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Brain Reward Circuits in Alcoholism

Published online by Cambridge University Press:  07 November 2014

George F. Koob  and
Amanda J. Roberts
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Abstract

This article discusses the neurocircuitry and the neurochemical systems, as well as the molecular elements within these systems, that are believed to be important in the etiology of alcoholism. Alcoholism is a complex behavioral disorder characterized by excessive consumption of alcohol; a narrowing of the behavioral repertoire toward excessive consumption; the development of tolerance and dependence; and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome.

Recent work has begun to define the neurocircuits responsible for the major sources of positive and negative reinforcement that are key to animal models of excessive alcohol intake. Alcohol appears to interact with alcohol-sensitive elements within neuronal membranes that convey the specificity of neurochemical actions. Positive reinforcement appears to be mediated by an activation γ-aminobutyric acid A receptors, release of opioid peptides and dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic alcohol administration. This is reflected by their exhibiting opposite effects during acute alcohol withdrawal, and by the recruitment of other neurotransmitter systems, such as the stress neuropeptide corticotropin-releasing factor. These neuropharmacologic actions are believed to produce allostatic changes in set-point, which set up the vulnerability to relapse that is so characteristic of alcoholism. Future challenges include a focus on understanding exactly how these neuroadaptive changes convey vulnerability to relapse in animals with a history of alcohol dependence.

Type
Feature Articles
Information
CNS Spectrums , Volume 4 , Issue 1: Neural Mechanisms of the Alcohol Abuse Cycle , January 1999 , pp. 23 - 37
Copyright
Copyright © Cambridge University Press 1999

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References

REFERENCES

1.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association Press; 1994.Google Scholar
2.Wikler, A. Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch Gen Psychiatry. 1973;28:611–616.CrossRefGoogle ScholarPubMed
3.Koob, GF, Markou, A, Weiss, F, Schulteis, G. Opponent process and drug dependence: neurobiological mechanisms. Semin Neurosci. 1993;5:351–358.Google Scholar
4.Schuster, CR, Thompson, T. Self administration and behavioral dependence on drugs. Annu Rev Pharmacol Toxicol. 1969;9:483–502.Google Scholar
5.Samson, HH. Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res. 1986;10:436–442.Google Scholar
6.Olds, J, Milner, P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 1954;47:419–427.Google Scholar
7.Kornetsky, C, Esposito, RU. Euphorigenic drugs: effects on the reward pathways of the brain. Federation Proc. 1979;38:2473–2476.Google Scholar
8.Markou, A, Koob, GF. Postcocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology. 1991;4:17–26.Google Scholar
9.Schulteis, G, Markou, A, Gold, LH, Stinus, L, Koob, GF. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. J Pharmacol Exp Ther. 1994;271:1391–1398.Google Scholar
10.Leith, NJ, Barrett, RJ. Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia. 1976;46:19–25.Google Scholar
11.Parsons, LH, Koob, GF, Weiss, F. Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine. J Pharmacol Exp Ther. 1995;274:1182–1191.Google Scholar
12.Epping-Jordan, MP, Watkins, SS, Koob, GF, Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature. 1998;393:76–79.Google Scholar
13.Legault, M, Wise, RA. Effects of withdrawal from nicotine on intracranial self-stimulation. Neurosci Abstr. 1994;20:1032.Google Scholar
