Clinical studies indicate that prolonged ethanol abuse by alcoholics results in an increasing incidence of seizure susceptibility until the majority of alcoholics have this symptom. A kindling-like phenomenon produced by repetitive withdrawal from alcohol has been proposed to explain this observation. Recently, the inferior colliculus has been implicated in the genesis of audiogenic seizures following withdrawal from chronic ethanol. Since chronic electrical stimulation of the inferior collicus also produces a kindling-like phenomenon, we propose that, like repeated electrical stimulation, repeated withdrawal episodes from chronic ethanol """"""""kindles"""""""" the inferior colliculus or other sites. To test this hypothesis, we will determine if repeated withdrawal episodes from chronic ethanol exposure increases the sensitivity of the inferior colliculus to electrically elicited seizures after rats have recovered from the acute withdrawal. These results will be compared to studies of the amygdala, a classic site for kindling, as more than one site may be involved in the kindling process. Conversely, we will determine a chronic stimulation of the inferior colliculus or amygdala will increase seizure susceptibility of chronic ethanol-treated rats upon withdrawal. Since the inferior colliculus is a crucial component for audiogenic seizures in rats treated chronically with ethanol, the neural pathways involved in both the ethanol withdrawal seizures and electrically elicited seizures from the inferior colliculus will be mapped using site injection of local anesthetics. ln addition, pharmacological interventions are planned to determine if the seizure process induced by these treatments can be attenuated. An in vivo dialysis technique will be used to define the release of excitatory and inhibitors neuroactive amino acids in the inferior colliculus following acute or chronic ethanol treatment to allow a better understanding of the neurochemical changes induced be ethanol. Investigation will explore also the role of chloride channels in ethanol's actions and will compare the biochemical consequences of kindling with changes induced by repeated ethanol withdrawal. Electrophysiological investigations in the inferior colliculus will define changes in cell responsiveness of excitatory and inhibitory transmitters after acute or chronic ethanol. These multidisciplinary investigations should provide new information concerning the genesis of seizures induced by chronic ethanol consumption and allow us to examine the neurochemical basis for the acute actions of ethanol on CNS function as well as the associated adaptation with continued ethanol exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026595-02
Application #
3412510
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Knapp, D J; Duncan, G E; Crews, F T et al. (1998) Induction of Fos-like proteins and ultrasonic vocalizations during ethanol withdrawal: further evidence for withdrawal-induced anxiety. Alcohol Clin Exp Res 22:481-93
Criswell, H E; Knapp, D J; Overstreet, D H et al. (1994) Effects of ethanol, chlordiazepoxide, and MK-801 on performance in the elevated-plus maze and on locomotor activity. Alcohol Clin Exp Res 18:596-601
Simson, P E; Criswell, H E; Breese, G R (1993) Inhibition of NMDA-evoked electrophysiological activity by ethanol in selected brain regions: evidence for ethanol-sensitive and ethanol-insensitive NMDA-evoked responses. Brain Res 607:9-16
Criswell, H E; Simson, P E; Duncan, G E et al. (1993) Molecular basis for regionally specific action of ethanol on gamma-aminobutyric acidA receptors: generalization to other ligand-gated ion channels. J Pharmacol Exp Ther 267:522-37
McCown, T J; Breese, G R (1993) A potential contribution to ethanol withdrawal kindling: reduced GABA function in the inferior collicular cortex. Alcohol Clin Exp Res 17:1290-4
McCown, T J; Breese, G R (1992) The developmental profile of seizure genesis in the inferior collicular cortex of the rat: relevance to human neonatal seizures. Epilepsia 33:2-10
McCown, T J; Breese, G R (1991) The role of the inferior collicular cortex in the neonatal rat: sensorimotor modulation. Brain Res Dev Brain Res 59:1-5
Simson, P E; Criswell, H E; Breese, G R (1991) Ethanol potentiates gamma-aminobutyric acid-mediated inhibition in the inferior colliculus: evidence for local ethanol/gamma-aminobutyric acid interactions. J Pharmacol Exp Ther 259:1288-93
McCown, T J; Duncan, G E; Breese, G R (1991) Neuroanatomical characterization of inferior collicular seizure genesis: 2-deoxyglucose and stimulation mapping. Brain Res 567:25-32
McCown, T J; Breese, G R (1991) Seizure interactions between the inferior collicular cortex and the deep prepiriform cortex. Epilepsy Res 8:21-9

Showing the most recent 10 out of 14 publications