Skip to main content
SpringerLink
Log in

Conceptual framework for the etiology of alcoholism: a “kindling”/stress hypothesis

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The rationale for proposing the “kindling”/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.

Objective and results

An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize (“kindle”) anxiety-like behavior (“anxiety”) in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence—a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.

Conclusions

The “kindling”/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse—and with relapse an inability to limit an abusive pattern of alcohol intake. The “kindling”/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adinoff B, O’Neill HK, Ballenger JC (1995) Alcohol withdrawal and limbic kindling: a hypothesis of relapse. Am J Addict 4:5–17

    Google Scholar 

  • Alheid GF, De OImos JS, Beltramino CA (1995) Amygdala and extended amygdala. In: Paxinos G (ed) The rat nervous system. Academic, San Diego, pp 495–578

    Google Scholar 

  • Altshuler HL, Phillips PE, Feinhandler DA (1980) Alteration of ethanol self-administration by naltrexone. Life Sci 26:679–688

    Article  CAS  PubMed  Google Scholar 

  • Ansoms C, Deckers F, Lehert P, Pelc I, Potgieter A (2000) An open study with acamprosate in Belgium and Luxemburg: results on sociodemographics, supportive treatment and outcome. Eur Addict Res 6:132–140

    Article  CAS  PubMed  Google Scholar 

  • Bäckström P, Bachteler D, Koch S, Hyytia P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology. 21 Jan 2004 (Epub ahead of print)

  • Badia-Elder NE, Mosemiller AK, Elder RL, Froehlich JC (1999) Naloxone retards the expression of a genetic predisposition toward alcohol drinking. Psychopharmacology 144:205–212

    Article  CAS  PubMed  Google Scholar 

  • Baker TB, Cannon DS (1979) Potentiation of ethanol withdrawal. Psychopharmacology 60:105–110

    CAS  PubMed  Google Scholar 

  • Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557

    Article  CAS  PubMed  Google Scholar 

  • Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24:410–414

    Article  CAS  PubMed  Google Scholar 

  • Ballenger JC, Post RM (1978) Kindling as a model for alcohol withdrawal syndromes. Br J Psychiatry 133:1–14

    CAS  PubMed  Google Scholar 

  • Becker HC, Hale RL (1993) Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal “kindling”. Alcohol Clin Exp Res 17:94–98

    CAS  PubMed  Google Scholar 

  • Becker HC, Diaz-Granados JL, Weathersby RT (1997) Repeated ethanol withdrawal experience increases the severity and duration of subsequent withdrawal seizures in mice. Alcohol 14:319–326

    Article  CAS  PubMed  Google Scholar 

  • Becker HC, Veatch LM, Diaz-Granados JL (1998) Repeated ethanol withdrawal experience selectively alters sensitivity to different chemoconvulsant drugs in mice. Psychopharmacology 139:145–153

    Article  CAS  PubMed  Google Scholar 

  • Begleiter H, Porjesz B (1979) Persistence of a “subacute withdrawal syndrome” following chronic ethanol intake. Drug Alcohol Depend 4:353–357

    Article  CAS  PubMed  Google Scholar 

  • Besheer J, Cox AA, Hodge CW (2003) Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res 27:450–456

    PubMed  Google Scholar 

  • Besson J, Aeby F, Kasas A, Lehert P, Potgieter A (1998) Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res 22:573–579

    CAS  PubMed  Google Scholar 

  • Bienkowski P, Koros E, Kostowski W, Bogucka-Bonikowska A (2000) Reinstatement of ethanol seeking in rats: behavioral analysis. Pharmacol Biochem Behav 66:123–128

    Article  CAS  PubMed  Google Scholar 

  • Booth BM, Blow FC (1993) The kindling hypothesis: further evidence from a US national study of alcoholic men. Alcohol Alcohol 28:593–598

    CAS  PubMed  Google Scholar 

  • Breese GR, Knapp DJ, Overstreet DH (2004a) Stress sensitization of the ethanol withdrawal-induced deficit in social interaction: inhibition by CRF-1 and benzodiazepine receptor antagonists and a 5-HT1A agonist. Neuropsychopharmacology 29:470–482

    Article  CAS  PubMed  Google Scholar 

  • Breese GR, Knapp DJ, Overstreet DH (2004b) Stress-induced anxiety-like behavior during abstinence from previous chronic ethanol exposure. Alcohol Clin Exp Res 28:191A

    Google Scholar 

  • Brown ME, Anton RF, Malcolm R, Ballenger JC (1988) Alcoholic detoxification and withdrawal seizures: clinical support for a kindling hypothesis. Biol Psychiatry 23:507–514

    Article  CAS  PubMed  Google Scholar 

  • Brown SA, Vik PW, McQuaid JR, Patterson TL, Irwin MR, Grant I (1990) Severity of psychosocial stress and outcome of alcoholism treatment. J Abnorm Psychol 99:344–348

    Article  CAS  PubMed  Google Scholar 

  • Brown SA, Vik PW, Patterson TL, Grant I, Schuckit MA (1995) Stress, vulnerability and adult alcohol relapse. J Stud Alcohol 56:538–545

    CAS  PubMed  Google Scholar 

  • Brown G, Jackson A, Stephens DN (1998) Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule. Behav Pharmacol 9:149–161

    CAS  PubMed  Google Scholar 

  • Chester JA, Blose AM, Zweifel M, Froehlich JM (2004) Effects of stress on alcohol consumption in rats selectively bred for high or low alcohol drinking. Alcohol Clin Exp Res 28:385–393

    PubMed  Google Scholar 

  • Chiamulera C, Valerio E, Tessari M (1995) Resumption of ethanol seeking behaviour in rats. Behav Pharmacol 6:32–39