14.Schulteis, G, Markou, A, Cole, M, Koob, GF. Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci USA. 1995;92:5880–5884.Google Scholar
15.Markou, A, Kosten, TR, Koob, GF. Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology. 1998;18:135–174.Google Scholar
16.Heyser, CJ, Schulteis, G, Durbin, P, Koob, GF. Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacology. 1998;18:125–133.Google Scholar
17.Samson, HH. Initiation of ethanol-maintained behavior: a comparison of animal models and their implication for human drinking. In: Thompson, T, Dews, PB, Barrett, JE, eds. Neurobehavioral Pharmacology. Hillsdale, NJ: Lawrence Erlbaum; 1987:221–248.Google Scholar
18.Samson, HH, Pfeffer, AO, Tolliver, GA. Oral ethanol self-administration in rats: models of alcohol-seeking behavior. Alcohol Clin Exp Res. 1988;12:591–598.Google Scholar
19.Samson, HH, Hodge, CW, Tolliver, GA, Haraguchi, M. Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: the involvement of the nucleus accumbens. Brain Res Bull. 1993;30:133–141.Google Scholar
20.Tabakoff, B, Hoffman, PL. Alcohol: neurobiology. In: Lowinson, JH, Ruiz, P, Millman, RB, eds. Substance Abuse: A Comprehensive Textbook. 2nd ed. Baltimore, MD: Williams & Wilkins; 1992:152–185.Google Scholar
21.Deitrich, RA, Dunwiddie, TV, Harris, RA, Erwin, VG. Mechanism of action of ethanol: initial central nervous system actions. Pharmacol Rev. 1989;41:489–537.Google Scholar
22.Hyytia, P, Koob, GF. GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats. Eur J Pharmacol. 1995;283:151–159.Google Scholar
23.Rassnick, S, Pulvirenti, L, Koob, GF. Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology. 1992;109:92–98.Google Scholar
24.Weiss, F, Hurd, YL, Ungerstedt, U, Markou, A, Plotsky, PM, Koob, GF. Neurochemical correlates of cocaine and ethanol self-administration. Ann NY Acad Sci. 1992;654:220–241.Google Scholar
25.Rassnick, S, Stinus, L, Koob, GF. The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res. 1993;623:16–24.Google Scholar
26.Murai, T, Koshikawa, N, Kanayama, T, Takada, K, Tomiyama, K, Kobayashi, M. Opposite effects of midazolam and beta-carboline-3-carboxylate ethyl ester on the release of dopamine from rat nucleus accumbens measured by in vivo microdialysis. Eur J Pharmacol. 1994;261:65–71.Google Scholar
27.Engel, JA, Enerback, C, Fahlke, C, et al.Serotonergic and dopaminergic involvement in ethanol intake. In: Naranjo, CA, Sellers, EM, eds. Novel Pharmacological Interventions for Alcoholism. New York, NY: Springer-Verlag; 1992:68–82.Google Scholar
28.Heyser, CJ, Roberts, AJ, Schulteis, G, Hyytia, P, Koob, GF. Central administration of an opiate antagonist decreases oral ethanol self-administration in rats. Neurosci Abstr. 1995;21:1698.Google Scholar
29.Zabik, JE, Blinkerd, K, Roache, JD. Serotonin and ethanol aversion in the rat. In: Naranjo, CA, Sellers, EM, eds. Research Advances in New Psychopharmacological Treatments for Alcoholism. New York, NY: Excerpta Medica; 1985:87–100.Google Scholar
30.Fadda, F, Garau, B, Marchei, F, Colombo, G, Gessa, GL. MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats. Alcohol Alcohol. 1991;26:107–110.Google Scholar
31.Hodge, CW, Samson, HH, Lewis, RS, Erickson, HL. Specific decreases in ethanol—but not water—reinforced responding produced by the 5-HT3 antagonist ICS 205-930. Alcohol. 1993;10:191–196.Google Scholar
32.Grant, KA, Barrett, JE. Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists. Psychopharmacology. 1991;104:451–456.Google Scholar
33.Roberts, AJ, McArthur, RA, Hull, EE, Post, C, Koob, GF. Effects of amperozide, 8-OH-DPAT, and FG 5974 on operant responding for ethanol. Psychopharmacology. 1998;137:25–32.Google Scholar
34.Hoffman, PL, Rabe, C, Moses, F, Tabakoff, B. N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. J Neurochem. 1989;52:1937–1940.Google Scholar
