UCSF UC San Francisco Previously Published Works Title The role of the neuromodulator adenosine in alcohols actions. Permalink https://escholarship.org/uc/item/8p89j1k8 Journal Alcohol Research and Health, 21(2) ISSN 0090-838X Authors Dohrman, D Diamond, Ivan Gordon, A Publication Date 1997 Peer reviewed eScholarship.org Powered by the California Digital Library University of California NEUROTRANSMITTER REVIEW the brain with potent opiate agonist activity. Nature 258:577–579, 1975. One chemical that modifies (i.e., modulates) brain func- O’BRIEN, C.P.; VOLPICELLI, L.A.; AND VOLPICELLI, J.R. Naltrexone in the tion and has been implicated in several of alcohol’s acute treatment of alcoholism: A clinical review. Alcohol 13(1):35–39, 1996. and chronic effects is adenosine. This article reviews cur- rent knowledge about alcohol’s interactions with adenosine- PERT, C.B., AND SNYDER, S.H. Opiate receptor: Demonstration in nervous tissue. Science 179:1011–1014, 1973. mediated modulation of nerve-cell activity in the central nervous system (CNS). After summarizing adenosine’s role PERT, A.; PERT, C.B.; DAVIS, G.C.; AND BUNNEY, W.E., JR. Opiate pep- tides and brain function. In: van Praag, E., ed. Handbook of Biological in signal transmission in the CNS, this article discusses Psychiatry. Part 4. New York: Marcel Decker, 1981. pp. 547–582. studies investigating alcohol’s interactions with adenosine in cell-culture (i.e., in vitro) models. Finally, the article reviews the evidence that adenosine may be an important THE ROLE OF THE mediator of alcohol’s effects in both animals and humans. NEUROMODULATOR ADENOSINE IN ALCOHOL’S ACTIONS ADENOSINE ISANEUROMODULATOR Signal transmission among nerve cells, or neurons, is me- Douglas P. Dohrman, Ph.D.; Ivan Diamond, diated primarily by neurotransmitter molecules that are M.D., Ph.D.; and Adrienne S. Gordon, Ph.D. released from the signal-emitting (i.e., presynaptic) cell and interact with specific molecules (i.e., receptors) on the surface of the signal-receiving (i.e., postsynaptic) cell.1 The interaction between the neuromodulator adenosine This interaction results in the excitation or inhibition of the and adenosine receptors on the surface of neurons mod- postsynaptic cell. Adenosine also alters neuronal activity, ifies the neurons’ responses to neurotransmitters. The ac- thereby affecting behavior; however, it does not meet all tivated adenosine receptors alter the levels of small the requirements for a neurotransmitter. For example, signaling molecules (i.e., second messengers) in the cells. adenosine by itself does not excite or inhibit postsynaptic Depending on the receptors and cells involved, these cells. Instead, adenosine regulates or modulates the activity changes can make it easier or more difficult for neuro- of neurons in response to other neurotransmitters; it is transmitters to excite the cell. Adenosine’s activity is reg- therefore called a neuromodulator. ulated by proteins called nucleoside transporters, which Adenosine is generated in all living cells during the breakdown of adenosine triphosphate (ATP), which occurs carry adenosine into and out of the cell. Alcohol inter- during most energy-requiring chemical reactions in the cell. feres with the function of the adenosine system. For ex- Large, channel-forming proteins2 called nucleoside trans- ample, both acute and chronic alcohol exposure affect porters then carry some of the adenosine out of the cells the function of the adenosine-carrying nucleoside trans- into the fluid surrounding the cells (i.e., the extracellular porters, thereby indirectly altering the second-messenger fluid). In addition, some neurons release ATP along with levels in the cells. Through this mechanism, adenosine their neurotransmitters. This ATP also is converted into may mediate some of alcohol’s effects, such as intoxica- adenosine. The adenosine in the extracellular fluid can tion, motor incoordination, and sedation. KEY WORDS: interact with receptors on the surfaces of surrounding cells adenosine; neurotransmitters; receptors; neuron; cell sig- (including the cell that released it) and modulate these cells’ naling; second messenger; nucleosides; biological trans- port; brain; central nervous system; animal cell line; DOUGLAS P. DOHRMAN, PH.D., is a postdoctoral fellow in human cell line; cAMP; signal transduction; AOD intox- the Department of Neurology; IVAN DIAMOND, M.D., PH.D., is professor and vice chairman in the Department of ication; motor coordination; sleep; literature review Neurology, a professor in the Department of Cellular and Molecular Pharmacology, and a member of the lcohol abuse and dependence are among the most Neuroscience Program; and ADRIENNE S. GORDON, PH.D., common and costly health problems worldwide. In