Discriminative stimulus effects of ethyl-β-carboline-3-carboxylate at two training doses in rats

Rowlett, James K.; Wilcox, Kristin M.; Woolverton, William L.

doi:10.1007/s002130051065

Cited by 5 publications

(6 citation statements)

References 21 publications

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“…Similar pA 2 values for flumazenil in rats discriminating pregnanolone or midazolam indicated that effects of midazolam and flunitrazepam are mediated by the same population of receptors in the two groups. The pA 2 values for flumazenil obtained in the current study are similar to those reported for flumazenil in another study in which it antagonized the discriminative stimulus effects of β-CCE, a negative GABA A modulator acting at benzodiazepine sites (Rowlett et al 1999). Although the discriminative stimulus effects of β-CCE are very different from those of benzodiazepines (current study; Rowlett et al 1999; Lelas et al 2000), similar pA 2 values for flumazenil indicate that the same population of receptors mediates their effects.…”

Section: Discussionsupporting

confidence: 89%

Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Bai

Gerak

2010

Psychopharmacology

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Rationale-Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative and anticonvulsant effects, and their actions at different modulatory sites on GABA A receptors might confer differences in adverse effects.Objectives-This study used drug discrimination to compare discriminative stimuli produced by positive GABA A modulators that vary in their site of action on GABA A receptors.Methods-Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation.Results-Pregnanolone, midazolam and flunitrazepam produced ≥80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ≥80% drug-lever responding in all rats discriminating pregnanolone and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity and pA 2 values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone.Conclusions-The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines. Keywordsregnanolone; midazolam; flumazenil; drug discrimination; Schild analyses; rats γ-Aminobutyric acid A (GABA A ) receptors are important therapeutic targets, and drugs that act at benzodiazepine binding sites on GABA A receptors are used clinically. Despite their effectiveness and large margin of safety, there are adverse effects associated with the clinical use of benzodiazepines, including the development of tolerance and dependence (Lader 2008; Cloos and Ferreira 2008). Treatment might be improved by developing drugs that retain the therapeutic effects of benzodiazepines while reducing their adverse effects. One strategy for identifying potential replacements for benzodiazepines is to target different Given the differences between benzodiazepines and neuroactive steroids, their acute behavioral effects might also not be identical. One procedure in which differences in the acute effects of benzodiazepines and neuroactive steroids have been observed is drug discrimination. Drugs acting at benzodiazepine, barbiturate or neuroactive steroid binding sites have been established as discriminative stimuli, and generally, they share discriminative stimulus effects (e.g., de la Garza and Johanson 1987;Ator et al. 1993;McMahon et a...

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Section: Discussionsupporting

confidence: 89%

Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Bai

Gerak

2010

Psychopharmacology

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“…DMCM did not antagonize pregnanolone at the same doses that antagonized midazolam, and doses of DMCM larger than 3.2 mg/kg were not tested in combination with pregnanolone because seizures occurred with these doses in diazepam-treated monkeys. That β-CCE, and not DMCM, antagonized pregnanolone is consistent with a previous study demonstrating that β-CCE and DMCM did not share discriminative stimulus effects (Rowlett et al 1999). The antagonism of pregnanolone by negative modulators (β-CCE and β-CCM) could involve two different sites that are allosterically linked to the same Cl − ionophore.…”

Section: Discussionsupporting

confidence: 81%

Negative GABAA modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys

McMahon

2005

Psychopharmacology

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Negative modulators are qualitatively similar to neutral modulators in diazepam-treated animals; however, interactions between negative modulators and midazolam suggest that different receptors mediate the effects of some (DMCM) and not other (beta-CCM) negative modulators. Negative modulators at benzodiazepine sites exert efficacy-dependent antagonism of positive modulators at neuroactive steroid sites. Without competitive antagonists at neuroactive steroid or barbiturate sites, negative modulators could prove useful for examining the mechanism of action of different classes of positive GABA(A) modulator.

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Section: Gaba-mimeticsmentioning

confidence: 99%

“…Two stand-alone investigations provide preliminary insights into the role of training dose for the α 1 -subunit selective agonist alpidem (Sanger and Zivkovic, 1994) and the partial inverse agonist β-CCE (Rowlett et al, 1999). Numerous studies demonstrated that benzodiazepine training dose magnitude was inversely proportional to the number of sessions to discrimination criteria in rats (Bruner and Anderson, 2009; De Vry and Slangen, 1986b; Shannon and Herling, 1983; Tang and Franklin, 1991; Sanger and Zivkovic, 1994; Rowlett et al, 1999) and gerbils (Järbe and Swedberg, 1998). It is similarly well documented that lower benzodiazepine training doses are associated with a leftward shift in the dose-response curve (i.e., lower ED 50 ) when compared to higher doses of the same training drug in rats (Ator and Griffiths, 1989; De Vry and Slangen, 1986b, 1986b; Bruner and Anderson, 2009; Sannerud and Ator, 1995a, 1995b; Shannon and Herling, 1983; Tang and Franklin, 1991; Sanger and Zivkovic, 1994; Rowlett et al, 1999) and humans (Rush et al, 1995).…”

Section: Gaba-mimeticsmentioning

confidence: 99%

Role of training dose in drug discrimination

Stolerman

Childs

Ford

et al. 2011

Behavioural Pharmacology

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Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED50 values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (i) changes in profiles of generalisation between partial and full agonists; (ii) reduced specificity of some discriminations at small training doses and (iii) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating ‘drug versus drug’ or “dose versus dose” contingencies enabled detection of more subtle differences than the simple ‘drug versus no drug’ approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that utilise either within- or between-subject designs for studying the discriminative stimulus effects of drugs.

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Discriminative stimulus effects of ethyl-β-carboline-3-carboxylate at two training doses in rats

Cited by 5 publications

References 21 publications

Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Negative GABAA modulators attenuate the discriminative stimulus effects of benzodiazepines and the neuroactive steroid pregnanolone in rhesus monkeys

Role of training dose in drug discrimination

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