    CAS  PubMed  Google Scholar 

  • Chick J, Howlett H, Morgan MY, Ritson B (2000) United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol 35:176–187

    Article  CAS  PubMed  Google Scholar 

  • Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellan AT, O’Brien CP (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95

    CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Martin-Fardon R, Weiss F (2002) Effect of selective blockade of μ1 or δ opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology 27:391–399

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Lin D, Martin-Fardon R, Weiss F (2003) Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone. Psychopharmacology 168:208–215

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig M, Massi M (2004) Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology 172:170–178

    Article  CAS  PubMed  Google Scholar 

  • Clemmesen L, Hemmingsen R (1984) Physical dependence on ethanol during multiple intoxication and withdrawal episodes in the rat: evidence of a potentiation. Acta Pharmacol Toxicol 55:345–350

    CAS  Google Scholar 

  • Cloninger CR (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416

    CAS  PubMed  Google Scholar 

  • Cloninger CR, Bohman M, Sigvardsson S (1981) Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch Gen Psychiatry 38:861–868

    CAS  PubMed  Google Scholar 

  • Cooney NL, Litt MD, Morse PA, Bauer LO, Gaupp LJ (1997) Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol 106:243–250

    Article  CAS  PubMed  Google Scholar 

  • Cooper ML, Russell M, Skinner JB, Frone MR, Mudar P (1992) Stress and alcohol use: moderating effects of gender, coping, and alcohol expectancies. J Abnorm Psychol 101:139–152

    Article  CAS  PubMed  Google Scholar 

  • Coper H, Rommelspacher H, Wolffgramm J (1990) The ‘point of no return’ as a target of experimental research on drug dependence. Drug Alcohol Depend 25:129–134

    Article  CAS  PubMed  Google Scholar 

  • Cowen MS, Rezvani AH, Jarrott B, Lawrence AJ (1999) Ethanol consumption by Fawn-Hooded rats following abstinence: effect of naltrexone and changes in μ-opioid receptor density. Alcohol Clin Exp Res 23:1008–1014

    CAS  PubMed  Google Scholar 

  • De Soto CB, O’Donnell WE, Allred LJ, Lopes CE (1985) Symptomatology in alcoholics at various stages of abstinence. Alcohol Clin Exp Res 9:505–512

    PubMed  Google Scholar 

  • Dick DM, Nurnberger J Jr, Edenberg HJ, Goate A, Crowe R, Rice J, Bucholz KK, Kramer J, Schuckit MA, Smith TL, Porjesz B, Begleiter H, Hesselbrock V, Foroud T (2002) Suggestive linkage on chromosome 1 for a quantitative alcohol-related phenotype. Alcohol Clin Exp Res 26:1453–1460

    CAS  PubMed  Google Scholar 

  • Duka T, Townshend JM, Collier K, Stephens, DN (2002) Kindling of withdrawal: a study of craving and anxiety after multiple detoxifications in alcoholic inpatients. Alcohol Clin Exp Res 26:785–795

    CAS  PubMed  Google Scholar 

  • Duka T, Townshend JM, Collier K, Stephens DN (2003) Impairment in cognitive functions after multiple detoxifications in alcoholic inpatients. Alcohol Clin Exp Res 27:1563–1572

    CAS  PubMed  Google Scholar 

  • Duka T, Gentry J, Malcolm R, Ripley TL, Borlikova G, Stephens DN, Veatch LM, Becker HC, Crews FT (2004) Consequences of multiple withdrawals from alcohol. Alcohol Clin Exp Res 28:233–246

    PubMed  Google Scholar 

  • Epstein DH, Preston KL (2003) The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology 168:31–41

    Article  CAS  PubMed  Google Scholar 

  • File SE (1980) The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods 2:219–238

    Article  CAS  PubMed  Google Scholar 

  • File SE, Hyde JR (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62:19–24

    CAS  PubMed  Google Scholar 

  • File SE, Seth P (2003) A review of 25 years of the social interaction test. Eur J Pharmacol 463:35–53

    Article  CAS  PubMed  Google Scholar 

  • Franken IH (2003) Drug craving and addiction: integrating psychological and neuropsychopharmacological approaches. Prog Neuropsychopharmacol Biol Psychiatry 27:563–579

    Article  PubMed  Google Scholar 

  • Froehlich JC, Harts J, Lumeng L, Li T-K (1990) Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference. Pharmacol Biochem Behav 35:385–390

    Article  CAS  PubMed  Google Scholar 

  • George MS, Anton RF, Bloomer C, Teneback C, Drobes DJ, Lorberbaum JP, Nahas Z, Vincent DJ (2001) Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Arch Gen Psychiatry 58:345–352

    Article  CAS  PubMed  Google Scholar 

  • Glautier S, Drummond DC (1994) Alcohol dependence and cue reactivity. J Stud Alcohol 55:224–229

    CAS  PubMed  Google Scholar 

  • Goddard GV (1967) Development of epileptic seizures through brain stimulation at low intensity. Nature 214:1020–1021

    CAS  PubMed  Google Scholar 

  • Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25:295–330

    Article  CAS  PubMed  Google Scholar 

  • Guardia J, Caso C, Arias F, Gual A, Sanahuja J, Ramírez M, Mengual I, Gonzalvo B, Segura L, Trujols J, Casas M (2002) A double-blind, placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial. Alcohol Clin Exp Res 26:1381–1387

    CAS  PubMed  Google Scholar 

  • Heath AC, Bucholz KK, Madden PA, Dinwiddie SH, Slutske WS, Bierut LJ, Statham DJ, Dunne MP, Whitfield JB, Martin NG (1997) Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol Med 27:1381–1396