is a professor in the Departments of Neurology and Athe United States alone, nearly 7 percent of adults Cellular and Molecular Pharmacology and a member of are alcohol dependent. Furthermore, the consequences of the Neuroscience Program, Ernest Gallo Clinic and heavy drinking account for more than 20 percent of all Research Center, University of California, San Francisco hospitalizations (Diamond and Gordon 1997). To address General Hospital, San Francisco, California. the plethora of medical and social problems associated with alcohol abuse and dependence and to identify the 1Whereas the presynaptic cell is always a neuron, the postsynaptic cell mechanisms underlying the development of tolerance to can be either a neuron or another cell type, such as a muscle cell. and dependence on alcohol, it is vital to understand alco- 2For a definition of this and other technical terms used in this article, see hol’s interactions with various brain systems. central glossary, pp. 177–179. 136 ALCOHOL HEALTH & RESEARCH WORLD NEUROTRANSMITTER REVIEW Adenosine A1 A2 Phospholipase C Adenylyl G Inhibitory cyclase Stimulatory protein G protein G protein produces activates inhibits activates produces Diacylglycerol cAMP activates activates Protein kinase C Protein kinase A Phosphorylation of certain proteins Phosphorylation of certain proteins Figure 1 The adenosine A1 and A2 receptors affect cell function by modulating the activities of the enzymes adenylyl cyclase and phospholipase C. Through their association with inhibitory and stimulatory G proteins, A1 inhibits and A2 activates adenylyl cyclase, the enzyme that produces the second messenger cAMP. In turn, cAMP activates the enzyme protein kinase A (PKA), which adds phosphate groups to (i.e., phosphorylates) various proteins. For example, PKA phosphorylates protein channels, which allow the transport of ions across the cell membrane, and transcription factors, which alter gene activity. Phosphorylation modifies the activities of these proteins. A1 also activates phospholipase C, which produces the second messenger diacylglycerol. This substance activates the enzyme protein kinase C, which also phosphorylates certain proteins. functions. To prevent adenosine accumulation in the extra- an adenosine receptor into changes in cell function requires cellular fluid and control adenosine’s effects on other cells, multiple steps, as follows (see also figure 1): adenosine is taken back up into the cells by the nucleoside transporters or broken down by extracellular enzymes. 1. The adenosine receptors are linked to regulatory molecules called G proteins. Two types of G proteins exist: stimula- Adenosine Receptors tory G proteins (Gs), which enhance the activities of other enzymes, and inhibitory G proteins (G ), which inhibit the Three different subgroups of adenosine receptors exist—A , i 1 activities of other enzymes. The interaction of adenosine A , and A —which differ in their structures and in the 2 3 with its receptors activates Gs or Gi proteins, depending molecules with which they can interact, in addition to adeno- on the receptor involved. sine (for a review, see Palmer and Stiles 1995). Each cell can carry more than one type of adenosine receptor. All 2. Certain activated Gs stimulate and activated Gi inhibit adenosine receptors modulate cell function primarily by the activity of the enzyme adenylyl cyclase, which gen- altering the levels of small signaling molecules (i.e., second erates cAMP. messengers) within the cells. Two important second messen- gers are cyclic adenosine monophosphate (cAMP) and dia- 3. cAMP activates PKA. cylglycerol (DAG). These compounds activate two enzymes (i.e., protein kinase A [PKA] and protein kinase C [PKC]), 4. A different set of G proteins modulates the activity of which add phosphate groups to other proteins. This process the enzyme phospholipase C, which generates DAG. is called phosphorylation. In this way, PKA and PKC acti- vate or inactivate these proteins. Translating the activation of 5. DAG activates PKC. VOL. 21, NO. 2, 1997 137 NEUROTRANSMITTER REVIEW 6. Both PKA and PKC phosphorylate numerous proteins, A1 and A2 receptors. In these cells, adenosine’s overall ef- including receptors for other neurotransmitters; proteins fect on cell functioning likely reflects the ratio of A1 to A2 that form channels allowing charged particles (i.e., ions) receptors. In addition, experimental evidence suggests that to enter or leave the cell; and certain proteins called the same receptor type can have different effects in different transcription factors, which regulate the activity of areas of the same cell and that A1 and A2 receptors can be many genes in the cell nucleus. concentrated in different regions of one cell (LeVier et al. 1992). Both of