35.Lovinger, DM, White, G, Weight, FF. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science. 1989;243:1721–1724.Google Scholar
36.Grant, KA, Colombo, G. Discriminative stimulus effects of ethanol: effect of training dose on the substitution of N-methyl-D-aspartate antagonists. J Pharmacol Exp Ther. 1993;264:1241–1247.Google Scholar
37.Fitzgerald, LW, Nestler, EJ. Molecular and cellular adaptations in signal transduction pathways following ethanol exposure. Clin Neurosci. 1995;3:165–173.Google Scholar
38.Koob, GF, Rassnick, S, Heinrichs, S, Weiss, F. Alcohol, the reward system and dependence. In: Jansson, B, Jörnvall, H, Rydberg, U, Terenius, L, Vallee, BL, eds. Toward a Molecular Basis of Alcohol Use and Abuse. Boston, Mass: Birkhauser-Verlag; 1994:103–114.Google Scholar
39.Thiele, TE, Marsh, DJ, Ste. Marie, L, Bernstein, IL, Palmiter, RD. Ethanol consumption and resistance are inversely related to neuropeptide y levels. Nature. 1998;396:366–369.Google Scholar
40.Koob, GF. Drugs of abuse: anatomy, pharmacology, and function of reward pathways. Trends Pharmacol Sci. 1992;13:177–184.CrossRefGoogle ScholarPubMed
41.Mereu, G, Fadda, F, Gessa, GL. Ethanol stimulates the firing rate of nigral dopaminergic neurons in unanesthetized rats. Brain Res. 1984;292:63–69.Google Scholar
42.Weiss, F, Lorang, MT, Bloom, FE, Koob, GF. Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther. 1993;267:250–258.Google Scholar
43.Givens, BS, Breese, GR. Site-specific enhancement of gamma-aminobutyric acid-mediated inhibition of neural activity by ethanol in the rat medial septal area. J Pharmacol Exp Ther. 1990;254:528–538.Google Scholar
44.Koob, GF, Sanna, PP, Bloom, FE. Neuroscience of addiction. Neuron. 1998;21:467–476.Google Scholar
45.Koob, GF, Robledo, P, Markou, A, Caine, SB. The mesocorticolimbic circuit in drug dependence and reward: a role for the extended amygdala? In: Kalivas, PW, Barnes, CD, eds. Limbic Motor Circuits and Neuropsychiatry. Boca Raton, Fla: CRC Press; 1993:289–309.Google Scholar
46.Koob, GF, Le Moal, M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278:52–58.Google Scholar
47.Koob, GF. Drug addiction: the yin and yang of hedonic homeostasis. Neuron. 1996;16:893–896.Google Scholar
48.Russell, MAH. What is dependence? In: Edwards, G, Russell, MAH, Hawks, D, MacCafferty, M, eds. Drugs and Drug Dependence. Lexington, Mass: Lexington Books; 1976:182–187.Google Scholar
49.Markou, A, Koob, GF. Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations. Physiol Behav. 1992;51:111–119.Google Scholar
50.Robinson, TE, Berridge, KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev. 1993;18:247–291.Google Scholar
51.Solomon, RL, Corbit, JD. An opponent-process theory of motivation. I: temporal dynamics of affect. Psychol Rev. 1974;81:119–145.Google Scholar
52.Siegel, S. Evidence from rats that morphine tolerance is a learned response. J Comp Physiol Psychol. 1975;89:498–506.Google Scholar
53.Poulos, CX, Cappell, H. Homeostatic theory of drug tolerance: a general model of physiological adaptation. Psychol Rev. 1991;98:390–408.Google Scholar
54.Koob, GF, Bloom, FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;242:715–723.Google Scholar
55.Weiss, F, Markou, A, Lorang, MT, Koob, GF. Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimitedaccess self-administration. Brain Res. 1992;593:314–318.Google Scholar
56.Roberts, AJ, Cole, M, Koob, GF. Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res. 1996;20:1289–1298.Google Scholar
57.Weiss, F, Parsons, LH, Schulteis, G, et al.Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J Neurosci. 1996;16:3474–3485.CrossRefGoogle ScholarPubMed
58.Kreek, MJ. Multiple drug abuse patterns and medical consequences. In: Meltzer, HY, ed. Psychopharmacology: The Third Generation of Progress. New York, NY: Raven Press; 1987:1597–1604.Google Scholar