    Article  CAS  PubMed  Google Scholar 

  • Heinälä P, Alho H, Kiianmaa K, Lonnqvist J, Kuoppasalmi K, Sinclair JD (2001) Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 21:287–292

    Article  PubMed  Google Scholar 

  • Heinz A, Lober S, Georgi A, Wrase J, Hermann D, Rey ER, Wellek S, Mann K (2003a) Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake. Alcohol Alcohol 38:35–39

    Article  PubMed  Google Scholar 

  • Heinz A, Schafer M, Higley JD, Krystal JH, Goldman D (2003) Neurobiological correlates of the disposition and maintenance of alcoholism. Pharmacopsychiatry 36(Suppl 3):S255–S258

    Article  CAS  PubMed  Google Scholar 

  • Henniger MS, Spanagel R, Wigger A, Landgraf R, Hölter SM (2002) Alcohol self-administration in two rat lines selectively bred for extremes in anxiety-related behavior. Neuropsychopharmacology 26:729–736

    Article  CAS  PubMed  Google Scholar 

  • Heyne A, May T, Goll P, Wolffgramm J (2000) Persisting consequences of drug intake: towards a memory of addiction. J Neural Transm 107:613–638

    Article  CAS  PubMed  Google Scholar 

  • Heyser CJ, Schulteis G, Koob GF (1997) Increased ethanol administration after a period of imposed ethanol deprivation in rats trained in a limited access paradigm. Alcohol Clin Exp Res 21:784–791

    CAS  PubMed  Google Scholar 

  • Heyser CJ, Schulteis G, Durbin P, Koob GF (1998) Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacology 18:125–133

    Article  CAS  PubMed  Google Scholar 

  • Heyser CJ, Roberts AJ, Schulteis G, Koob GF (1999) Central administration of an opiate antagonist decreases oral ethanol self-administration in rats. Alcohol Clin Exp Res 23:1468–1476

    CAS  PubMed  Google Scholar 

  • Heyser CJ, Moc K, Koob GF (2003) Effects of naltrexone alone and in combination with acamprosate on the alcohol deprivation effect in rats. Neuropsychopharmacology 28:1463–1471

    Article  CAS  PubMed  Google Scholar 

  • Hodge CW, Cox AA (1998) The discriminative stimulus effects of ethanol are mediated by NMDA and GABA(A) receptors in specific limbic brain regions. Psychopharmacology 139:95–107

    Article  CAS  PubMed  Google Scholar 

  • Hodge CW, Slawecki CJ, Aiken AS (1996) Norepinephrine and serotonin receptors in the paraventricular nucleus interactively modulate ethanol consumption. Alcohol Clin Exp Res 20:1669–1674

    CAS  PubMed  Google Scholar 

  • Hölter SM, Spanagel R (1999) Effects of opiate antagonist treatment on the alcohol deprivation effect in long-term ethanol-experienced rats. Psychopharmacology 145:360–369

    Article  PubMed  Google Scholar 

  • Hölter SM, Landgraf R, Zieglgansberger W, Spanagel R (1997) Time course of acamprosate action on operant ethanol self-administration after ethanol deprivation. Alcohol Clin Exp Res 21:862–868

    PubMed  Google Scholar 

  • Hölter SM, Engelmann M, Kirschke C, Liebsch G, Landgraf R, Spanagel R (1998) Long-term ethanol self-administration with repeated ethanol deprivation episodes changes ethanol drinking pattern and increases anxiety-related behaviour during ethanol deprivation in rats. Behav Pharmacol 9:41–48

    PubMed  Google Scholar 

  • Hölter SM, Linthorst AC, Reul JM, Spanagel R (2000) Withdrawal symptoms in a long-term model of voluntary alcohol drinking in Wistar rats. Pharmacol Biochem Behav 66:143–151

    Article  PubMed  Google Scholar 

  • Hyytia P, Sinclair JD (1993) Responding to oral alcohol after naloxone treatment by alcohol-preferring AA rats. Alcohol Clin Exp Res 17:631–636

    CAS  PubMed  Google Scholar 

  • Isbell H (1955) Craving for alcohol. Q J Stud Alcohol 16:38–42

    CAS  PubMed  Google Scholar 

  • Johnson EO, van den Bree MB, Uhl GR, Pickens RW (1996a) Indicators of genetic and environmental influence in alcohol-dependent individuals. Alcohol Clin Exp Res 20:67–74

    CAS  PubMed  Google Scholar 

  • Johnson EO, van den Bree MB, Pickens RW (1996b) Subtypes of alcohol-dependent men: a typology based on relative genetic and environmental loading. Alcohol Clin Exp Res 20:1472–1480

    CAS  PubMed  Google Scholar 

  • June HL, Foster KL, McKay PF, Seyoum R, Woods JE, Harvey SC, Eiler WJ, Grey C, Carroll MR, McCane S, Jones CM, Yin W, Mason D, Cummings R, Garcia M, Ma C, Sarma PV, Cook JM, Skolnick P (2003) The reinforcing properties of alcohol are mediated by GABA(A1) receptors in the ventral pallidum. Neuropsychopharmacology 28:2124–2137

    CAS  PubMed  Google Scholar 

  • Kalodner CR, Delucia JL, Ursprung AW (1989) An examination of the tension reduction hypothesis: the relationship between anxiety and alcohol in college students. Addict Behav 14:649–654

    Article  CAS  PubMed  Google Scholar 

  • Kalynchuk LE, Pinel JP, Treit D, Kippin TE (1997) Changes in emotional behavior produced by long-term amygdala kindling in rats. Biol Psychiatry 41:438–451

    Article  CAS  PubMed  Google Scholar 

  • Katner SN, Magalong JG, Weiss F (1999) Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat. Neuropsychopharmacology 20:471–479

