cellular regions can be modified by the addition of phos-phate groups - PDF document

128A& RESEARCHcellular regions can be m
128A& RESEARCHcellular regions can be modified by the addition of phos-phate groups (i.e., can become phosphorylated). As de-Many different GABAidentified. These fall into three groups: , , and sub-1and 2most GABAreceptor consists of two subunits, one subunit, and twosubunits (see figure). Each subunit type only interactswith specific molecules. Thus, the and subunits can interact with GABA,and 
overall characteristics.GABAreceptorsinneurons or brain regions or at various developmentalECEPTOROLEINNTOXICATIONNumerous clinically useful sedating medications (e.g.,benzodiazepines, such as Valiumas phenobarbital) and anesthetic agents (e.g., halothane)sbalance of excitatory and inhibitory influences in the brainUsing several different approaches, researchers haveattempted to determine which of alcoholfects are mediated by changes in GABAtion. One strategy has been to administer alcohol togetherA notic effects (Deitrich et al. 1989). Similarly, rats that weretreated with a compound that inhibits GABA degradationexhibited increased alcohol-induced incoordination4513, which inhibits GABAAshown to prevent some of alcoholexample, Ro 15-4513 reduced the severity of alcoholstherefore must be interpreted with caution.More direct evidence of alcoholGABAfrom studies in mouse and rat strains bred to differ in theirsensitivities to some of alcoholhavioral effects. Neurochemical stud-GABA-mediated ClÓÑmembranes isolatedfrom brain cells that form sealedin tissue culture. Many of these studiesup-Researchers also have investigated

alcoholGABAincoordination or loss of rig
alcoholGABAincoordination or loss of righting reflex. Forexample, so-called long-sleep (LS) mice exhibit a longerunderlie the behavioral differences observed between theAlcoholinvolve the actions of other cellular proteins, such as thespecific sites. In one experiment, for example, mice lack-tion further strengthens the hypothesis that alcohol-inducedvolves proteins other than the receptor proteins but alsoassess alcoholstudies have employed different experimental systems: (1)NEUROTRANSMITTER REVIEWSome alcoholics mayexhibit abnormalGABA metabolismVO. 2, 1997129normally do not produce GABAinduced artificially to manufacture receptors composed ofFor example, one study found that alcohol enhanced thebellum of rats only in the presence of the neurotransmitter--also interact in the absence of alcohol, but this interactioninteractions among the -adrenergic receptor, the GABAs-adrenergic receptor,thereby increasing that receptorGABA-adrenergic enhancementof GABAof norepinephrine from the synapses.-adrenergic signal transmission results in increased pro-tein phosphorylation. Thus, whatever the exact mechanismand -adrenergic receptors supports the conclu-sions from the C1alcoholvation of phosphorylating proteins, such as PKC (for ativity to alcohol of the GABAfirmed in studies analyzing alcoholthe 22S) and a long variant (2LÑin size by eight amino acids. Analyses in cultured cells2Lsubunit showedalcohol-induced enhancement of their activity, whereas2Ssubunit generally were insensi-tive to intoxicating alcohol concentr

ations (Wafford and2Lcontain a siteth
ations (Wafford and2Lcontain a sitethat can be phosphorylated by PKC, indicating that phos-sbe performed in cultured cells or other artificial systems,not in intact brains. Therefore, one cannot conclude un-tordetermined by differences in receptor subunits, phosphory-ECEPTORANDANDAfter continuous alcohol consumption, both humansand laboratory animals develop tolerance to alcoholsto achieve the same effects. Moreover, continuousNEUROTRANSMITTER REVIEWPSchematic representation of the gamma-aminobutyric acid(GABAsGABABarbituratesBenzodiazepinesAlcoholAlcoholInterior130A& RESEARCHhelp explain both tolerance and dependence. For exam-receptor antagonist called bicuculline and of acompound called picrotoxin, which inhibits chloride chan-so that lower levels of the GABAalcoholadministrationbydeterminingthemessengersubunits (i.e., the 111995). These findings support the hypothesis that tolerancedevelopment involves reduced GABAA receptor numbers.The levels of other GABAA receptor subunits, however,appear to be elevated. Furthermore, studies in humans1be controlled as accurately as in animals. Additional stud-1significantly in animals that were genetically predisposedA subunitlevels prevent GABA-induced signal transmission, therebyBUSEANDRecent research findings suggest that the GABA systemalso may play a role in determining a personbility to developing alcohol abuse or alcohol dependence.glucose metabolism) in nonalcoholic subjects with a fam-of the brain that is responsible for motor coordination.A receptorsin the cerebellu

