (-) isomer of Bay K 8644, but these patterns of activity were not seen in control slices in the absence of Bay K 8644. Spontaneous activity during ethanol withdrawal was seen in intracellular recordings, but such activity was not seen in the field potential recordings. It is suggested that withdrawal from chronic ethanol treatment produced hyperexcitability in both area CAl and area CA3 of the isolated hippocampal slice, and that the epileptiform activity in area CA3 is effectively transmitted to area CAl. The effects of the isomers of Bay K 8644 suggested that this epileptiform activity was mediated, in part, by activity of dihydropyridinesensitive calcium channels.

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A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices

Cited by 53 publications

References 29 publications

Glutamatergic Neurotransmission in Alcoholism

Glutamatergic Neurotransmission in Alcoholism

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Changes in voltage‐operated calcium channels modify ethanol withdrawal hyperexcitability in mouse hippocampal slices

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