    Article  CAS  PubMed  Google Scholar 

  • Katz JL, Higgins ST (2003) The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168:21–30

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, Hooshmand F, Hermanson O, Rosenfeld MG, Spiess J (2000) Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat Genet 24:415–419

    Article  CAS  PubMed  Google Scholar 

  • Knapp DJ, Overstreet DH, Breese GR (2001) Persistent effects of repeated ethanol withdrawal are blunted by pharmacological treatments during early withdrawal episodes. Alcohol Clin Exp Res 25:23A

    Google Scholar 

  • Knapp DJ, Overstreet DH, Breese GR (2003) CRF and benzodiazepine antagonists modulate restraint stress sensitization of alcohol-withdrawal anxiety. Alcohol Clin Exp Res 27:98A

    Google Scholar 

  • Knapp DJ, Angel RA, Overstreet DH, Breese GR (2004a) The prophylactic effects of flumazenil on repeated ethanol withdrawal-induced anxiety are mediated by the amygdala. Alcohol Clin Exp Res 28:142A

    Google Scholar 

  • Knapp DJ, Overstreet DH, Moy SS, Breese GR (2004b) SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety. Alcohol 32:101–111

    Article  CAS  PubMed  Google Scholar 

  • Kokka N, Sapp DW, Taylor AM, Olsen RW (1993) 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 17:525–531

    CAS  PubMed  Google Scholar 

  • Koob GF (2000) Animal models of craving for ethanol. Addiction 95(Suppl 2):S73–S81

    PubMed  Google Scholar 

  • Koob GF (2003a) Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243

    CAS  PubMed  Google Scholar 

  • Koob GF (2003b) Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 13:442–452

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, LeMoal M (1997) Drug abuse: hedonic homeostatic dysfunction. Science 278:52–58

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, LeMoal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Roberts AJ, Kieffer BL, Heyser CJ, Katner SN, Ciccocioppo R, Weiss F (2003) Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology. Recent Dev Alcohol 16:263–281

    PubMed  Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O’Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Article  CAS  PubMed  Google Scholar 

  • Koros E, Piasecki J, Kostowski W, Bienkowski P (1999a) Development of alcohol deprivation effect in rats: lack of correlation with saccharin drinking and locomotor activity. Alcohol Alcohol 34:542–550

    Article  CAS  PubMed  Google Scholar 

  • Koros E, Kostowski W, Danysz W, Bienkowski P (1999b) Ethanol discrimination in the rat: lack of modulation by restraint stress and memantine. Naunyn Schmiedebergs Arch Pharmacol 359:117–122

    CAS  PubMed  Google Scholar 

  • Kranzler HR, Van Kirk J (2001) Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta analysis. Alcohol Clin Exp Res 25:1335–1341

    Article  CAS  PubMed  Google Scholar 

  • Krystal JH, Webb E, Grillon C, Cooney N, Casal L, Morgan CA III, Southwick SM, Davis M, Charney DS (1997) Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-chlorophenylpiperazine (mCPP). Psychopharmacology 131:207–215

    Article  CAS  PubMed  Google Scholar 

  • Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA (2001) Naltrexone in the treatment of alcohol dependence. N Engl J Med 345:1734–1739

    Article  CAS  PubMed  Google Scholar 

  • Kushner MG, Sher KJ, Wood MD, Wood PK (1994) Anxiety and drinking behavior: moderating effects of tension-reduction alcohol outcome expectancies. Alcohol Clin Exp Res 18:852–860

    CAS  PubMed  Google Scholar 

  • Kushner MG, Abrams K, Borchardt C (2000) The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings. Clin Psychol Rev 20:149–171

    Article  CAS  PubMed  Google Scholar 

  • Kushner MG, Thuras P, Abrams K, Brekke M, Stritar L (2001) Anxiety mediates the association between anxiety sensitivity and coping-related drinking motives in alcoholism treatment patients. Addict Behav 26:869–885

    Article  CAS  PubMed  Google Scholar 

  • Lê AD, Shaham Y (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137–156

    Article  PubMed  Google Scholar 

  • Lê AD, Quan B, Juzytsch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology 135:169–174

    Article  PubMed  Google Scholar 

  • Lê AD, Poulos CX, Harding S, Watchus J, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21:435–444

    Article  PubMed  Google Scholar 

  • Lê AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology 150:317–324

    Article  PubMed  Google Scholar 

  • Lê AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci 22:7844–7849

    PubMed  Google Scholar 

  • Lê AD, Wang A, Harding S, Juzytsch W, Shaham Y (2003) Nicotine increases alcohol self-administration and reinstates alcohol seeking behavior in rats. Psychopharmacology 168:216–221

    Article  PubMed  Google Scholar 

  • Lechtenberg R, Worner TM (1990) Seizure risk with recurrent alcohol detoxification. Arch Neurol 47:535–538

    CAS  PubMed  Google Scholar 

  • Lechtenberg R, Worner TM (1991) Relative kindling effect of detoxification and non-detoxification admissions in alcoholics. Alcohol Alcohol 26:221–225

    CAS  PubMed  Google Scholar 

  • Lechtenberg R, Worner TM (1992) Seizure incidence enhancement with increasing alcohol intake. Ann NY Acad Sci 654:474–476

    CAS  PubMed  Google Scholar 

  • Lesch OM, Riegler A, Gutierrez K, Hertling I, Ramskogler K, Semler B, Zoghlami A, Benda N, Walter H (2001) The European acamprosate trials: conclusions for research and therapy. J Biomed Sci 8:89–95

    Article  CAS  PubMed  Google Scholar 

  • Li T-K (2000) Clinical perspectives for the study of craving and relapse in animal models. Addiction 95(Suppl 2):S55–S60