59.Kreek, MJ, Ragunath, J, Plevy, S, Hamer, D, Schneider, B, Hartman, N. ACTH, cortisol and beta-endorphin response to metyrapone testing during chronic methadone maintenance treatment in humans. Neuropeptides. 1984;5:277–278.Google Scholar
60.Koob, GF, Heinrichs, SC, Menzaghi, F, Merlo-Pich, E, Britton, KT. Corticotropin-releasing factor, stress and behavior. Semin Neurosci. 1994;6:221–229.Google Scholar
61.Heinrichs, SC, Menzaghi, F, Schulteis, G, Koob, GF, Stinus, L. Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal. Behav Pharmacol. 1995;6:74–80.Google Scholar
62.Rodriguez de Fonseca, F, Carrera, MRA, Navarro, M, Koob, GF, Weiss, F. Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science. 1997;276:2050–2054.Google Scholar
63.Richter, RM, Weiss, F. In vivo CRF release in rat amygdala is increased during cocaine withdrawal in self-administrating rats. Synapse. In press.Google Scholar
64.Rassnick, S, Heinrichs, SC, Britton, KT, Koob, GF. Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res. 1993;605:25–32.Google Scholar
65.Sarnyai, Z, Biro, E, Gardi, J, Vecsernyes, M, Julesz, J, Telegdy, G. Brain corticotropin-releasing factor mediates “anxiety-like” behavior induced by cocaine withdrawal in rats. Brain Res. 1995;675:89–97.Google Scholar
66.Morrow, AL, Suzdak, PD, Karanian, JW, Paul, SM. Chronic ethanol administration alters gamma-aminobutyric acid, pentobarbital and ethanol-mediated 36Cl-uptake in cerebral cortical synaptoneurosomes. J Pharmacol Exp Ther. 1988;246:158–164.Google Scholar
67.Karobath, M, Rogers, J, Bloom, FE. Benzodiazepine receptors remain unchanged after chronic ethanol administration. Neuropharmacology. 1980;19:125–128.Google Scholar
68.Mhatre, MC, Pena, G, Sieghart, W, Ticku, MK. Antibodies specific for GABA-A receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions. J Neurochem. 1993;61:1620–1625.Google Scholar
69.Devaud, LL, Smith, FD, Grayson, DR, Morrow, AL. Chronic ethanol consumption differentially alters the expression of gamma-aminobutyric acidA receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. Mol Pharmacol. 1995;48:861–868.Google Scholar
70.Tabakoff, B, Hoffman, PL. Alcohol addiction: an enigma among us. Neuron. 1996;16:909–912.Google Scholar
71.Devaud, LL, Fritschy, JM, Sieghart, W, Morrow, AL. Bidirectional alterations of GABAA receptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal. J Neurochem. 1997;69:126–130.Google Scholar
72.Mahmoudi, M, Kang, MH, Tillakaratne, N, Tobin, AJ, Olsen, RW. Chronic intermittent ethanol treatment in rats increases GABAA receptor α4-subunit expression: possible relevance to alcohol dependence. J Neurochem. 1997;68:2485–2492.CrossRefGoogle ScholarPubMed
73.Charlton, ME, Sweetnam, PM, Fitzgerald, LW, Terwilliger, RZ, Nestler, EJ, Duman, RS. Chronic ethanol administration regulates the expression of GABAA receptor α 1 and α 5 subunits in the ventral tegmental area and hippocampus. J Neurochem. 1997;68:121–127.Google Scholar
74.Trevisan, L, Fitzgerald, LW, Brose, N, et al.Chronic ingestion of ethanol up-regulates NMDA-R1 receptor subunit immunoreactivity in rat hippocampus. J Neurochem. 1994;62:1635–1638.Google Scholar
75.Hu, XJ, Ticku, MK. Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons. Mol Brain Res. 1995;30:347–356.Google Scholar
76.Chandler, LJ, Sutton, G, Norwood, D, Sumners, C, Crews, FT. Chronic ethanol increases N-methyl-D-aspartate-stimulated nitric oxide formation but not receptor density in cultured cortical neurons. Mol Pharmacol. 1997;51:733–740.Google Scholar
77.Rossetti, ZL, Carboni, S. Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol. 1995;283:177–183.Google Scholar
78.Ortiz, J, Fitzgerald, LW, Charlton, M, et al.Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse. 1995;21:289–298.CrossRefGoogle ScholarPubMed
