Changes in GABAA receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats

Lovick, T.A.; Griffiths, J.L.; Dunn, Susan M. J.; Martin, Ian L.

doi:10.1016/j.neuroscience.2004.11.010

Cited by 112 publications

(107 citation statements)

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“…Furthermore, a correlation has been shown between activity at β1-subunit-containing GABA A receptors and ataxia, which is a proposed GHB receptor-mediated effect, because it is induced by GHB receptor-specific ligands and not antagonized by GABA B antagonists (14). The α4β1δ-subtype has been identified as an important target for endogenous neurosteroids, and receptor expression is modulated by fluctuating levels of these subtypes throughout the estrus cycle, potentially causing great sex differences in response to α4β1δ-receptor ligands (41,42). Furthermore, α4β1δ up-regulation has been associated with increased anxiety and hyperalgesia because of disinhibition of GABAergic output neurons (43).…”

Section: Discussionmentioning

confidence: 99%

α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

Absalom

Eghorn

Villumsen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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γ-Hydroxybutyric acid (GHB) binding to brain-specific high-affinity sites is well-established and proposed to explain both physiological and pharmacological actions. However, the mechanistic links between these lines of data are unknown. To identify molecular targets for specific GHB high-affinity binding, we undertook photolinking studies combined with proteomic analyses and identified several GABA A receptor subunits as possible candidates. A subsequent functional screening of various recombinant GABA A receptors in Xenopus laevis oocytes using the two-electrode voltage clamp technique showed GHB to be a partial agonist at αβδ-but not αβγ-receptors, proving that the δ-subunit is essential for potency and efficacy. GHB showed preference for α4 over α(1,2,6)-subunits and preferably activated α4β1δ (EC 50 = 140 nM) over α4β (2/3)δ (EC 50 = 8.41/1.03 mM). Introduction of a mutation, α4F71L, in α4β1(δ)-receptors completely abolished GHB but not GABA function, indicating nonidentical binding sites. Radioligand binding studies using the specific GHB radioligand [ 3 H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid showed a 39% reduction (P = 0.0056) in the number of binding sites in α4 KO brain tissue compared with WT controls, corroborating the direct involvement of the α4-subunit in high-affinity GHB binding. Our data link specific GHB forebrain binding sites with α4-containing GABA A receptors and postulate a role for extrasynaptic α4δ-containing GABA A receptors in GHB pharmacology and physiology. This finding will aid in elucidating the molecular mechanisms behind the proposed function of GHB as a neurotransmitter and its unique therapeutic effects in narcolepsy and alcoholism.γ-hydroxybutyric acid receptor | γ-hydroxybutyric acid high-affinity binding sites | α4-subunit knockout | photoaffinity ligand T he GABA metabolite γ-Hydroxybutyric acid (GHB) is present in micromolar concentrations in the mammalian brain, where it has been proposed to act as a neurotransmitter (1). Additionally, GHB is a drug of abuse (Fantasy) and a registered drug for treating narcolepsy (2) and alcoholism (3). GHB binds to at least two distinct populations of low-and high-affinity binding sites in the brain (4). When GHB is ingested in high doses and reaches millimolar concentrations in the brain, it induces behavioral effects such as sedation, motor incoordination and hypothermia (3). These actions are largely mediated by metabotropic GABA B receptors, because effects are prevented by GABA B receptor antagonist pretreatment (5) and completely abolished in GABA B(1)

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Section: Discussionmentioning

confidence: 99%

α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

Absalom

Eghorn

Villumsen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The appearance of stressinduced hyperalgesia correlated with a four-to fivefold increase in the number of Fos-immunoreactive nuclei in the caudal half of the PAG in rats in late diestrus as well as in the PWD group. During late diestrus, the PAG circuitry becomes intrinsically more excitable due to a reduction in ongoing GABAergic tone, which is linked to upregulation of a4, b1, and d GABA A receptor subunits on GABAergic neurons (Brack and Lovick 2007;Lovick et al, 2005;Griffiths and Lovick 2005a). These neuronal changes are linked with the fall in brain levels of progesterone and hence allopregnanolone, the major neuroactive metabolite of progesterone (Butcher et al, 1975;Purdy et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…The changing hormonal profile of the female brain during the estrous cycle has been shown to produce differential effects on neuronal excitability in the PAG (Brack and Lovick, 2007). During the late diestrus phase, the fall in progesterone level is associated with upregulation of GABA A receptor subunit expression in the PAG (Griffiths and Lovick, 2005a, b;Lovick et al, 2005). New extrasynaptic receptors with the a4b1d configuration are expressed on GABAergic interneurons in the PAG and as a consequence, the output neurons become disinhibited, which leads to the circuitry becoming intrinsically more excitable.…”

Section: Introductionmentioning

confidence: 99%

Differential Activation of the Periaqueductal Gray by Mild Anxiogenic Stress at Different Stages of the Estrous Cycle in Female Rats