    PubMed  Google Scholar 

  • Liappas J, Paparrigopoulos T, Tzavellas E, Christodoulou G (2002) Impact of alcohol detoxification on anxiety and depressive symptoms. Drug Alcohol Depend 68:215–220

    Article  CAS  PubMed  Google Scholar 

  • Litten RZ, Allen JP (1998) Advances in development of medications for alcoholism treatment. Psychopharmacology 139:20–33

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Weiss F (2002a) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861

    CAS  PubMed  Google Scholar 

  • Liu X, Weiss F (2002b) Reversal of ethanol-seeking behavior by D1 and D2 antagonists in an animal model of relapse: differences in antagonist potency in previously ethanol-dependent versus nondependent rats. J Pharmacol Exp Ther 300:882–889

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Weiss F (2003) Stimulus conditioned foot-shock stress reinstates alcohol-seeking behavior in an animal model of relapse. Psychopharmacology 168:184–191

    Article  CAS  PubMed  Google Scholar 

  • Longo LP, Campbell T, Hubatch S (2002) Diovalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. J Addict Dis 21:55–64

    Article  Google Scholar 

  • Maier DM, Pohorecky LA (1989) The effect of repeated withdrawal episodes on subsequent withdrawal severity in ethanol-treated rats. Drug Alcohol Depend 23:103–110

    Article  CAS  PubMed  Google Scholar 

  • Malcolm R, Herron JE, Anton RF, Roberts J, Moore J (2000a) Recurrent detoxification may elevate alcohol craving as measured by the obsessive compulsive drinking scale. Alcohol 20:181–185

    Article  CAS  PubMed  Google Scholar 

  • Malcolm R, Roberts JS, Wang W, Myrick H, Anton RF (2000b) Multiple previous detoxifications are associated with less responsive treatment and heavier drinking during an index outpatient detoxification. Alcohol 22:159–164

    Article  CAS  PubMed  Google Scholar 

  • Malcolm R, Myrick H, Brady KT, Ballenger JC (2001) Update on anticonvulsants for the treatment of alcohol withdrawal. Am J Addict 10(Suppl):16–23

    Article  Google Scholar 

  • Malcolm R, Myrick H, Roberts J, Wang W, Anton RF, Ballenger JC (2002) The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med 17:349–355

    Article  CAS  PubMed  Google Scholar 

  • Martin-Fardon R, Ciccocioppo R, Massi M, Weiss F (2000) Nociceptin prevents stress-induced ethanol but not cocaine-seeking behavior in rats. Neuroreport 11:1939–1943

    CAS  PubMed  Google Scholar 

  • Mason BJ (2001) Treatment of alcohol-dependent outpatients with acamprosate: a clinical review. J Clin Psychiatry 62(Suppl 20):42–48

    CAS  PubMed  Google Scholar 

  • McBride WJ, Lê AD, Noronha A (2002) Central nervous system mechanisms in alcohol relapse. Alcohol Clin Exp Res 26:280–286

    CAS  PubMed  Google Scholar 

  • McCown TJ, Breese GR (1990) Multiple withdrawals from chronic ethanol “kindles” inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism. Alcohol Clin Exp Res 14:394–399

    CAS  PubMed  Google Scholar 

  • McCown TJ, Greenwood RS, Breese GR (1987) Inferior collicular interactions with limbic seizure activity. Epilepsia 28:234–241

    CAS  PubMed  Google Scholar 

  • McEwen BS (1998) Stress, adaptation, and disease. Allostasis and allostatic load. Ann NY Acad Sci 840:33–44

    CAS  PubMed  Google Scholar 

  • McEwen BS (2000) Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22:108–124

    Article  CAS  PubMed  Google Scholar 

  • McHugh SB, Deacon RM, Rawlins JN, Bannerman DM (2004) Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav Neurosci 118:63–78

    Article  CAS  PubMed  Google Scholar 

  • McKinzie DL, Nowak KL, Yorger L, McBride WJ, Murphy JM, Lumeng L, Li T-K (1998) The alcohol deprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions. Alcohol Clin Exp Res 22:1170–1176

    CAS  PubMed  Google Scholar 

  • Meert TF, Huysmans H (1994) Repeated characterization of alcohol withdrawal reactions in rats chronically exposed to an alcohol liquid diet. Prog Neuropsychopharmacol Biol Psychiatry 18:947–960

    Article  CAS  PubMed  Google Scholar 

  • Merikangas KR (1990) The genetic epidemiology of alcoholism. Psychol Med 20:11–22

    CAS  PubMed  Google Scholar 

  • Merikangas KR, Stolar M, Stevens DE, Goulet J, Preisig MA, Fenton B, Zhang H, O’Malley SS, Rounsaville BJ (1998) Familial transmission of substance use disorders. Arch Gen Psychiatry 55:973–979

    Article  CAS  PubMed  Google Scholar 

  • Merlo Pich E, Lorang M, Yeganeh M, de Fonseca FR, Raber J, Koob GF, Weiss F (1995) Increase in extracellular corticotropin-releasing factor-like immunoreactivitiy levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439–5447

    CAS  PubMed  Google Scholar 

  • Monti PM, Rohsenow DJ, Hutchison KE (2000) Toward bridging the gap between biological, psychobiological and psychosocial models of alcohol craving. Addiction 95(Suppl 2):S229–S236

    PubMed  Google Scholar 

  • Monti PM, Rohsenow DJ, Swift RM, Gulliver SB, Colby SM, Mueller TI, Brown RA, Gordon A, Abrams DB, Niaura RS, Asher MK (2001) Naltrexone and cue exposure with coping and communication skills training for alcoholics: treatment process and 1-year outcomes. Alcohol Clin Exp Res 25:1634–1647