79.Messing, RO, Petersen, PJ, Henrich, CJ. Chronic ethanol exposure increases levels of protein kinase C delta and epsilon and protein kinase C-mediated phosphorylation in cultured neural cells. J Biol Chem. 1991;66:23428–23432.Google Scholar
80.Messing, RO, Sneade, AB, Savidge, B. Protein kinase C participates in upregulation of dihydropyridine-sensitive calcium channels by ethanol. J Neurochem. 1990;55:1383–1389.Google Scholar
81.Watson, WP, Little, JJ. Effects of dihydropyridines on the components of the ethanol withdrawal syndrome: possible evidence for involvement of potassium, as well as calcium? Alcohol Clin Exp Res. 1997;21:409–416.Google Scholar
82.Colombo, G, Agabio, R, Lobina, C, et al.Effects of the calcium channel antagonist darodipine on ethanol withdrawal in rats. Alcohol Alcohol. 1995;30:125–131.Google ScholarPubMed
83.Shindou, T, Watanabe, S, Kamata, O, Yamamoto, K, Nakanishi, H. Calcium-dependent hyperexcitability of hippocampal CA1 pyramidal cells in an in vitro slice after ethanol withdrawal of the rat. Brain Res. 1994;656:432–436.Google Scholar
84.Diana, M, Pistis, M, Muntoni, AL, Gessa, GL. Ethanol withdrawal does not induce a reduction in the number of spontaneously active dopaminergic neurons in the mesolimbic system. Brain Res. 1995;682:29–34.Google Scholar
85.Ryabinin, AE, Criado, JR, Henriksen, SJ, Bloom, FE, Wilson, MC. Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol. Mol Psychiatry. 1997;2:32–43.Google Scholar
86.Koob, GF, Wall, TL, Schafer, J. Rapid induction of tolerance to the antipunishment effects of ethanol. Alcohol. 1987;4:481–484.Google Scholar
87.Li, DH, Depoortere, RY, Emmett-Oglesby, MW. Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm. Psychopharmacology. 1994;116:326–332.Google Scholar
88.Young, AM, Goudie, AJ. Adaptive processes regulating tolerance to the behavioral effects of drugs. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:733–742.Google Scholar
89.Khanna, JM, Kalant, H, Shah, G, Chau, A. Effect of (+)MK-801 and ketamine on rapid tolerance to ethanol. Brain Res Bull. 1992;28:311–314.Google Scholar
90.Khanna, JM, Morato, GS, Chau, A, Shah, G, Kalant, H. Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: importance of intoxicated practice. Pharmacol Biochem Behav. 1994;48:755–763.Google Scholar
91.Collingridge, GL, Singer, W. Excitatory amino acid receptors and synaptic plasticity. Trends Pharmacol Sci. 1990;11:290–296.Google Scholar
92.Hoffman, PL. Neuroadaptive functions of the neuropeptide arginine vasopressin: ethanol tolerance. In: Strand, FL, Beckwith, B, Chronwall, B, Sandman, CA, eds. Models of Neuropeptide Action. New York, NY: New York Academy of Sciences; 1994:168–175.Google Scholar
93.Szabo, G, Tabakoff, B, Hoffman, PL. Receptors with VI characteristics mediate the maintenance of ethanol tolerance by vasopressin. J Pharmacol Exp Ther. 1988;247:536–541.Google Scholar
94.Szabo, G, Nunley, KR, Hoffman, PL. Antisense oligonucleotide to c-fos blocks the ability of arginine vasopressin to maintain ethanol tolerance. Eur J Pharmacol. 1996;306:67–72.Google Scholar
95.Nestler, EJ, Hope, BT, Widnell, KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron. 1993;11:995–1006.Google Scholar
96.Krauss, SW, Ghirnikar, RB, Diamond, I, Gordon, AS. Inhibition of adenosine uptake by ethanol is specific for one class of nucleoside transporters. Mol Pharmacol. 1993;44:1021–1026.Google Scholar
97.Nagy, LE, Diamond, I, Casso, DJ, Franklin, C, Gordon, AS. Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J Biol Chem. 1990;265:1946–1951.Google Scholar
98.Coe, IR, Dohrman, DP, Constantinescu, A, Diamond, I, Gordon, AS. Activation of cyclic AMP-dependent protein kinase reverses tolerance of a nucleoside transporter to ethanol. J Pharmacol Exp Ther. 1996;276:365–369.Google Scholar
99.Coe, IR, Yao, L, Diamond, I, Gordon, AS. The role of protein kinase C in cellular tolerance to ethanol. J Biol Chem. 1996;71:29468–29472.Google Scholar
