Modulation of Ethanol Withdrawal???Induced Anxiety-Like Behavior During Later Withdrawals by Treatment of Early Withdrawals With Benzodiazepine/??-Aminobutyric Acid Ligands

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

doi:10.1097/01.alc.0000158840.07475.97

Cited by 41 publications

(61 citation statements)

References 50 publications

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“…To determine if the repeated LPS/withdrawal and the TNFa/ withdrawal protocols share sensitivity to flumazenil inhibition of withdrawal-induced anxiety-like behavior after the repeated withdrawal and repeated stress/withdrawal protocols Knapp et al, 2004Knapp et al, , 2005, rats were treated with flumazenil (5 mg/kg, 2 ml/kg i.p. ; Roche, Basel, Switzerland) or 0.5% carboxymethylcellulose vehicle 30 min before each of the two weekly doses of LPS (250 m; i.p.)…”

Section: Flumazenil Treatment Before Repeated Lps Administrationmentioning

confidence: 99%

“…), but not during withdrawal from the 5 days of ethanol diet. This dose of flumazenil was chosen based upon effectiveness in previous studies to diminish the adaptive change induced by the repeated withdrawal protocol (Knapp et al, , 2005 and the repeated stress/ withdrawal protocol . Subsequently, social interaction was measured in controls and drugtreated groups as noted above.…”

Section: Flumazenil Treatment Before Repeated Lps Administrationmentioning

confidence: 99%

“…Subsequently, to address the possibility that a central action of cytokines by the repeated LPS exposure could be responsible for its sensitization of withdrawalinduced anxiety, experiments were conducted to determine whether repeated central administration of IL-1b, CCL2 (MCP-1), or TNF-a before a single exposure to chronic ethanol would, like LPS, sensitize withdrawal-induced anxiety. Finally, given that flumazenil administered during the repeated withdrawal and repeated stress/withdrawal protocols prevented the cumulative adaptation that supported withdrawal-induced anxiety Knapp et al, 2004Knapp et al, , 2005Overstreet et al, 2003), we examined whether administration of this drug before the initial exposures to LPS or TNF-a would have a similar inhibitory effect on anxiety during withdrawal and whether the flumazenil would prevent the persistent sensitivity to withdrawal from a future re-exposure to 5 days of ethanol diet (Overstreet et al, 2003;Breese et al, 2004;Knapp et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior

Breese

Knapp

Overstreet

et al. 2007

Neuropsychopharmacol

100

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Previous investigations demonstrated that repeated stresses before an ethanol exposure sensitize ethanol withdrawal-induced anxietylike behavior ('anxiety'). In addition to activating the hypothalamic-pituitary-adrenal axis, acute stress also elevates cytokines in brain. Initially, to test possible cytokine involvement in this stress/withdrawal protocol, cytokines were increased in brain with 2 weekly repeated lipopolysaccharide (LPS) administrations (1000 m/kg) (LPS/withdrawal protocol) or with twice weekly intracerebroventricular (i.c.v.) administrations of the cytokines IL-1b, CCL2 (MCP-1) or TNFa (cytokine/withdrawal protocol) before exposure and withdrawal from a 5-day cycle of chronic ethanol diet. Both protocols sensitized withdrawal-induced anxiety and confirm cytokine involvement in the sensitized anxiety response. Testing of various doses of LPS (16-1000 mg/kg) and TNFa (3-100 ng, i.c.v.) demonstrated the dose-related nature of these protocols to sensitize withdrawal-induced anxiety. The sensitized anxiety was not produced by a single 5-day ethanol diet cycle or by repeated LPS or cytokine treatments alone. Likewise, sensitized anxiety in these protocols could not be attributed to differences in ethanol ingestion. When challenged with a subsequent re-exposure to a 5-day ethanol diet cycle 16 days after completion of the LPS/withdrawal or cytokine/withdrawal protocols, an increase in withdrawal-induced anxiety was observedFan indication of induction of an underlying persistent adaptive change. Finally, just as found previously with the stress/withdrawal protocol, administration of the benzodiazepine receptor antagonist flumazenil before the LPS or TNF treatments prevented anxiety sensitization. Together, these findings indicate that increased cytokine activity induces adaptive change that supports sensitization of ethanol withdrawal-induced anxiety that may be linked to GABA A -receptor function.

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Section: Flumazenil Treatment Before Repeated Lps Administrationmentioning

confidence: 99%

Section: Flumazenil Treatment Before Repeated Lps Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior

Breese

Knapp

Overstreet

et al. 2007

Neuropsychopharmacol

100

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“…These treatments previously blocked the reduced social interaction seen following this repeated ethanol cycling (Overstreet et al, 2003a(Overstreet et al, , b, 2004bKnapp et al, 2004bKnapp et al, , 2005. Treatment with the these drugs during the initial repeated withdrawal cycles prevented the stressinduced reduction in social interaction induced 3 days after removal from the multiple-withdrawal protocol (Figure 4).…”

Section: Effect Of Selected Drugs Administered During Repeatedmentioning

confidence: 87%

“…Previous work demonstrated that a CRF 1 -receptor antagonist, a 5-HT 1A -receptor agonist, and the benzodiazepine receptor antagonist administered during repeated withdrawals prevent withdrawal-induced anxiety-like behavior (Knapp et al, , 2005Overstreet et al, 2003bOverstreet et al, , 2004a. This inhibitory drug action is proposed to relate to blockade of the cumulative adaptive change induced by the repeated withdrawals (Overstreet et al, 2003a(Overstreet et al, , b, 2004a.…”

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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Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit Disorder

Koob

2011

Current Topics in Behavioral Neurosciences

241

205

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Alcoholism can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Alcoholism impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of specific neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreased dopamine and γ-aminobutyric acid function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and that may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least partially, the compulsivity of alcoholism.

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Modulation of Ethanol Withdrawal???Induced Anxiety-Like Behavior During Later Withdrawals by Treatment of Early Withdrawals With Benzodiazepine/??-Aminobutyric Acid Ligands

Cited by 41 publications

References 50 publications

Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior

Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior

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

Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit Disorder

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