Animal models of addiction: models for therapeutic strategies?

Wolffgramm, Jochen; Galli, Gabriel; Thimm, F.; Heyne, Andrea

doi:10.1007/s007020070067

Cited by 64 publications

(68 citation statements)

References 33 publications

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“…EtOH abstinence did not alter AGS3 expression in several other forebrain nuclei related to motivated, goal-directed behavior (Table S1), indicating relatively specific regulation of AGS3 expression in the NAcore during EtOH abstinence. Like the EtOH deprivation effect (2,(6)(7)(8)(9), the increase in NAcore AGS3 expression was apparent after several weeks but not after 24 h of abstinence. Thus, increased NAcore AGS3 expression may represent a neural substrate of the enhanced motivation to seek EtOH during protracted abstinence.…”

Section: Resultsmentioning

confidence: 85%

“…2, 6, and 8, but see ref. 9). Thus, these data suggest that enhanced motivation to seek EtOH during abstinence may represent some aspects of human alcoholic, compulsive behavior (1,2,29).…”

Section: Motivation To Seek Etoh Is Enhanced During Etoh Abstinencementioning

confidence: 99%

“…Accordingly, there is considerable interest in neuroadaptations that develop during periods of abstinence that may promote drug seeking and relapse (3). Enhanced EtOH seeking during abstinence is observed in heavy social drinkers (4), non-human primates (5), and rodents (2,(6)(7)(8)(9), where this EtOH deprivation effect is hypothesized to model many aspects of compulsive EtOH seeking and consumption (refs. 2, 6, 8, but see ref.…”

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confidence: 99%

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Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Bowers

Hopf

Chou

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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Approximately 90% of alcoholics relapse within 4 years, in part because of an enhanced motivation to seek alcohol (EtOH). A novel G protein modulator (Gpsm1/AGS3) was up-regulated in the rat nucleus accumbens core (NAcore) but not in other limbic nuclei during abstinence from operant EtOH self-administration. Furthermore, NAcore AGS3 knockdown reduced EtOH seeking to preabstinence levels in a novel rat model of compulsive, human EtOH seeking. AGS3 can both inhibit G protein Gi␣-mediated signaling and stimulate G␤␥-mediated signaling. Accordingly, sequestration of G␤␥, but not Gi␣ knockdown, significantly reduced EtOH seeking to pre-abstinence levels. Thus, AGS3 and G␤␥ are hypothesized to gate the uncontrolled motivation to seek EtOH during abstinence. AGS3 up-regulation during abstinence may be a key determinant of the transition from social consumption to compulsionlike seeking during relapse.self-administration ͉ reinstatement ͉ alcohol deprivation effect ͉ Gi␣ ͉ G protein

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Section: Resultsmentioning

confidence: 85%

“…2, 6, and 8, but see ref. 9). Thus, these data suggest that enhanced motivation to seek EtOH during abstinence may represent some aspects of human alcoholic, compulsive behavior (1,2,29).…”

Section: Motivation To Seek Etoh Is Enhanced During Etoh Abstinencementioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Bowers

Hopf

Chou

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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“…When alcohol drinking occurs during an acute withdrawal state, alcoholics indicate they "feel better." Drinking to alleviate the "distress" induced by the negative affective state during withdrawal requires previous knowledge that alcohol intake diminishes acute withdrawal symptoms-a conclusion consistent with views of Heyne et al (2000) and Wolffgramm et al (2000). In accord with a report by Cooney et al (1997), Koob et al (2004) recently reviewed the concept that a negative motivational state drives addiction.…”

Section: Stress During Withdrawal From Multiple Alcohol Exposures Incmentioning

confidence: 84%

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

2004

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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.

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“…The emotional state observed during withdrawal in the alcoholic can result in craving (Duka et al, 2002;Heinz et al, 2003;Malcolm et al, 2000), because of their knowledge that symptoms would be reduced by ethanol (see Heyne et al, 2000;Wolffgramm et al, 2000). Since symptoms of withdrawal from ethanol abuse induce a desire to drink in some alcoholics (Duka et al, 2002), stress during abstinence is proposed to contribute to the craving alcoholics experience during this period (see Sinha, 2001;Breese et al, 2005a, b).…”

Section: Discussionmentioning

confidence: 99%

Prior Multiple Ethanol Withdrawals Enhance Stress-Induced Anxiety-Like Behavior: Inhibition by CRF1- and Benzodiazepine-Receptor Antagonists and a 5-HT1a-Receptor Agonist

Breese

Overstreet

Knapp

et al. 2005

Neuropsychopharmacol

116

110

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Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior ('anxiety'). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restraint stress 3, 7, or 14 days after rats were exposed to multiple withdrawals from a chronic 4.5% ethanol diet. Restraint stress reduced social interaction (ie anxiety-like behavior) at 3, but not at 7 or 14 days, after the multiple withdrawals. No anxiety response was observed in animals that received multiple withdrawals without stress or in animals that received stress when exposed only to control liquid diet. Drugs (ie a CRF 1 -receptor antagonist, a benzodiazepine receptor antagonist, and a 5-HT 1A -receptor agonist) previously demonstrated to block the cumulative adaptation, when administered during repeated withdrawals, prevented stress-induced anxiety-like behavior during abstinence. Additionally, these drugs applied prior to stress in the rats previously exposed to the repeated withdrawal protocol, likewise, minimized stress-induced anxiety. The anxiety following stress during abstinence from previous chronic ethanol exposure is indicative of an interaction of stress with the persistent adaptive change caused by repeated withdrawals. Stress eliciting anxiety-like behavior during abstinence from previous ethanol exposures in rats is consistent with stress inducing anxiety during recovery (sobriety) in the alcoholic, a circumstance that can facilitate craving and relapse.

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Animal models of addiction: models for therapeutic strategies?

Cited by 64 publications

References 33 publications

Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

Nucleus accumbens AGS3 expression drives ethanol seeking through Gβγ

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

Prior Multiple Ethanol Withdrawals Enhance Stress-Induced Anxiety-Like Behavior: Inhibition by CRF1- and Benzodiazepine-Receptor Antagonists and a 5-HT1a-Receptor Agonist

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