100.Phillips, TJ, Feller, DJ, Crabbe, JC. Selected mouse lines, alcohol and behavior. Experientia. 1989;45:805–827.CrossRefGoogle ScholarPubMed
101.Phillips, TJ, Roberts, AJ, Lessov, CN. Behavorial sensitization to ethanol: genetics and the effects of stress. Pharmacol Biochem Behav. 1997;57:487–493.Google Scholar
102.Wise, RA, Leeb, K. Psychomotor-stimulant sensitization: a unitary phenomenon? Behav Pharmacol. 1993;4:339–349.Google Scholar
103.Koechling, UM, Smith, BR, Amit, Z. Differential effects of catecholamine antagonists on ethanol-induced excitation in mice. Psychopharmacology. 1990;102:234–238.Google Scholar
104.Kalivas, PW, Stewart, J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev. 1991;16:223–244.Google Scholar
105.White, FJ, Wolf, ME. Psychomotor stimulants. In: Pratt, JA, ed. The Biological Bases of Drug Tolerance and Dependence. London, England: Academic Press; 1991:153–197.Google Scholar
106.Henry, DJ, White, FJ. Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J Pharmacol Exp Ther. 1991;258:882–890.Google Scholar
107.Koob, GF, Cador, M. Psychomotor stimulant sensitization: the corticotropin-releasing factor-steroid connection. Behav Pharmacol. 1993;4:351–354.Google Scholar
108.Karler, R, Calder, LD, Chaudhry, IA, Turkanis, SA. Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci. 1989;45:599–606.Google Scholar
109.Wise, RA. The neurobiology of craving: implications for the understanding and treatment of addiction. J Abnorm Psychol. 1988;97:118–132.Google Scholar
110.Ballenger, JC, Post, RM. Kindling as a model for alcohol withdrawal syndromes. Br J Psychiatry. 1978;133:1–14.Google Scholar
111.Becker, HC, Diaz-Granados, JL, Weathersby, RT. Repeated ethanol withdrawal experience increases the severity and duration of subsequent withdrawal seizures in mice. Alcohol. 1997;14:319–326.Google Scholar
112.Kokka, N, Sapp, DW, Taylor, AM, Olsen, RW. The kindling model of alcohol dependence: similar persistent reduction in seizure threshold to pentylenetetrazol in animals receiving chronic ethanol or chronic pentylenetetrazol. Alcohol Clin Exp Res. 1993;17:525–531.CrossRefGoogle ScholarPubMed
113.Becker, HC, Hale, RL. Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal “kindling.” Alcohol Clin Exp Res. 1993;17:94–98.Google Scholar
114.Ulrichsen, J, Bech, B, Allerup, P, Hemmingsen, R. Diazepam prevents progression of kindled alcohol withdrawal behaviour. Psychopharmacology. 1995;121:451–460.Google Scholar
115.Kang, M, Spigelman, I, Sapp, DW, Olsen, RW. Persistent reduction of GABAA receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment. Brain Res. 1996;709:221–228.Google Scholar
116.Hope, BT, Nye, HE, Kelz, MB, et al.Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron. 1994;13:1235–1244.Google Scholar
117.Hyman, SE. Addiction to cocaine and amphetamine. Neuron. 1996;16:901–904.Google Scholar
118.Widnell, K, Self, DW, Lane, SB, et al.Regulation of CREB expression: in vivo evidence for a functional role in morphine action in the nucleus accumbens. J Pharmacol Exp Ther. 1996;276:306–315.Google Scholar
119.Muller, N, Hoehe, M, Klein, HE, et al.Endocrinological studies in alcoholics during withdrawal and after abstinence. Psychoneuroendocrinology. 1989;14:113–123.Google Scholar
120.Costa, A, Bono, G, Martignoni, E, Merlo, P, Sances, G, Nappi, G. An assessment of hypothalamo-pituitary-adrenal axis functioning in non-depressed, early abstinent alcoholics. Psychoneuroendocrinology. 1996;21:263–275.Google Scholar
121.Koob, GF. Animal models of drug addiction. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:759–772.Google Scholar
122.deWit, H, Stewart, J. Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology. 1981;75:134–143.Google Scholar