Devall¹,

Lovick²

2010

Neuropsychopharmacol

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The effect of acute exposure to mild anxiogenic stress on cutaneous nociceptive threshold was investigated in female Wistar rats at different stages of the estrous cycle. Baseline tail flick latencies did not change significantly during the cycle. However after brief exposure to vibration stress (4 Hz for 5 min), rats in late diestrus, but not at other cycle stages, developed a hyperalgesia (decrease in tail flick latency). Animals in late diestrus revealed a more than fivefold increase in the density of Fos-like immunoreactive nuclei in the dorsolateral, lateral, and ventrolateral columns in the caudal half of the periaqueductal gray matter (PAG). There was no change in the density of Fos-like immunoreactive nuclei in the PAG in rats in estrus and early diestrus, although rats in proestrus showed a smaller (50%) but significant increase. Rats undergoing withdrawal from a progesterone dosing regimen (5 mg/kg i.p. twice daily for 6 days) designed to mimic the fall in progesterone that occurs naturally during late diestrus, exhibited a stress-induced hyperalgesia that was similar to animals in late diestrus and a significant increase in Fos-positive cells in the PAG. We suggest that falling levels of progesterone during late diestrus may be a predisposing factor for the development of stress-induced hyperalgesia, which is linked to differential activation of descending pain control circuits in the PAG. Similar changes in women, when progesterone levels fall during the late luteal phase of the menstrual cycle, may contribute to the development of premenstrual symptoms that include increased anxiety and hyperalgesia.

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“…These receptors are extrasynaptic (Wei et al 2003), where they mediate a tonic inhibition via activation by ambient levels of GABA or via spillover from adjacent synapses (Wei et al 2003). Furthermore, fluctuations in circulating levels of THP have been shown to alter expression of the δ subunit (Sundstrom-Poromaa et al 2002;Lovick et al 2005;Maguire et al 2005). Although αβδ GABAR have been shown to exhibit an increased sensitivity to modulation by steroids (Wohlfarth et al 2002;Stell et al 2003), conflicting reports exist (Zhu et al 1996), and posttranslational mechanisms, such as receptor phosphorylation, are required for steroid modulation (Fancsik et al 2000;Harney et al 2003;Leidenheimer and Chapell 1997;Vicini et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

et al. 2005

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Rationale-3α-OH-5α[β]-pregnan-20-one (THP) is a positive modulator of the GABA A receptor (GABAR), which underlies its reported anxiolytic effect. However, there are conditions such as premenstrual dysphoric disorder (PMDD) where increases in THP levels can be associated with adverse mood.Objectives-In order to test for conditions where THP might be anxiogenic, we developed a mouse model of THP withdrawal. Because δ-containing GABAR are highly sensitive to THP modulation, results were compared in wild-type and δ knockout mice.Methods-Finasteride, a 5α-reductase blocker, was administered for 3 days to female wild-type or δ knockout mice. Then, animals were tested in the elevated plus maze, following acute administration of THP, lorazepam, flumazenil, or 4,5,6,pyridin-3-ol (THIP), and results compared to vehicle-injected controls. CA1 hippocampal GABAR α4 subunit levels were assessed by Western blot.Results-After THP withdrawal, THP produced anxiogenic effects, decreasing open arm entries on the elevated plus maze, following a brief shock, in contrast to its expected anxiolytic effects. As we have shown in rats, THP withdrawal also resulted in increased expression of the α4 subunit in mouse CA1 hippocampus. As expected for increases in α4-containing GABAR, THP withdrawn mice were relatively insensitive to the benzodiazepine (BDZ) lorazepam and had atypical responses to the BDZ antagonist flumazenil when tested on the plus maze. In contrast, they showed a greater anxiolytic response to THIP, which has greater efficacy at α4βδ than other GABAR. Although THP Correspondence to: Sheryl S. Smith, Sheryl.smith@downstate.edu. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl) withdrawal in δ knockout mice also increased the α4 GABAR subunit, the anxiogenic effects of THP and the anxiolytic effects of THIP were not observed, implicating α4βδ GABAR in these effects.Conclusions-Based on these behavioral and pharmacological findings, we suggest that THP withdrawal in the mouse may serve as a rodent model of PMDD.

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Changes in GABAA receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats

Cited by 112 publications

References 37 publications

α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

Differential Activation of the Periaqueductal Gray by Mild Anxiogenic Stress at Different Stages of the Estrous Cycle in Female Rats

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

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Changes in GABAA receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats

Cited by 112 publications

References 37 publications

α4βδ GABA A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

α4βδ GABA A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

Differential Activation of the Periaqueductal Gray by Mild Anxiogenic Stress at Different Stages of the Estrous Cycle in Female Rats

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

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α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

α4βδ GABA _A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)