    Article  CAS  PubMed  Google Scholar 

  • Myrick H, Anton RF, Li X, Henderson S, Drobes D, Voronin K, George MS (2004) Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving. Neuropsychopharmacology 29:393–402

    Article  CAS  PubMed  Google Scholar 

  • O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B (1992) Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 49:881–887

    CAS  PubMed  Google Scholar 

  • Overstreet DH, Kampov-Polevoy AB, Rezvani AH, Braun C, Bartus RT, Crews FT (1999) Suppression of alcohol intake by chronic naloxone treatment in P rats: tolerance development and elevation of opiate receptor binding. Alcohol Clin Exp Res 23:1761–1771

    CAS  PubMed  Google Scholar 

  • Overstreet DH, Knapp DJ, Breese GR (2002) Accentuated decrease in social interaction in rats subjected to multiple alcohol withdrawals. Alcohol Clin Exp Res 26:1259–1268

    PubMed  Google Scholar 

  • Overstreet DH, Knapp DJ, Breese GR (2003a) Restraint stress modifies the alcohol deprivation effect & alcohol withdrawal-induced anxiety in P rats. Alcohol Clin Exp Res 27:98A

    Google Scholar 

  • Overstreet DH, Knapp DJ, Moy SS, Breese GR (2003b) Prevention of the accentuated anxiety associated with repeated withdrawals from chronic ethanol exposure by a 5-HT2C antagonist and a 5-HT1A agonist. Psychopharmacology 167:344–352

    CAS  PubMed  Google Scholar 

  • Overstreet DH, Knapp DJ, Breese GR (2004a) Modulation of anxiety-like behavior in alcohol withdrawn rats by CRF and CRF-1 receptors. Pharmacol Biochem Behav 77:405–413

    Article  CAS  PubMed  Google Scholar 

  • Overstreet DH, Knapp DJ, Breese GR (2004b) Similar anxiety-like responses in male and female rats exposed to repeated withdrawals from ethanol. Pharmacol Biochem Behav 78:459–463

    Article  CAS  PubMed  Google Scholar 

  • Parkes H, Sinclair JD (2000) Reduction of alcohol drinking and upregulation of opioid receptors by oral naltrexone in AA rats. Alcohol 21:215–221

    Article  CAS  PubMed  Google Scholar 

  • Pelc I, Ansoms C, Lehert P, Fischer F, Fuchs WJ, Landron F, Pires Preto AJ, Morgan MY (2002) The European NEAT program: an integrated approach using acamprosate and psychosocial support for the prevention of relapse in alcohol-dependent patients with a statistical modeling of therapy success prediction. Alcohol Clin Exp Res 26:1529–1539

    PubMed  Google Scholar 

  • Pinel JP, Van Oot PH, Mucha RF (1975) Intensification of the alcohol withdrawal syndrome by repeated brain stimulation. Nature 254:510–511

    CAS  PubMed  Google Scholar 

  • Pohorecky LA (1990) Interaction of ethanol and stress: research with experimental animals—an update. Alcohol Alcohol 25:263–276

    CAS  PubMed  Google Scholar 

  • Pohorecky LA (1991) Stress and alcohol interaction: an update of human research. Alcohol Clin Exp Res 15:438–459

    CAS  PubMed  Google Scholar 

  • Rasmussen DD, Mitton DR, Green J, Puchalski S (2001) Chronic daily ethanol and withdrawal. 2. Behavioral changes during prolonged abstinence. Alcohol Clin Exp Res 25:999–1005

    Article  CAS  PubMed  Google Scholar 

  • Rassnick S, Heinrichs SC, Britton KT, Koob GF (1993) Microinjection of a corticotropin releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res 605:25–32

    Article  CAS  PubMed  Google Scholar 

  • Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P, Foroud T, Hesselbrock V, Schuckit MA, Bucholz K, Porjesz B, Li TK, Conneally PM, Nurnberger JI Jr, Tischfield JA, Crowe RR, Cloninger CR, Wu W, Shears S, Carr K, Crose C, Willig C, Begleiter H (1998) Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 81:207–215

    Article  CAS  PubMed  Google Scholar 

  • Rimondini R, Arlinde C, Sommer W, Heilig M (2002) Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to ethanol. FASEB J 16:27–35

    Article  CAS  PubMed  Google Scholar 

  • Ripley TL, Dunworth SJ, Stephens DN (2002) Effect of CGP39551 administration on the kindling of ethanol-withdrawal seizures. Psychopharmacology 163:157–165

    Article  CAS  PubMed  Google Scholar 

  • Ripley TL, O’Shea M, Stephens DN (2003) Repeated withdrawal from ethanol impairs acquisition but not expression of conditioned fear. Eur J Neurosci 18:441–448

    Article  CAS  PubMed  Google Scholar 

  • Ripley TL, Borikova G, Lyons S, Stephens DN (2004) Selective deficits in appetitive conditioning as a consequence of ethanol withdrawal. Eur J Neurosci 19:415–425

    Article  CAS  PubMed  Google Scholar 

  • Risbrough VB, Hauger RL, Roberts AL, Vale WW, Geyer MA (2004) Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci 24:6545–6552

    Article  CAS  PubMed  Google Scholar 

  • Roberts AJ, Cole M, Koob GF (1996) Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res 20:1289–1298

    CAS  PubMed  Google Scholar 

  • Roberts AJ, Heyser CJ, Cole M, Griffin P, Koob GF (2000) Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22:581–594

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95(Suppl 2):S91–S117

    PubMed  Google Scholar 

  • Rodd ZA, Bell RL, Kuc KA, Murphy JM, Lumeng L, Li TK, McBride WJ (2003) Effects of repeated alcohol deprivations on operant ethanol self-administration by alcohol-preferring (P) rats. Neuropsychopharmacology. 11 June (Epub ahead of print)

