Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats

McDonald, Louise; Sheppard, Wayne F. A.; Staveley, Suzanne M.; Sohal, Bindi; Tattersall, F.D.; Hutson, Pete H.

doi:10.1007/s00213-008-1077-z

Cited by 15 publications

(6 citation statements)

References 39 publications

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“…Tiagabine (Gabitril®), a new generation anti-epileptic and FDA-approved drug was selected because of its capacity to enhance the GABAergic activity through an inhibition of the GABA reuptake pathway [42]–[44]. Tiagabine binds to the GABA uptake carrier and potentially blocks the GABA uptake into presynaptic neurons, permitting more GABA to be available for binding to post-synaptic cell surface receptors.…”

Section: Resultsmentioning

confidence: 99%

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GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

et al. 2014

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Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder.

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Section: Resultsmentioning

confidence: 99%

“…The dose was chosen in accordance with previous reports [42]–[44]. A total of twenty three Mecp2 -deficient mice were studied (n = 10 tiagabine-treated and n = 13 untreated).…”

Section: Methodsmentioning

confidence: 99%

GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

et al. 2014

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“…(+)-Bicuculline [(+)-Bic] (2 or 4 mg/kg) was prepared similar to that described by McDonald et al (2008). The drug was first dissolved in 45 μL acetic acid, 150 μL propylene glycol and 200 μL NaOH (50%).…”

Section: Methodsmentioning

confidence: 99%

Use of the light–dark box to compare the anxiety-related behavior of virgin and postpartum female rats

Miller

Piasecki

Lonstein

2011

Pharmacology Biochemistry and Behavior

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Postpartum female rodents are less anxious than diestrous virgins and this difference contributes to dams’ ability to adequately care for pups and defend the nest. Low postpartum anxiety has been observed in many behavioral paradigms but the results of previous studies using the light-dark box have been inconsistent. We here reexamined the usefulness of the light-dark box to assess differences between postpartum and diestrous virgin female rats in anxiety-related behavior. We found a significant effect of reproductive state, such that dams spent more time in the light chamber than did diestrous virgins. This difference required recent physical contact with pups because a four-hour separation from pups reduced dams’ time spent in the light chamber by half, similar to what we previously found for litter-separated dams tested in an elevated plus maze. Lastly, we examined if dams’ low-anxiety behavior in the light-dark box depends on high GABAA receptor activity by inhibiting the receptor at different binding sites using (+)-Bicuculline to target the GABA site, FG-7142 to target the benzodiazepine site, and pentylenetetrazol to target the picrotoxin site. Only pentylenetetrazol was consistently anxiogenic in dams, while having little effect in diestrous virgins. Thus, the light-dark box can be a useful paradigm to study differences between postpartum and diestrous virgin female rats in their anxiety-related behaviors, and this difference is influenced by dams’ recent contact with pups and GABAA receptor neurotransmission particularly affected by activity at the picrotoxin site.

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“…Results obtained with other drugs provide a hint that the discriminative stimulus effects of gaboxadol are selective for these receptor subtypes. For example, tiagabine is an inhibitor of GABA reuptake (GAT-1) and therefore indirectly enhances GABA A receptor function; in rats discriminating gaboxadol, tiagabine modestly increases drug-lever responding and in rats discriminating tiagabine, gaboxadol produces ≥80% drug-lever responding only at doses that markedly disrupt response rates (McDonald et al 2007; 2008). Similarly, in rats discriminating the nonselective GABA A receptor agonist muscimol, gaboxadol produces substantial drug-lever responding only at doses that also decrease rates (Jones and Balster 1998).…”

Section: Discussionmentioning

confidence: 99%

Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

et al. 2016

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Rationale Gaboxadol is a selective agonist at GABAA receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAA-receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. Objectives The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAA receptors containing α4-δ subunits. Materials Eight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed-ratio 10 schedule for food. Modulators acting at GABAA receptors containing α4-δ subunits (pregnanolone, ethanol, flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle. Results Gaboxadol produced ≥80% gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80% drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32% gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol. Conclusions Drugs that modulate GABAA receptors containing α4-δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABAA-receptor subtype.

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Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats

Abstract: These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.

Cited by 15 publications

References 39 publications

GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

Use of the light–dark box to compare the anxiety-related behavior of virgin and postpartum female rats

Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

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