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Source: http://www.med.unc.edu/alcohol/cenline/11_4_1.htm
Researchers Elucidate New Mechanism of Alcohol Action
Nearly three years ago when the work of Dr. A. Leslie Morrow's laboratory was featured in this newsletter, she and her research team were devoting much of their effort to elucidating the effects of long term alcohol consumption in brain. Alcohol was believed to act on nerve cell GABAA receptors, to block transmission and produce relaxation, sleepiness and improve mood. Although researchers unanimously agreed that GABAA receptors are critical for alcoholÕs effects on brain function and behavior, they did not understand exactly how alcohol interacts with these receptors to produce its effects. Recent research conducted by the Morrow laboratory has significantly advanced understanding on this front. "The role of GABAA receptors in mediating the sedative, anticonvulsant, and motor-impairing effects of alcohol has been understood for the past 15 years," says Morrow, "however, the mechanism by which alcohol interacts with GABAA receptors to produce these effects has not been elucidated. A wealth of indirect evidence suggests that alcohol increases brain signals through GABAA receptors, but convincing direct evidence is lacking. The recent work of our laboratory suggests that at least some effects of alcohol-GABAA receptor interaction involve an intermediary, specifically, the neurosteroid allopregnanolone."
Allopregnanolone is a neuroactive steroid, that acts on brain GABAA receptors and is produced in the brain as well as glands such as the adrenals and the ovaries. Morrow reasoned that allopregnanolone and related steroids—the most potent known enhancers of GABAA receptor functionÑare likely candidates for mediating the effects of alcohol on behavior. To test this possibility, Morrow and her laboratory first sought to determine whether alcohol administered at intoxicating concentrations increases levels of allopregnanolone in the brain. They found that rats injected with an intoxicating dose of alcohol compared with control rats injected with saline exhibited ~700% increases of allopregnanolone in the cerebral cortex, a brain region important in the sedative and cognitive effects of alcohol. Alcohol-induced increases in allopregnanolone levels were observed beginning approximately 20 minutes after administration of alcohol and reached their maximum 40 to 80 minutes after alcohol injection.
Next, Morrow's group wanted to know how alcohol increased allopregnanolone levels in brain. To assess the role of allopregnanolone synthesis in the increases observed after administration of alcohol, Morrow measured the effects of alcohol on allopregnanolone levels after rats had been injected with the neurosteroid synthesis inhibitor finasteride. Pretreatment of rats with finasteride before they were administered alcohol significantly reduced alcohol-induced increases in allopregnanolone in the cerebral cortex. This finding suggests that alcohol increases allopregnanolone levels by increasing allopregnanolone synthesis. But since finasteride did not eliminate the alcohol-induced increases in allopregnanolone, other mechanisms, such as the release of steroid stores, may also contribute to increased allopregnanolone levels.
Having established that alcohol-induced increases in brain levels of GABAA receptor modulator allopregnanolone are dependent on allopregnanolone synthesis, Morrow examined the effects of allopregnanolone synthesis inhibition at the level of the individual brain cell. Other laboratoriesÕ work had shown that injections of alcohol reduce the activity of nerve cells in a region of the brain known as the medial septum—an effect that is probably attributed to stimulation of GABAA receptors. Morrow's group replicated this finding and determined that the time course of alcohol's effect on medial septal nerve cell activity paralleled that of alcohol-induced increases in allopregnanolone in the cerebral cortex; alcohol was most effective at reducing medial septal nerve cell activity when allopregnanolone levels were highest. Furthermore, Morrow showed that inhibition of allopregnanolone synthesis with finasteride blocked the effects of alcohol on medial septal nerve activity. These findings provide evidence at the level of the individual cell that neurosteroids are involved directly in modulating the actions of alcohol in brain.
Morrow next sought to determine the relevance of the alcohol-induced changes in allopregnanolone to the behavioral effects of alcohol. She chose sedation/hypnosis as a target behavior because the sedative-hypnotic effects of alcohol are known to involve activation of GABAA receptors. One measure of alcohol-induced sedation/hypnosis is sleep time, the amount of time animals sleep so deeply that they are unable to "turn over" after administration of alcohol. Are allopregnanolone levels, Morrow queried, related to alcohol-induced sleep time? Morrow in fact found that alcohol-induced increases in allopregnanolone were directly related to sleep time: across 37 rats, the longest sleep times were associated with the greatest increases in allopregnanolone levels in response to alcohol administration.
Alcohol is an anticonvulsant—a compound that prevents seizures. Morrow's group found evidence that allopregnanolone also contributes to the anticonvulsant effect of alcohol. In one series of experiments, the time course of alcohol's anticonvulsant effect matched the time course of alcohol-induced increases in cerebral cortical allopregnanolone. Alcohol exerted the most marked anticonvulsant effects 40 minutes post-dose when allopregnanolone levels began to peak, but not 10 minutes post-dose when allopregnanolone levels had not yet risen in response to alcohol. Moreover, the anticonvulsant effect of alcohol was prevented by pretreatment with the allopregnanolone synthesis inhibitor finasteride.