  • Rodd-Henricks ZA, McKinzie DL, Murphy JM, McBride WJ, Lumeng L, Li T-K (2000a) The expression of an alcohol deprivation effect in the high-alcohol-drinking replicate rat lines is dependent on repeated deprivations. Alcohol Clin Exp Res 24:747–753

    Article  CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, McKinzie DL, Shaikh SR, Murphy JM, McBride WJ, Lumeng L, Li T-K (2000b) Alcohol deprivation effect is prolonged in the alcohol preferring (P) rat after repeated deprivations. Alcohol Clin Exp Res 24:8–16

    Article  CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, McKinzie DL, Crile RS, Murphy JM, McBride WJ (2000c) Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats. Psychopharmacology 149:217–224

    Article  CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, Bell RL, Kuc KA, Murphy JM, McBride WJ, Lumeng L, Li T-K (2001) Effects of concurrent access to multiple ethanol concentrations and repeated deprivations on alcohol intake of alcohol-preferring rats. Alcohol Clin Exp Res 25:1140–1150

    Article  CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, McKinzie DL, Melendez RI, Berry N, Murphy JM, McBride WJ (2003) Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats. Psychopharmacology 165:252–259

    CAS  PubMed  Google Scholar 

  • Roelofs SM (1985) Hyperventilation, anxiety, craving for alcohol: a subacute alcohol withdrawal syndrome. Alcohol 2:501–505

    Article  CAS  PubMed  Google Scholar 

  • Rogowski A, Rokicki D, Kostowski W, Bienkowski P (2003) Relationship between dopamine D2 receptor-associated responses and operant ethanol self-administration in the rat: a factor analysis. Alcohol Alcohol 38:305–309

    Article  CAS  PubMed  Google Scholar 

  • Rubio G, Jiménez-Arriero MA, Ponce G, Palomo T (2001) Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment. Alcohol Alcohol 36:419–425

    Article  CAS  PubMed  Google Scholar 

  • Sams-Dodd F (1995) Automation of the social interaction test by a video-tracking system: behavioral effects of repeated phencyclidine treatment. J Neurosci Methods 59:157–167

    Article  CAS  PubMed  Google Scholar 

  • Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442

    CAS  PubMed  Google Scholar 

  • Samson HH, Chappell A (2001) Effects of alcohol deprivation on alcohol consumption using a sipper-tube procedure. Alcohol Clin Exp Res 25:680–686

    Article  CAS  PubMed  Google Scholar 

  • Samson HH, Doyle TF (1985) Oral ethanol self-administration in the rat: effect of naloxone. Pharmacol Biochem Behav 22:91–99

    Article  CAS  PubMed  Google Scholar 

  • Sass H, Soyka M, Mann K, Zieglgansberger W (1996) Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry 53:673–680

    Google Scholar 

  • Schulkin J, McEwen BS, Gold PW (1994) Allostasis, amygdala, and anticipatory angst. Neurosci Biobehav Rev 18:385–396

    Article  CAS  PubMed  Google Scholar 

  • Serra S, Brunetti G, Pani M, Vacca G, Carai MA, Gessa GL, Colombo G (2002) Blockade by the cannabinoid CB1 receptor antagonist SR 141716 of alcohol deprivation in alcohol-preferring rats. Eur J Pharmacol 443:95–97

    Article  CAS  PubMed  Google Scholar 

  • Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20

    Article  CAS  PubMed  Google Scholar 

  • Sillaber I, Rammes G, Zimmermann S, Mahal B, Zieglgansberger W, Wurst W, Holsboer F, Spanagel R (2002) Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 receptors. Science 296:823–824

    Article  PubMed  Google Scholar 

  • Sinclair JD (1972) The alcohol-deprivation effect: Influence of various factors. Q J Stud Alcohol 33:769–782

    CAS  PubMed  Google Scholar 

  • Sinclair JD (2001) Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism. Alcohol Alcohol 36:2–10

    Article  CAS  PubMed  Google Scholar 

  • Sinclair JD, Li TK (1989) Long and short alcohol deprivation: effects on AA and P alcohol-preferring rats. Alcohol 6:505–509

    Article  CAS  PubMed  Google Scholar 

  • Sinclair JD, Senter RJ (1967) Increased preference for ethanol in rats following alcohol-deprivation. Psychonomic Sci 8:11–12

    Google Scholar 

  • Sinclair JD, Senter RJ (1968) Development of an alcohol-deprivation effect in rats. Q J Stud Alcohol 29:863–867

    CAS  PubMed  Google Scholar 

  • Sinha R (2001) How does stress increase risk of drug abuse and relapse. Psychopharmacology 158:343–359

    Article  CAS  PubMed  Google Scholar 

  • Sinha R, O’Malley SS (1999) Craving for alcohol: findings from the clinic and the laboratory. Alcohol Alcohol 34:223–230

    Article  CAS  PubMed  Google Scholar 

  • Sloan TB, Roache JD, Johnson BA (2003) The role of anxiety in predicting drinking behaviour. Alcohol Alcohol 38:360–363

    Article  PubMed  Google Scholar 

  • Slutske WS, True WR, Scherrer JF, Heath AC, Bucholz KK, Eisen SA, Goldberg J, Lyons MJ, Tsuang MT (1999) The heritability of alcoholism symptoms: “indicators of genetic and environmental influence in alcohol-dependent individuals” revisited. Alcohol Clin Exp Res 23:759–769

    CAS  PubMed  Google Scholar 

  • Spanagel R, Hölter SM (1999) Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism? Alcohol Alcohol 34:231–243

    Article  CAS  PubMed  Google Scholar 

  • Spanagel R, Hölter SM (2000) Pharmacological validation of a new animal model of alcoholism. J Neural Transm 107:669–680