123.Stewart, J, deWit, H. Reinstatement of drug-taking behavior as a method of assessing incentive motivational properties of drugs. In: Bozarth, MA, ed. Methods of Assessing the Reinforcing Properties of Abused Drugs. New York, NY: Springer-Verlag; 1987:211–227.Google Scholar
124.Manley, SJ, Little, HJ. Enhancement of amphetamine and cocaine-induced locomotor activity after chronic ethanol administration. J Pharmacol Exp Ther. 1997;281:1330–1339.Google Scholar
125.Roberts, AJ, Koob, GF. Increased operant responding for ethanol in rats with a prior history of dependence. Alcohol Clin Exp Res. 1996;20(suppl):22A.Google Scholar
126.Roberts, AJ, Heyser, CJ, Griffin, P, Cole, M, Koob, GF. Operant responding for ethanol after chronic ethanol vapor exposure in rats. Alcohol Clin Exp Res. 1997;21(suppl):43A.Google Scholar
127.Koob, GF, Carrera, MRA, Gold, LH, et al.Substance dependence as a compulsive behavior. J Psychopharmacol. 1998;12:39–48.Google Scholar
128.Heyser, CJ, Schulteis, G, Durbin, P, Koob, GF. Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychophamacobgy. 1998;18:125–133.Google Scholar
129.Spanagel, R, Zieglgansberger, W. Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes. Trends Pharmacol Sci. 1997;18:54–59.Google Scholar
130.Holter, SM, Landgraf, R, Zieglgansberger, W, Spanagel, R. Time course of acamprosate action on operant ethanol self-administration after ethanol deprivation. Alcohol Clin Exp Res. 1997;21:862–868.Google Scholar
131.Heyser, CJ, Schulteis, G, Koob, GF. Increased ethanol self-administration after a period of imposed ethanol deprivation in rats trained in a limited access paradigm. Alcohol Clin Exp Res. 1997;21:784–791.CrossRefGoogle Scholar
132.Madamba, SG, Schweitzer, P, Zieglgansberger, W, Siggins, GR. Acamprosate (calcium acetylhomotaurinate) enhances the N-methyl-D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro. Alcohol Clin Exp Res. 1996;20:651–658.Google Scholar
133.Zeise, ML, Kasparov, S, Capogna, M, Zieglgansberger, W. Acamprosate (calcium acetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol. 1993;231:47–52.Google Scholar
134.Volpicelli, JR, Davis, MA, Olgin, JE. Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci. 1986;38:841–847.Google Scholar
135.O'Malley, SS, Jaffe, AJ, Chang, G, Schottenfeld, RS, Meyer, RE, Rounsaville, B. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry. 1992;49:881–887.Google Scholar
136.Volpicelli, JR, Alterman, Al, Hayashida, M, O'Brien, CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49:876–880.Google Scholar
137.Alheid, GF, Heimer, L. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience. 1988;27:1–39.Google Scholar
138.Johnston, JB. Further contributions to the study of the evolution of the forebrain. J Comp Neurol. 1923;35:337–481.Google Scholar
139.Heimer, L, Zahm, DS, Churchill, L, et al.Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience. 1991;41:89–125.Google Scholar
140.Hyytia, P, Koob, GF. GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats. Eur J Pharmacol. 1995;283:151–159.Google Scholar
141.Roberts, AJ, Koob, GF. Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res. 1996;20:1289–1298.Google Scholar
142.Pontieri, FE, Tanda, G, Di Chiara, G. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci USA. 1995;92:12304–12308.Google Scholar
143.Tanda, G, Pontieri, FE, Di Chiara, G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mul opioid receptor mechanism. Science. 1997;276:2048–2050.Google Scholar
144.Pontieri, FE, Tanda, G, Orzi, F, Di Chiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature. 1996;382:255–257.Google Scholar
145.Merlo-Pich, E, Lorang, M, Yeganeh, M, et al.Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neumsci. 1995;15:5439–5447.Google Scholar
146.Davis, M. Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci. 1997;9:382–402.Google Scholar