Morrow has thus uncovered strong evidence linking allopregnanolone to the anticonvulsant and sedative/hypnotic effects of alcohol. Her recent work suggests that allopregnanolone also influences alcohol craving. Morrow's group has shown that allopregnanolone increases alcohol consumption in rats genetically bred to prefer alcohol when they are exposed to alcohol for the first time or for short periods of time. However, allopregnanolone reduces alcohol consumption in these rats if they are dependent (i.e., if they are alcoholic). These data show that allopregnanolone influences drinking behavior, and that the direction of influence is determined by prior long-term exposure to alcohol.
These findings with allopregnanolone have generated considerable excitement in the alcohol research community. In July, 2000, Morrow's work on neurosteroids and alcohol earned her a National Institutes of Alcohol Abuse and Alcoholism (NIAAA) Merit Award. Margaret VanDoren, a doctoral student who has conducted many of the allopregnanolone experiments, was recognized in 1999 with a Research Society for Alcoholism (RSA) student research award. The work also formed the backbone of a neurosteroids-and-alcohol symposium organized and chaired by Morrow and held as part of the 1999 RSA annual meeting. Morrow's group continues to explore the role of neurosteroids and to develop novel neurosteroids as potential treatments for alcohol-related problems.
Morrow is pleased with the progress on the role of neurosteroids in alcohol action but cites several unanswered questions. The complete mechanism(s) by which alcohol increases allopregnanolone levels remains unclear. Current efforts to establish the mechanism of alcohol-induced increases in allopregnanolone are delayed by the lack of appropriate pharmacologic tools. Accordingly, future efforts in the Morrow lab will be devoted to developing pharmacologic agents that selectively block neurosteroid actions in brain. Morrow notes that though the work of her lab has focused on allopregnanolone, other neurosteroids undoubtedly play a role in alcoholÕs effects.
Despite the questions that remain, Morrow acknowledges that her lab has made significant strides: "Although more research remains to be done, our data are consistent with the premise that allopregnanolone contributes to the actions of alcohol in the brain and represents a new mechanism of alcohol action. Continued assessment of the role of allopregnanolone and other neurosteroids in the effects of alcohol will comprise a significant part of our ongoing quest to determine the causes of alcoholism and develop novel treatments."—Jane Saiers
Source: http://www.med.unc.edu/alcohol/cenline/11_4_1.htm
Researchers Elucidate New Mechanism of Alcohol Action
Nearly three years ago when the work of Dr. A. Leslie Morrow's laboratory was featured in this newsletter, she and her research team were devoting much of their effort to elucidating the effects of long term alcohol consumption in brain. Alcohol was believed to act on nerve cell GABAA receptors, to block transmission and produce relaxation, sleepiness and improve mood. Although researchers unanimously agreed that GABAA receptors are critical for alcoholÕs effects on brain function and behavior, they did not understand exactly how alcohol interacts with these receptors to produce its effects. Recent research conducted by the Morrow laboratory has significantly advanced understanding on this front. "The role of GABAA receptors in mediating the sedative, anticonvulsant, and motor-impairing effects of alcohol has been understood for the past 15 years," says Morrow, "however, the mechanism by which alcohol interacts with GABAA receptors to produce these effects has not been elucidated. A wealth of indirect evidence suggests that alcohol increases brain signals through GABAA receptors, but convincing direct evidence is lacking. The recent work of our laboratory suggests that at least some effects of alcohol-GABAA receptor interaction involve an intermediary, specifically, the neurosteroid allopregnanolone."
Allopregnanolone is a neuroactive steroid, that acts on brain GABAA receptors and is produced in the brain as well as glands such as the adrenals and the ovaries. Morrow reasoned that allopregnanolone and related steroids—the most potent known enhancers of GABAA receptor functionÑare likely candidates for mediating the effects of alcohol on behavior. To test this possibility, Morrow and her laboratory first sought to determine whether alcohol administered at intoxicating concentrations increases levels of allopregnanolone in the brain. They found that rats injected with an intoxicating dose of alcohol compared with control rats injected with saline exhibited ~700% increases of allopregnanolone in the cerebral cortex, a brain region important in the sedative and cognitive effects of alcohol. Alcohol-induced increases in allopregnanolone levels were observed beginning approximately 20 minutes after administration of alcohol and reached their maximum 40 to 80 minutes after alcohol injection.
Next, Morrow's group wanted to know how alcohol increased allopregnanolone levels in brain. To assess the role of allopregnanolone synthesis in the increases observed after administration of alcohol, Morrow measured the effects of alcohol on allopregnanolone levels after rats had been injected with the neurosteroid synthesis inhibitor finasteride. Pretreatment of rats with finasteride before they were administered alcohol significantly reduced alcohol-induced increases in allopregnanolone in the cerebral cortex. This finding suggests that alcohol increases allopregnanolone levels by increasing allopregnanolone synthesis. But since finasteride did not eliminate the alcohol-induced increases in allopregnanolone, other mechanisms, such as the release of steroid stores, may also contribute to increased allopregnanolone levels.