m was disrupted in the FP subjects, mak-
m was disrupted in the FP subjects, mak-a,b). It is un-clear, however, whether these reduced receptor levels were aNEUROTRANSMITTER REVIEWVO. 2, 1997131lower GABA levels in the blood, a finding that likely re-flects reduced GABA levels in the brain (Adinoff et al.A receptor functionsured by benzodiazepinebehaviorfamily history of alcoholism and therefore may be related toCdependenceonalcoholandmayunderliesomeofthealcoholism and for treating the disease. R, F.Levels of gamma-amino-Psychiatry Research, R.A.Neuroadaptive responses to chronicAlcoholism , D.W.Response toAlcoholism: Clinical and ExperimentalResearch, F.Effect of diazepam on plasma gamma-aminobutyric acid in sonsAlcoholism: Clinical and Experimental Research20:343Ð347, 1996.DARRISPharmacological Reviews, W.E.Decrease of benzodiazepine receptorsAlcohol5:275Ð282, 1988a.Loss of muscarinic and benzo-Alcohol6:23Ð31, 1988b.F, M.R. Beta adrenergic sensitization ofgamma-aminobutyric acid receptors to ethanol involves a cyclic AMPJournal of Pharmacologyand Experimental Therapeutics, P.J.Comparison of drug effects on recombinant GABAXenopusoocytes.Alcoholism: Clinical and Experimental Research, P.J.Which GABATrends in Neuroscience,S.J.;,R.A.AlcoholactionsattheGABAPharmacological Effects of Ethanol on the Nervous System., A.L.Regulation of GABAInternational Review of Neurobiology, P.L.Alcohol addiction: An enigma amongNeuron, A.P.RegionalAlcoholism: Clinical and Experimental Research , P.J.Ethanol potentiation of GABA2 subunit. FEBS Letters, T.V.Elevat

ion of basal protein kinase C activity i
ion of basal protein kinase C activity increasesJournal of Neurochemistry, K.A.Structure andInternational Review of Neurobiology., J.N.Modulation of GABAAlcoholism: Clinical and ExperimentalResearch20:1313Ð1319, 1996.NEUROTRANSMITTER REVIEW132A& RESEARCHOPIOID PEPTIDESJanice C. Froehlich, Ph.D.the opioid peptide system decrease alcohol self-EYWORDStransmitters; opioid receptors; central nervous system;Endogenous opioid peptides1are naturally produced in the central nervous system(CNS) and in various glands throughout the body,such as the pituitary and adrenal glands. These peptidesneurotransmitters. (For more information on these neuro-transmitters, see the related articles in this section.)Through these two mechanisms, endogenous opioid pep-tides produce many effects, ranging from preventing diar-This article reviews the physiology of endogenous opi-oid peptides and their interactions with other neurotrans-between alcohol and the endogenous opioid system andpresents evidence that opioid peptides play a role in alco-a; Herz 1997.)HYSIOLOGYOFOpioid Peptide ProductionMany peptides with opioidlike effects have been found inthe CNS and in peripheral tissues. Molecular biologicalfrom three distinct precursor molecules. The active, func-the processing of opioid peptides from larger precursormet-enkephalin) and one of the endorphins (i.e., beta-Opioid ReceptorsTo affect the functions of their target cells, opioid peptidesmust bind to specific molecules, or receptors, on the sur-delta, and kappatheir functions and in their binding charact

eristics. A givenNEUROTRANSMITTER REVIE
eristics. A givenNEUROTRANSMITTER REVIEWJDepartments of Medicine and Physiology/Biophysics, Indianaon Alcohol Abuse and Alcoholism grants AAÐ07611,AAÐ08312, and AAÐ10709.1central glossary, pp. 177VO. 2, 1997127campus. Journal of Neurochemistry, H.Excitatory amino acids and drugs of abuse: AN-methyl-physical dependence.Drug and Alcohol Dependence, J.T.The glutamatergic basis ofAmerican Journal of Psychiatry, R.A.Ethanol inhibition of N-methyl--Journal of Neurochemistry54:712Ð715, 1990.GABA AND THE GABAS. John Mihic, Ph.D., and R. Adron Harris, Ph.D.allows the passage of chloride ions into the cells.K: GABA; GABA receptors; neurotransmission;brain; sedative hypnotics; receptor proteins; chloridechannel; ion; protein kinases; AOD dependence; AODtolerance; AOD intoxication; AOD use susceptibility;animal model; literature reviewNthrough chemical messengers called neurotransmit-emitting neuron and bind to specific proteins (i.e.,Communication,transmitters and neurotransmitter receptorsand inhibitoryreceiving neuron. Excitatory neurotransmitters and theirand excitability, whereas inhibitory neurotransmitters andtheir receptors reduce neuronal excitability. For optimalfunctioning, the brain must balance the excitatory andhibitory neurotransmitter in the central nervous system.ECEPTORGABAmembranes of neurons (see figure). Each receptor consistsS. JDepartment of Physiology and Pharmacology, BowmanGrey School of Medicine, Winston-Salem, North Carolina.R. ADRONof Pharmacology and director of the Alcohol Research1central glossary, pp. 17