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

Abstract

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.

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

“…Previous data show that rats previously exposed to the repeated withdrawal (Overstreet et al, 2002) or the stress/ withdrawal (Breese et al, 2005b) protocols exhibited sensitized anxiety-like behavior upon withdrawal from a future re-exposure to an additional 5 days of ethanol diet 16 days after the initial withdrawal. Therefore, the possibility that the repeated LPS/withdrawal and the .01 compared to vehicle-control diet or the LPS-ethanol groups; these data are associated with Figure 2.…”

Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin 1 -independent mechanism

“…Spontaneous withdrawal from benzodiazepines, for instance, has been shown to be mediated by CRF and CRF 1 receptors (68, 69). These data appear to be especially interesting in view of the shared behavioral effects of EtOH and benzodiazepines and the common effects of these drugs on CRF systems (12,68,69). A role of extrahypothalamic CRF in the expression of drug-induced psychomotor sensitization has also been proposed (28).…”

“…Common sequelae of these neuroplastic changes can be seen in behavior, and include negative affective symptoms associated with drug withdrawal (4,5), robust changes in motivated behavior predicted by associative learning about drug-related environmental cues that are resistant to extinction (2,6,7), and protracted periods of sensitization (8)(9)(10)(11). Sensitization occurs to behavioral stimulating effects of addictive drugs (8)(9)(10) and to symptoms of hyperexcitability associated with repeated bouts of drug withdrawal (12,13). Repeated administration of drugs sensitizes neural circuits that assign biological significance to drugs and drug-related cues, a consequence underlying increased motivational effects (10,(14)(15)(16).…”

Baclofen Blocks Expression and Sensitization of Anxiety‐Like Behavior in an Animal Model of Repeated Stress and Ethanol Withdrawal

“…Thus, these 2 stress sessions substituted for the first 2 cycles of ED exposure and withdrawal. Another group received 45 minutes of restraint stress 3 days into abstinence 30 minutes before SI testing (Breese et al, 2005b).…”

“…Furthermore, restraint stress substitutes for the first 2 cycles to sensitize anxiety during withdrawal from a future single cycle and elicits anxiety during abstinence (Breese et al, , 2005a(Breese et al, , 2005b. These protocols extend work with sensitized or "kindled" seizures in rats (e.g., McCown and Breese, 1990) and model sensitization of symptoms in human alcoholic individuals (Ballenger and Post, 1978;Malcolm et al, 2000;Sinha, 2001).…”