Having established that alcohol-induced increases in brain levels of GABAA receptor modulator allopregnanolone are dependent on allopregnanolone synthesis, Morrow examined the effects of allopregnanolone synthesis inhibition at the level of the individual brain cell. Other laboratoriesÕ work had shown that injections of alcohol reduce the activity of nerve cells in a region of the brain known as the medial septum—an effect that is probably attributed to stimulation of GABAA receptors. Morrow's group replicated this finding and determined that the time course of alcohol's effect on medial septal nerve cell activity paralleled that of alcohol-induced increases in allopregnanolone in the cerebral cortex; alcohol was most effective at reducing medial septal nerve cell activity when allopregnanolone levels were highest. Furthermore, Morrow showed that inhibition of allopregnanolone synthesis with finasteride blocked the effects of alcohol on medial septal nerve activity. These findings provide evidence at the level of the individual cell that neurosteroids are involved directly in modulating the actions of alcohol in brain.
Morrow next sought to determine the relevance of the alcohol-induced changes in allopregnanolone to the behavioral effects of alcohol. She chose sedation/hypnosis as a target behavior because the sedative-hypnotic effects of alcohol are known to involve activation of GABAA receptors. One measure of alcohol-induced sedation/hypnosis is sleep time, the amount of time animals sleep so deeply that they are unable to "turn over" after administration of alcohol. Are allopregnanolone levels, Morrow queried, related to alcohol-induced sleep time? Morrow in fact found that alcohol-induced increases in allopregnanolone were directly related to sleep time: across 37 rats, the longest sleep times were associated with the greatest increases in allopregnanolone levels in response to alcohol administration.
Alcohol is an anticonvulsant—a compound that prevents seizures. Morrow's group found evidence that allopregnanolone also contributes to the anticonvulsant effect of alcohol. In one series of experiments, the time course of alcohol's anticonvulsant effect matched the time course of alcohol-induced increases in cerebral cortical allopregnanolone. Alcohol exerted the most marked anticonvulsant effects 40 minutes post-dose when allopregnanolone levels began to peak, but not 10 minutes post-dose when allopregnanolone levels had not yet risen in response to alcohol. Moreover, the anticonvulsant effect of alcohol was prevented by pretreatment with the allopregnanolone synthesis inhibitor finasteride.
Morrow has thus uncovered strong evidence linking allopregnanolone to the anticonvulsant and sedative/hypnotic effects of alcohol. Her recent work suggests that allopregnanolone also influences alcohol craving. Morrow's group has shown that allopregnanolone increases alcohol consumption in rats genetically bred to prefer alcohol when they are exposed to alcohol for the first time or for short periods of time. However, allopregnanolone reduces alcohol consumption in these rats if they are dependent (i.e., if they are alcoholic). These data show that allopregnanolone influences drinking behavior, and that the direction of influence is determined by prior long-term exposure to alcohol.
These findings with allopregnanolone have generated considerable excitement in the alcohol research community. In July, 2000, Morrow's work on neurosteroids and alcohol earned her a National Institutes of Alcohol Abuse and Alcoholism (NIAAA) Merit Award. Margaret VanDoren, a doctoral student who has conducted many of the allopregnanolone experiments, was recognized in 1999 with a Research Society for Alcoholism (RSA) student research award. The work also formed the backbone of a neurosteroids-and-alcohol symposium organized and chaired by Morrow and held as part of the 1999 RSA annual meeting. Morrow's group continues to explore the role of neurosteroids and to develop novel neurosteroids as potential treatments for alcohol-related problems.
Morrow is pleased with the progress on the role of neurosteroids in alcohol action but cites several unanswered questions. The complete mechanism(s) by which alcohol increases allopregnanolone levels remains unclear. Current efforts to establish the mechanism of alcohol-induced increases in allopregnanolone are delayed by the lack of appropriate pharmacologic tools. Accordingly, future efforts in the Morrow lab will be devoted to developing pharmacologic agents that selectively block neurosteroid actions in brain. Morrow notes that though the work of her lab has focused on allopregnanolone, other neurosteroids undoubtedly play a role in alcoholÕs effects.
Despite the questions that remain, Morrow acknowledges that her lab has made significant strides: "Although more research remains to be done, our data are consistent with the premise that allopregnanolone contributes to the actions of alcohol in the brain and represents a new mechanism of alcohol action. Continued assessment of the role of allopregnanolone and other neurosteroids in the effects of alcohol will comprise a significant part of our ongoing quest to determine the causes of alcoholism and develop novel treatments."—Jane Saiers
