New Wine in a New Bottle - Essay Example

New Wine in a New Bottle Introduction Alcohol abuse has become one of the major health problems of the modern world. In the developed societies ofthe Western world more than fifty percent of the adults consume alcohol on a regular basis and nearly ten percent of these alcohol consumers end up with alcohol dependence problems. This has increased the emphasis on a better understanding of the mechanisms involved in alcohol dependence, so that more effective means of providing more effective relief to individuals with alcohol dependence problems (Al-Sanouri, Dikin & Soubani, 2005). Early theories on the action of alcohol pointed towards alcohol dissolving cellular membranes and enhancing membrane fluidity. This was believed to change the function of the macromolecules like receptors present in the cell membrane, which led to ethanol intoxication. However, evidence that emerged from later studies suggests that alcohol binds to the hydrophobic pockets of proteins causing alteration to their structure and function. This sensitivity to alcohol is demonstrated by ion channels, neurotransmitters and their receptors that include GABA. These neurotransmitters and receptors can be used as targets for drugs in the treatment of alcohol dependence. Even low levels of alcohol can affect the chloride channel, for which GABA is an important inhibitory neurotransmitter. Under normal circumstances GABA binds to the GABAA receptor, causing the chloride channel to open and allow the negatively charged chloride ions to enter the cell, which results in inhibition of neuronal cell activity. The presence of alcohol inhibits this action of GABA. When this inhibition of GABA is continual, the receptor compensation is in the form of reduction in the number of GABAA receptor subunits. Sedative drugs like benzodiazepines have the ability to bind to the chloride channel and cause GABA inhibition. It is this common mechanism in the action of alcohol and sedative-hypnotics that is responsible for the cross tolerance seen with these substances (Kenna, McGeary & Swift, 2006). Lead investigator Jing Ling and her colleagues at the University of California provide another step forward towards a better understanding of the mechanisms involved in ethanol abuse (Ling et al, 2007). Description of Contents Evidence from earlier studies has all pointed to acute ethanol intoxication enhancing the functioning of the GABAA receptor (GABAAR), while chronic intoxication results in GBAAR function. The subunit composition has a strong influence on the acute potentiation by ethanol with particular emphasis on A4BD GABAAR, which demonstrates strong affinity for GABA, insensitivity to benzodiazepine, slow desensitizing kinetics and strong sensitivity for ethanol. There are suggestions that development of quick ethanol tolerance in rats and humans may stem from mediation from mediation from the functional changes in GABAARs. Therefore, in this study the investigators set out to find out whether the function and the subunit composition of GABAARs could be changed by just one intoxicating of ethanol and study the mechanisms involved in these changes with regard to the hippocampal CAI and dentate gyrus regions (Ling et al, 2007). Approval was taken from the Animal Care and use committee for the use of Male Sprague Dawley rats that were used for the test experiments. The rats were initially given a single dose of ethanol (0.5-5g/kg), which was followed by 2-14 days of withdrawal. A control group was created and were placed on a chronic ethanol regimen (CIE), which consisted of first five doses at 5g/kg of ethanol once every other day and the subsequent 55 doses at 6g/kg of ethanol once every day. At varying intervals of time the rats were tested for their response to GABAergic drugs or they were killed and the tissues used for the experimental purposes (Ling et al, 2007). The response of the rats and the experiments carried out on the tissues of the dead rats were used to measure changes in ethanol responsiveness of synaptic and tonic GABAAR currents subsequent to ethanol intoxication; mIPSC decay and tonic current intensity subsequent to ethanol intoxication; changes in cell-surface and intracellular levels of GABAAR subunits subsequent to ethanol intoxication; tolerance of diazepam GABAAR currents subsequent to ethanol intoxication; reversible tolerance to diazepam and isoflurane subsequent to a single dose of ethanol intoxication and the dose dependence of ethanol induced tolerance to the sedative or anaesthetic effects of diazepam (Ling et al, 2007). The results of the study make it possible to show for the first time that just a single intoxicating ethanol dose brings about severe changes in GABAAR subunit composition as well as function that are accompanied with changes in behavioural and in vitro pharmacological sensitivity to diazepam, isoflurane and ethanol. Another importance finding of the study was that these changes were Figure 1 Summary Graph of Cell Changes in Cell-surface A4 and A1 Subunit Content after Single Dose Ethanol and CIE Treatments Relative to Vehicle-Treated Controls completely reversible in a time frame of two weeks or less, which is in sharp contrast to the persistent alterations that are induced through CIE treatment? Another important observation was the sharp tolerance to ethanol enhancement of GABAAR mediated Itonic, within a time frame of an hour after the in vivo exposure to ethanol, which is suggestive of this being the physiological mechanism involved in the acute behavioural tolerance to ethanol as seen in rats and humans (Ling et al, 2007). The study also demonstrates that the changes in mIPSC kinetics and pharmacology happen in a gradual manner over a period of 12 to 48 hours subsequent to ethanol intoxication are temporally separable from the early decreases in Itonic. This coincides with the enhanced cell-surface expression of A4 and Y2 and the reduced expression of A1 units. This is suggestive of A4BY2 being the freshly inserted synaptic GABAARs (Ling et al, 2007). Figure 2 Schematic of Hypothesized Mechanism of Ethanol Induced