This page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

Alcohol's Effect on

Glutamate Neurotransmission the Brain

In the original study, conducted by Vadasz, et al. (2007), that identified the role of GRM7 in alcoholism, the researchers found that mice with lowered expression of Grm7, the mouse homolog of human GRM7, exhibited increased levels of alcohol preference. Examining the big picture, it seems easy to relate these findings in mice to our understanding of human alcoholism: someone who enjoys alcohol more might be more prone to drink and, therefore, more likely to practice behaviors that lead to alcoholism, as well as more susceptible to physical and mental dependence on alcohol. However, the question remains as to how exactly decreased GRM7 expression could lead to increased alcohol preference. To explore the role of GRM7 in the brain's response to alcohol, the effects of alcohol on glutamate transmission in the brain, specifically with regard to GRM7, were investigated.

Glutamate Neurotransmission

As a first step in this investigation, the role of GRM7 in glutamate neurotransmission was examined. Glutamate is the principal excitatory neuron in the brain, acting to start new action potentials or keep already traveling potentials running (Danbolt, 2001; Genetic Science Learning Center, 2009). It plays a role in most of the normal functions of the brain, including learning, memory, and cognition (Danbolt, 2001). Shown below is the chemical structure of glutamate, as well as some of its chemical properties.
Glutamate neurotransmission is accomplished via both ionotropic and metabotropic receptors, as well as with general transporters (Meldrum, 2000). As was discovered through the analyses conducted on this website, GRM7 belongs to the class III metabotropic glutamate receptors, and functions both pre- and postsynaptically (Meldrum, 2000). In the presynapse, GRM7 is known to control release of glutamate into the synapse (Meldrum, 2000). In the postsynapse, GRM7 responds to glutamate by inhibiting forskolin-stimulated cyclic AMP accumulation (Okamoto, et al., 1994).

Chemical Formula: C5H9NO4

Synonyms: L-Glutamate; Glutamic Acid,

        L-Glutaminic acid

Chemical Formula: C5H9NO4
Molecular Weight: 147.12926

Isoelectric Point: 2.23

Melting Point: 224 ºC

 

Information from DrugBank.

Accession number: DB00142

Figure 1. Glutamic Acid Structure in 2D. Image from ChemBank (ChemBank, 2009).

Alcohol and Glutamate Neurotransmission

When alcohol is consumed, it passes directly from the digestive tract into the blood stream, where it travels throughout the body, including to the brain (Canadian Institutes of Health Research, 2009). If alcohol exposure is only short term, alcohol acts to decrease glutamate activity (Genetic Science Learning Center, 2009). While the short term effect of alcohol on metabotropic glutamate receptors remains unexplored, researchers have found that this decrease in glutamate activity is in part caused by alcohol's inhibition of glutamate ionotropoic receptors (Valenzuela, 1997; Genetic Science Learning Center, 2009). A fun summary of how alcohol affects glutamate transmission in the short term, can be found by putting the "Alcohol" mouse in the chair at Utah's Genetic Science Learning Center's Mouse Party.
While short term exposure to alcohol decreases glutamate activity, long term exposure has the opposite effect (Valenzuela, 1997). The increase in glutamate activity caused by chronic alcohol exposure is thought to function as a compensation mechanism: the brain offsets the prolonged inhibition of glutamate activity by enhancing it (Valenzuela, 1997). The schematic in Figure 2 summarizes the long and short term effects alcohol is thought to have on the brain as a result of this compensation mechanism (Valenzuela, 1997). Ionotropic receptors, in particular, have been found to play an important role in this compensation mechanism, increasing with chronic alcohol abuse (Valenzuela, 1997). The role of metabotropic glutamate receptors in this compensation mechanism is less clear, however. In the only study of its kind, Simonyi, et al. (2004), found that rats chronically exposed to ethanol had decreased levels of metabotropic glutamate receptor mRNA, including decreased levels of Grm7 mRNA. Puzzled by their findings, Simonyi, et al. (2004), raise some possible explanations for this, including that mRNA levels may not correspond to protein levels, as well as that the relative levels of the various glutamate receptors may matter more than the absolute levels. However, further experimentation is needed.
Picture
Figure 2. Schematic representation of alcohol’s effects on the balance of inhibitory and excitatory neurotransmission in the brain. (From Valenzuela, 1997).

