Dose‐ and Time‐Dependent Expression of Anxiety‐Like Behavior in the Elevated Plus‐Maze During Withdrawal From Acute and Repeated Intermittent Ethanol Intoxication in Rats

Zhang, Zhongqi; Morse, Andrew C.; Koob, George F.; Schulteis, Gery

doi:10.1111/j.1530-0277.2007.00483.x

Cited by 60 publications

(54 citation statements)

References 71 publications

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Section: Discussionmentioning

confidence: 99%

“…Acute exposure to a high dose of alcohol reliably produces increases in anxiety-like behavior (Zhang et al, 2007) and a negative emotional state as measured by brain stimulation reward thresholds (Schulteis and Liu, 2006). These effects are amplified after multiple ethanol exposures (Schulteis and Liu, 2006;Zhang et al, 2007), suggesting a role for negative emotional states during early-stage alcohol use and in the subsequent transition to addiction. A similar correspondence has been observed in studies of opioid withdrawal where both rat and human studies have validated that acute withdrawal after single doses of drug mimics much of the pharmacology of acute withdrawal after chronic drugs (Stitzer et al, 1991;Schulteis et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Roberto¹,

Gilpin²,

O’Dell³

et al. 2008

J. Neurosci.

118

128

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Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA B receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA B receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA B receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogeniclike effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependenceinduced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Roberto¹,

Gilpin²,

O’Dell³

et al. 2008

J. Neurosci.

118

128

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“…The similarity in GABA A R alterations after chronic or single dose EtOH suggests that withdrawal symptoms should be detectable after single dose EtOH. Indeed, transient decreases in seizure thresholds (Goldstein, 1972;Mucha and Pinel, 1979) and heightened anxiety (Doremus et al, 2003;Zhang et al, 2007) have been documented after single-dose EtOH intoxication in rodents. Although we are unaware of published reports, it seems reasonable to suggest that transient sleep disturbances should also be detectable after a single intoxicating EtOH dose.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Reversible GABA_AReceptor Plasticity after Ethanol Intoxication

Liang¹,

Suryanarayanan²,

Abriam³

et al. 2007

J. Neurosci.

142

211

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The time-dependent effects of ethanol (EtOH) intoxication on GABA A receptor (GABA A R) composition and function were studied in rats. A cross-linking assay and Western blot analysis of microdissected CA1 area of hippocampal slices obtained 1 h after EtOH intoxication (5 g/kg, gavage), revealed decreases in the cell-surface fraction of ␣4 and ␦, but not ␣1, ␣5, or ␥2 GABA A R subunits, without changes in their total content. This was accompanied (in CA1 neuron recordings) by decreased magnitude of the picrotoxin-sensitive tonic current (I tonic ), but not miniature IPSCs (mIPSCs), and by reduced enhancement of I tonic by EtOH, but not by diazepam. By 48 h after EtOH dosing, cell-surface ␣4 (80%) and ␥2 (82%) subunit content increased, and cell-surface ␣1 (Ϫ50%) and ␦ (Ϫ79%) and overall content were decreased. This was paralleled by faster decay of mIPSCs, decreased diazepam enhancement of both mIPSCs and I tonic , and paradoxically increased mIPSC responsiveness to EtOH (10 -100 mM). Sensitivity to isoflurane-or diazepam-induced loss of righting reflex was decreased at 12 and 24 h after EtOH intoxication, respectively, suggesting functional GABA A R tolerance. The plastic GABA A R changes were gradually and fully reversible by 2 weeks after single EtOH dosing, but unexplainably persisted long after withdrawal from chronic intermittent ethanol treatment, which leads to signs of alcohol dependence. Our data suggest that early tolerance to EtOH may result from excessive activation and subsequent internalization of ␣4␤␦ extrasynaptic GABA A Rs. This leads to transcriptionally regulated increases in ␣4 and ␥2 and decreases in ␣1 subunits, with preferential insertion of the newly formed ␣4␤␥2 GABA A Rs at synapses.

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“…The elevated plus maze was utilized in the present study because it was previously shown to be a sensitive index of anxiety-like behavior accompanying antagonistprecipitated withdrawal from chronic opioids (Higgins and Sellers, 1994;Schulteis et al, 1998). In addition, this model has been shown to produce consistent anxiety-like behavioral profiles during withdrawal from both chronic and acute ethanol exposure (Baldwin et al, 1991;Doremus et al, 2003;File, 1994;Valdez et al, 2004;Zhang et al, 2007). Although the elevated plus maze is a novelty-based task that requires a between-subjects approach, a withinsubjects approach is not optimal when seeking to study the withdrawal response to a single acute opioid treatment; moreover, our previous work has shown that conditioned withdrawal responses may contribute to the magnitude of naloxone-precipitated withdrawal if animals are repeatedly tested under both acute and repeated intermittent morphine conditions (Schulteis et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

“…It is noteworthy that brain reward deficits and anxiety-like behavior during withdrawal from acute morphine closely parallel negative emotional consequences of withdrawal from acute ethanol Schulteis and Liu, 2006;Zhang et al, 2007). Throughout these studies it has been clearly demonstrated that a single exposure to morphine or alcohol is sufficient to induce a state of acute dependence as measured by negative emotional indices of withdrawal, and severity of said negative emotional withdrawal is further potentiated with several repeated intermittent daily or weekly exposure to opioids or ethanol, suggesting rapid induction and progression of neuroadaptation within brain emotional and reward circuitry.…”

mentioning

confidence: 99%

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Zhang

Schulteis

2008

Pharmacology Biochemistry and Behavior

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Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in timedependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when rats were tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels in the plasma remaining at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxoneprecipitated withdrawal from acute opioid dependence.

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Dose‐ and Time‐Dependent Expression of Anxiety‐Like Behavior in the Elevated Plus‐Maze During Withdrawal From Acute and Repeated Intermittent Ethanol Intoxication in Rats

Cited by 60 publications

References 71 publications

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Mechanisms of Reversible GABA_AReceptor Plasticity after Ethanol Intoxication

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

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Dose‐ and Time‐Dependent Expression of Anxiety‐Like Behavior in the Elevated Plus‐Maze During Withdrawal From Acute and Repeated Intermittent Ethanol Intoxication in Rats

Cited by 60 publications

References 71 publications

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Mechanisms of Reversible GABAAReceptor Plasticity after Ethanol Intoxication

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

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Mechanisms of Reversible GABA_AReceptor Plasticity after Ethanol Intoxication