GABAAR Plasticity Behavioural hyper-excitability consisting of enhanced anxiety, reduction in seizure thresholds and sleep disorders are characteristics demonstrated by rats subjected to withdrawal from chronic ethanol or CIE treatment. The similarity observed in GABAAR changes points to the possibility of detecting withdrawal symptoms after a single dose of ethanol intoxication. The study is unable to demonstrate the exact brain regions, circuits and receptors that mediate behavioural drug aspects. The authors however, speculate that similar GAABAR plasticity may happen in the relevant circuits of the brain (Ling et al, 2007). Assessment of Value Many of the theories and concepts regarding the mechanisms involved in the pharmacological effects of ethanol on the central nervous system is based on ion channel disruption and GAABA receptors. Furthering the understanding of this mechanism is important for a clinical understanding of the tolerance and dependence on ethanol (Chandler, Harris & Crews, 1998). This study confirms the importance of ion channel disruption and GAABA receptors in the mechanism involved in the tolerance and dependence of ethanol. The GABAAR are made up of very distinct families of sub units that differ in their sequence and function. These sub units demonstrate varying sensitivity to pharmacological agents including ethanol. For a better understanding of the mechanism involving GABAAR in the tolerance and dependence of ethanol, greater clarity is required in the sensitivity of these sub units to ethanol both in acute and chronic exposure (Woodward, 2009). Repeated exposure to alcohol causes plasticity, which reduces the effect of drugs like diazepam or vice versa (Lee, 2006). This study clearly indicates the role in the reduction of receptor sites as the mechanism involved in this tolerance. Withdrawal symptoms of ethanol intoxication have generally been associated with chronic ethanol intoxication (Wolf, 2002). This study however makes an important first time contribution time that just a single intoxicating ethanol dose brings about severe changes in GABAAR subunit composition as well as function that are accompanied with changes in behavioural and in vitro pharmacological sensitivity to diazepam and that this plasticity is completely reversible. Comparison Animal studies suffer from a lacuna that they may not actually reflect mechanisms involved in humans. However, Olsen et al 2005 recommend the use of the chronic intermittent ethanol (CIE) model in the rat for the study of ethanol intoxication for an understanding of the mechanism of ethanol intoxication in humans. Jacob, Moss and Jurd, 2008 point out that GAABARs are responsible for the mediation of the fastest synaptic inhibition in the brain of mammals, by exerting control both at the network as well as the cellular levels. The diverse functioning of GABAARs can be explained through the complex trafficking mechanisms and protein to protein interactions. According to Chandra et al 2006, mediation by extrasynaptic GABAARs containing the A4 sub unit is responsible for tonic inhibition in dentate granular cells and thalamic relay neurons. Conclusion This article takes us further in our journey towards understanding of the mechanisms involved in alcohol dependence and tolerance of drugs like diazepam and the interaction with ethanol intoxication. In addition to the new contributions that this study makes towards this understanding, it also provides direction for better understanding of the GABBAR mechanism in ethanol intoxication. It highlights the gaps in the body of knowledge like the absence of any knowledge on the mechanism through which the relative abundance and localization of specific GABAAR units are changed with ethanol intoxication and the lack of definition of all the brain regions, circuits and receptors that are responsible for the mediation of behavioural drug effects. It thus points to these areas for further research to enhance the body of knowledge in the mechanisms involved in ethanol intoxication. Literary Reference Al-Sanouri, I., Dikin, M. & Soubani, A. O. 2005, ‘Critical Care Aspects of Alcohol Abuse’, Southern Medical Journal, vol.98, no.3, pp.372-381. Chandler, J. L., Harris. A. R. & Crews, F. T. 1998, ‘Ethanol tolerance and synaptic plasticity’, Trends in Pharmacological Sciences, vol.19, no.12, pp.491-495. Chandra, D. Jian, F, Liang, J., Peng, Z., Suryanarayanan, A., Werner, D. F., Spigelman, I., Houser, C. R., Olsen. R. W., Harrison, N. L. & Homanics, G. E. 2006, ‘GABAA receptor _4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol’, PNAS, vol.103, no.41, pp.15230-15235. Kenna, G. A., McGeary, J. E. & Swift, R. M. 2006, ‘Pharmacotherapy, Pharmacogenomics, and the Future of Alcohol Dependence Treatment’, American Journal of Health-System Pharmacy, vol.61, no.21 [Online] Available at: http://www.medscape.com/viewarticle/493411 (Accessed March 13, 2010). Lee, D. C. 2006, ‘Sedative-Hypnotics’, in Goldfrank’s Toxicologic Emergencies, Eighth Edition, eds., Lewis R. Goldfrank, Neal Flomenbaum Mary Ann Howland, Neal, A. Lewin & Lewis, S. Nelson, McGraw-Hill, New York, pp.1098-1111 Liang, J., Suyranarayanan, A., Abriam, A., Snyder, B., Olsen, R. W. & Spigelman, I. Mechanisms of Reversible GABAA Receptor Plasticity after Ethanol Intoxication. Journal of Neuroscience, vol.27, no.45, pp.12367-12377. Jacob, C. T., Moss, J. S. & Jurd, R. 2008, ‘GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition’, Nature Reviews Neuroscience, vol.9, pp.331-343. Olsen, R. W., Liang, J., Cagetti, E., & Spigelman, I. 2005, ‘Plasticity of GABAA Receptors in Brains of Rats Treated with Chronic Intermittent Ethanol’, Neurochemical Research, vol.30, no.12, pp.1579-1588. Woodward, J. J. 2009, ‘The Pharmacology of Alcohol’, in Principles of Addiction Medicine, Fourth Edition, eds., Richard, K. Ries, David, A. Fiellin, Shannon, C. Miller & Richard Saitz, Lippincott Williams & Wilkins, Philadelphia, PA, pp.85-98 Wolf, M. E. 2002, ‘Addiction’, in Basic Neurochemistry” Molecular, Cellular and Medical Aspects, Seventh Edition, Elsevier Academic Press, Burlington, MA, pp.911-926. Read More