How does GRM7 modulate alcohol dependence?

While further experiments are clearly needed to ascertain how GRM7 expression levels influence alcohol dependence, the current literature suggests that the relative levels of glutamate receptor expression within the brain, including the levels GRM7 expression, play a central role in creating alcohol addiction. In particular, considering both the model proposed in Figure 2 and the findings of Simonyi et al. (2004) that lowered Grm7 expression in rats is associated with chronic alcohol abuse, it seems possible that people who carry a low-expression variant of GRM7 might have an inborn imbalance in glutamate transmission that causes them be more prone to feeling alcohol withdrawal symptoms than those people carrying a high-expression variant (Valenzuela, 1997). Therefore, these low-expression individuals might be more likely to develop a physical dependence on alcohol. An interesting future study to test this hypothesis would be to compare the effects of chronic alcohol use on the levels of Grm7 mRNA, as well as on the level of alcohol withdrawal experienced, in mice with the lower expressing Grm7 variant to mice with the higher expressing Grm7 variant.

References

References

 

Canadian Institutes of Health Research: Institute of Neurosciences, Mental Health and Addiction. (2009, May 13). How drugs affect neurotransmitters: alcohol. The brain from top to bottom. Retrieved May 13, 2009, from http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_alcool.html

ChemBank. (2009). Glutamic acid. Retrieved May 2, 2009, from http://chembank.broad.harvard.edu/chemistry/viewMolecule.htm?cbid=2674.

Danbolt, N.C. (2009, May 13). Glutamate as a neurotransmitter – an overview. Retrieved May 13, 2009, from http://www.neurotransporter.org/glutamate.html

DrugBank. (2009, April 16). Showing drug card for L-Glutamic Acid (DB00142). Retrieved May 2, 2009, from http://www.drugbank.ca/drugs/DB00142.

Genetic Science Learning Center. (2009, May 13). Beyond the Reward Pathway. Learn.Genetics. Retrieved May 13, 2009, from http://learn.genetics.utah.edu/content/addiction/reward/pathways.html

Meldrum, B.S. (2000). Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology. Journal of Nutrition, 130(4S Suppl):1007S. Retrieved from http://jn.nutrition.org/cgi/content/full/130/4/1007S

Okamoto, N., Hori, S., Akazawa, C., Hayashi, Y., Shigemoto, R., Mizuno, M., and Nakanishi, S. (1994, January 14). Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibatory cyclic AMP signal transduction. [Abstract]. The Journal of Biological Chemistry, 269(2):1231. Retrieved February 2, 2009, from http://www.ncbi.nlm.nih.gov/pubmed/8288585?dopt=Abstract

Simonyi, A., Christian, M.R., Sun, A.Y., Sun, G.Y. (2004). Chronic ethanol-induced subtype- and subregion-specific decrease in the mRNA expression of metabotropic glutamate receptors in rat hippocampus. Alcohol Clin Exp Res, 28(9):1419. doi: 10.1097/01.ALC.0000139825.35438.A4

Vadasz, C., Saito, M., Gyetvai, B. M., Oros, M., Szakall, I., Kovacs, K. M., Prasad, V. V. T. S., Toth, R. (2007). Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. Genomics, 90(6):690. doi:10.1016/j.ygeno.2007.08.006

Valenzuela, C.F. (1997). Alcohol and neurotransmitter interactions. Alcohol Health and Research World, 21(2):144. Retrieved from, http://pubs.niaaa.nih.gov/publications/arh21-2/144.pdf


Jennifer Wagner
wagner4@wisc.edu
Updated May 14, 2009
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