Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats

et al. 2007

Neuropsychopharmacol

100

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.

Section: Measurement Of Social Interactionmentioning

confidence: 99%

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

et al. 2007

Neuropsychopharmacol

100

“…The social interaction test, first introduced by File and Hyde (1978), has been validated as a measure of anxiety-like behavior in many investigations (File, 1980;Guy and Gardner, 1985;Irvine et al, 2001; see review by File and Seth, 2003). Testing was carried out under relatively low lighting in a square open field (60 cm Â 60 cm, with 16 squares marked out on the floor); rats were unfamiliar with this environment (Overstreet et al, 2002).…”

Section: Measurement Of Social Interactionmentioning

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

et al. 2005

Neuropsychopharmacol

116

110

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.

“…This test involves placing a pair of animals in an arena and measuring the amount of time engaged in such behaviors as grooming, sniffing, crawling over or under, and boxing; locomotor activity is simultaneously recorded and provides a measure that is independent of social interaction (File, 1980). Social interaction has been repeatedly validated as an index of anxiety-related behavior because it is decreased following anxiety-provoking stimuli, such as bright lights or exposure to cat odor (File, 1980;File and Hyde, 1978), after administration of anxiogenic drugs (e.g., Battacharya et al, 1997;File and Lister, 1984;Guy and Gardner, 1985;Sams-Dodd, 1995) or following withdrawal from drugs of abuse, including ethanol (Andrews et al, 1997;File et al, 1989;Irvine et al, 2001;Kampov-Polevoy et al, 2000;Overstreet et al, 2002). Conversely, social interaction can be increased by prior exposure to the test arena (File, 1980;File and Hyde, 1978) or the administration of anxiolytic drugs at doses that have little effect on locomotor activity (Barnes et al, 1990;File, 1980;Lightowler et al, 1994).…”

Section: Social Interaction Testmentioning

confidence: 99%

“…According to File (1980), the most sensitive procedure is to match up pairs of rats that have the same treatment on the basis of their body weights and then treat the total number of interactions by the pair as the unit of measure. However, for other experiments where the index rat may have an implanted cannula (Gonzalez et al, 1998;Irvine et al, 2001), an untreated dummy partner is used, and only the interactions of the index rat are recorded. In the present studies, pairs of rats with the same treatment were placed in the arena and the social interactions initiated by each member of the pair were recorded, thereby requiring fewer rats.…”

Section: Social Interaction Testmentioning

confidence: 99%

Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors

Pharmacology Biochemistry and Behavior

2004

152

153

Previous work demonstrated that rats subjected to multiple withdrawals from chronic ethanol exhibit a sensitization of anxiety-like behavior compared to animals withdrawn from treatment with an equal but continuous amount of ethanol. This study sought to examine whether corticotropin-releasing factor (CRF) could modulate this ethanol-withdrawal-induced anxiety-like behavior. Initially, rats were administered with CRF (1 μg) or vehicle intraventricularly on two occasions 5 days apart while on control diet (CD) followed by exposure to 7% ethanol diet (ED) for 5 days, with social interaction assessed 5 h into withdrawal. Social interaction was significantly reduced in the CRF-treated animals compared to vehicle-treated rats and vehicle-and CRF-treated rats maintained on CD, indicative that CRF given before ethanol exposure was capable of inducing an adaptive change that sensitized withdrawal-induced anxiety-like behavior. Next, the CRF 1 receptor antagonist CRA1000 (3 mg/kg, systemically), the CRF 2 receptor antagonist antisauvagine-30 (20 μg intraventricularly), or vehicle was injected 4 h after the ethanol was removed following the first and second cycles of chronic ethanol exposure and the effect on the multiple-withdrawal-induced anxiety-like behavior determined after the third withdrawal cycle. The CRF 1 receptor antagonist blocked the reduced social interaction behavior, whereas the CRF 2 receptor antagonist was without effect. Similar pretreatment with another CRF 1 receptor antagonist CP-154,526 (10 mg/kg systemically) during the first and second withdrawals also counteracted anxiety-like behavior. These findings indicate that the CRF system and CRF 1 receptors play key roles in the adaptive change responsible for the anxiety-like behavior induced by repeated withdrawals from chronic ethanol.