Selection for pentobarbital withdrawal severity: correlated differences in withdrawal from other sedative drugs

Kliethermes, Christopher L.; Metten, Pamela; Belknap, John K.; Buck, Kari J.; Crabbe, John C.

doi:10.1016/j.brainres.2004.02.040

Cited by 25 publications

(17 citation statements)

References 23 publications

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“…Kcnj9 knockout, heterozygote and wildtype littermates were compared for their acute zolpidem and ethanol withdrawal severities. Adult mice were scored twice for baseline HICs immediately before administration of zolpidem (20 mg/kg, i.p., 2 mg/ml in saline containing 0.1% Tween 80; Tocris Bioscience, Bristol, UK) and then 15, 30, 45, 60, 75, 90, 120, 150, 180, and 360 min post-zolpidem administration as in previous work (Kliethermes et al, 2004). A different group of mice were scored twice for baseline HICs immediately before administration of ethanol (4 g/kg, 20% v/v in saline, i.p.…”

Section: Methodsmentioning

confidence: 99%

“…; Aapers Alcohol and Chemical Co, Shelbyville, KY) and then hourly between 2 and 12 h post-ethanol administration as in previous work (Buck et al, 1997). In order to create an index of drug withdrawal that is independent of individual differences in baseline HIC scores and reflects differences in withdrawal convulsion severity, post-drug HIC scores were corrected for the individual's average baseline (pre-drug) HIC score (described above), and drug withdrawal was indexed as the area under the curve (AUC), calculated as a sum of corrected post-drug HIC scores over the time course as in previous work (Buck et al, 1997; Metten et al, 1998; Kliethermes et al, 2004). …”

Section: Methodsmentioning

confidence: 99%

“…It is well-established that there is common genetic influence on withdrawal from a variety of sedative-hypnotics in mice (Belknap et al, 1987; 1988; 1989; Crabbe et al, 1991; Buck et al, 1999; Metten and Crabbe, 1999; Kliethermes et al, 2004; Shirley et al, 2004; Hood et al, 2006; Metten et al, 2007). Although no animal model duplicates clinically-defined sedative-hypnotic dependence, models for specific factors, including the withdrawal syndrome, are useful for identifying potential genetic determinants of liability in humans.…”

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confidence: 99%

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Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role forKcnj9(GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol

Kozell¹,

Walter²,

Milner³

et al. 2009

J. Neurosci.

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Here, we map a quantitative trait locus (QTL) with a large effect on predisposition to barbiturate (pentobarbital) withdrawal to a 0.44 Mb interval of mouse chromosome 1 syntenic with human 1q23.2. We report a detailed analysis of the genes within this interval and show that it contains 15 known and predicted genes, 12 of which demonstrate validated genotype-dependent transcript expression and/or nonsynonymous coding sequence variation that may underlie the influence of the QTL on withdrawal. These candidates are involved in diverse cellular functions including intracellular trafficking, potassium conductance and spatial buffering, and multimolecular complex dynamics, and indicate both established and novel aspects of neurobiological response to sedative-hypnotics. This work represents a substantial advancement toward identification of the gene(s) that underlie the phenotypic effects of the QTL. We identify Kcnj9 as a particularly promising candidate and report the development of a Kcnj9-null mutant model that exhibits significantly less severe withdrawal from pentobarbital as well as other sedative-hypnotics (zolpidem and ethanol) versus wild-type littermates. Reduced expression of Kcnj9, which encodes GIRK3 (Kir3.3), is associated with less severe sedative-hypnotic withdrawal. A multitude of QTLs for a variety of complex traits, including diverse responses to sedative-hypnotics, have been detected on distal chromosome 1 in mice, and as many as four QTLs on human chromosome 1q have been implicated in human studies of alcohol dependence. Thus, our results will be primary to additional efforts to identify genes involved in a wide variety of behavioral responses to sedative-hypnotics and may directly facilitate progress in human genetics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role forKcnj9(GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol

Kozell¹,

Walter²,

Milner³

et al. 2009

J. Neurosci.

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“…However, these reports have been contrasted by other studies in which zolpidem-induced physical dependence was apparent (e.g. Griffiths et al, 1992; Weerts and Griffiths, 1998; Kliethermes et al, 2004), and is in concordance with numerous clinical accounts of zolpidem dependence (cf. Victorri-Vigneau et al, 2007).…”

Section: Discussionmentioning

confidence: 58%

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

et al. 2013

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Rationale Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. Objective The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Methods Squirrel monkeys (n=6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist) and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Results Chlordiazepoxide, zolpidem and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCt and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCt and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. Conclusions These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

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“…Among the possible explanations for why these findings differ from ours is that CD-1 mice may not possess the full range of gene alleles conferring zolpidem dependence and withdrawal. Quantitative trait locus mapping studies suggest the possibility of loci with common pleiotropic effects on withdrawal HIC from ethanol, pentobarbital, zolpidem, and diazepam in populations of mice including DBA/2J, DBA/1J, and C57BL/6J (Hood et al 2006;Kliethermes et al 2004;Metten et al 1998;Crabbe 1994, 1999;Roberts et al 1994). Another possibility is that the intensity of isoniazidinduced convulsions in the Perrault et al (1992) study masked the zolpidem withdrawal-induced hyperexcitability we were able to detect with the milder HIC, or that the earlier study examined time points that were too late or too infrequent.…”

Section: Discussionmentioning

confidence: 99%

Use of a Novel Mouse Genotype to Model Acute Benzodiazepine Withdrawal

et al. 2006

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Withdrawal from benzodiazepines in physically dependent rodents often requires that the drug be dislodged from its receptor with a competitive antagonist. Withdrawal Seizure-Prone (WSP) mice were selectively bred for their susceptibility to handling-induced withdrawal convulsions following chronic treatment with ethanol. Reflecting pleiotropic genetic influences, they also experience more severe withdrawal from other sedative-hypnotics including the benzodiazepine, diazepam. We used this susceptible genotype to test whether other benzodiazepine receptor (BZR) agonists also produce physical dependence following acute administration, comparing studies of spontaneous withdrawal with those where convulsions were precipitated by a BZR antagonist (flumazenil). Separate groups of mice were tested following a single injection of one of eight BZR agonists. Several doses of each drug were tested for spontaneous withdrawal, and a single dose of each drug was tested for precipitated withdrawal. Withdrawal convulsions were seen after all of the drugs by at least one method, suggesting that BZR agonists as a class elicit acute physical dependence in this susceptible genotype.

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Selection for pentobarbital withdrawal severity: correlated differences in withdrawal from other sedative drugs

Cited by 25 publications

References 23 publications

Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role forKcnj9(GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol

Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role forKcnj9(GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

Use of a Novel Mouse Genotype to Model Acute Benzodiazepine Withdrawal

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