    Article  CAS  PubMed  Google Scholar 

  • Spanagel R, Hölter SM, Allingham K, Landgraf R, Zieglgansberger W (1996) Acamprosate and alcohol. I. Effects of alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol 305:39–44

    Article  CAS  PubMed  Google Scholar 

  • Stephens DN, Brown G, Duka T, Ripley TL (2001) Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcohol. Eur J Neurosci 14:2023–2031

    Article  CAS  PubMed  Google Scholar 

  • Sterling P, Eyer J (1988) Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of life stress, cognition and health. Wiley, Chichester

    Google Scholar 

  • Stewart SH, Karp J, Pihl RO, Peterson RA (1997) Anxiety sensitivity and self-reported reasons for drug use. J Subst Abuse 9:223–240

    Article  CAS  PubMed  Google Scholar 

  • Stockwell T, Sutherland G, Edwards G (1984) The impact of a new alcohol sensitizing agent (nitrefazole) on craving in severely dependent alcoholics. Br J Addict 79:403–409

    CAS  PubMed  Google Scholar 

  • Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A (2000) Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol 35:202–209

    Article  CAS  PubMed  Google Scholar 

  • Townshend JM, Duka T (2001) Attentional bias associated with alcohol cues: differences between heavy and occasional social drinkers. Psychopharmacology 157:67–74

    Article  CAS  PubMed  Google Scholar 

  • Townshend JM, Duka T (2003) Mixed emotions: alcoholics’ impairments in the recognition of specific emotional facial expressions. Neuropsychologia 41:773–782 (Erratum in: Neuropsychologia 2003;41:1563)

    Article  CAS  PubMed  Google Scholar 

  • True WR, Heath AC, Bucholz K, Slutske W, Romeis JC, Scherrer JF, Lin N, Eisen SA, Goldberg J, Lyons MJ, Tsuang MT (1996) Models of treatment seeking for alcoholism: the role of genes and environment. Alcohol Clin Exp Res 20:1577–1581

    CAS  PubMed  Google Scholar 

  • Ulrichsen J, Bech B, Allerup P, Hemmingsen R (1995) Diazepam prevents progression of kindled alcohol withdrawal behaviour. Psychopharmacology 121:451–460

    CAS  PubMed  Google Scholar 

  • Ulrichsen J, Haugbol S, Brandt CF, Allerup P, Hemmingsen R (1998) Irreversibility of kindled alcohol-withdrawal behaviour in rats. Alcohol Alcohol 33:230–243

    CAS  PubMed  Google Scholar 

  • Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, Koob GF (2002) Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 26:1494–1501

    CAS  PubMed  Google Scholar 

  • Valdez GR, Zorrilla EP, Roberts AJ, Koob GF (2003) Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol 29:55–60

    Article  CAS  PubMed  Google Scholar 

  • Veatch LM, Gonzalez LP (1999) Repeated ethanol withdrawal delays development of focal seizures in hippocampal kindling. Alcohol Clin Exp Res 23:1145–1150

    CAS  PubMed  Google Scholar 

  • Veatch LM, Gonzalez LP (2000) Nifedipine alleviates alterations in hippocampal kindling after repeated ethanol withdrawal. Alcohol Clin Exp Res 24:484–491

    Article  CAS  PubMed  Google Scholar 

  • Vengeliene V, Siegmund S, Singer MV, Sinclair JD, Li TK, Spanagel R (2003) A comparative study on alcohol-preferring rat lines: effects of deprivation and stress phases on voluntary alcohol intake. Alcohol Clin Exp Res 27:1048–1054

    PubMed  Google Scholar 

  • Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–880

    Google Scholar 

  • Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463:199–216

    Article  CAS  PubMed  Google Scholar 

  • Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258

    CAS  PubMed  Google Scholar 

  • Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, Ben-Shahar O, Angeletti S, Richter RR (2001) Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann NY Acad Sci 937:1–26

    CAS  PubMed  Google Scholar 

  • Willinger U, Lenzinger E, Hornik K, Fischer G, Schönbeck G, Aschauer HN, Meszaros K (2002) Anxiety as a predictor of relapse in detoxified alcohol-dependent patients. Alcohol Alcohol 37:609–612

    Article  PubMed  Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75:134–143

    CAS  PubMed  Google Scholar 

  • Wolffgramm J, Heyne A (1995) From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav Brain Res 70:77–94

    Article  CAS  PubMed  Google Scholar 

  • Wolffgramm J, Galli G, Thimm F, Heyne A (2000) Animal models of addiction: models for therapeutic strategies? J Neural Transm 107:649–668

    Article  CAS  PubMed  Google Scholar 

  • Worner TM (1996) Relative kindling effect of readmissions in alcoholics. Alcohol Alcohol 31:375–380

    CAS  PubMed  Google Scholar 

  • Young RM, Oei TP, Knight RG (1990) The tension reduction hypothesis revisited: an alcohol expectancy perspective. Br J Addict 85:31–40

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by NIAAA grants AA-11605, AA00243, AA00214, AA12655, AA14284, and AA14949.

Author information

Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Departments of Psychiatry and Pharmacology, University of North Carolina School of Medicine, 3007 Thurston-Bowles Building CB-7178, Chapel Hill, NC, 27599-7178, USA

    George R. Breese, David H. Overstreet & Darin J. Knapp

Authors
  1. George R. Breese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Overstreet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Darin J. Knapp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George R. Breese.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breese, G.R., Overstreet, D.H. & Knapp, D.J. Conceptual framework for the etiology of alcoholism: a “kindling”/stress hypothesis. Psychopharmacology 178, 367–380 (2005). https://doi.org/10.1007/s00213-004-2016-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-2016-2

Keywords

Search

Navigation