Neurosteroids and GABAA receptor function

Lambert, Jeremy J.; Belelli, Delia; Hill-Venning, Claire; Peters, John A.

doi:10.1016/s0165-6147(00)89058-6

Cited by 681 publications

(391 citation statements)

References 26 publications

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“…We have shown that clozapine, but not haloperidol or sulpiride, increases in a dose-and time-dependent manner the brain concentrations of progesterone as well as AP and THDOC, two potent endogenous positive modulators of the action of GABA at GABA A receptors (Majewska et al 1986;Robel and Baulieu 1994;Gee et al 1995;Lambert et al 1995), to an extent compatible with modulation of GABA A receptor activity in vivo (Pinna et al 2000). The active doses of clozapine with regard to this effect, as well as the doses of haloperidol used in this study, are comparable to those that are therapeutically efficacious in humans.…”

Section: Discussionmentioning

confidence: 91%

“…Thus, the effects of these steroids may be graded depending on the subunit composition of the GABA A receptors expressed by a given neuron, on the amount of GABA released at given synapses (Lambert et al 1995), and, possibly, on the brain region-dependent extent of inhibition of GABAergic transmission exerted by clozapine itself (Korpi et al 1995). The latter factor may explain why systemic administration of high doses of AP induces catalepsy (Khisti et al 1998); whereas, clozapine, which increases the brain concentration of AP, does not.…”

Section: Discussionmentioning

confidence: 99%

“…Allopregnanolone (AP) and allotetrahydrodeoxycorticosterone (THDOC) are endogenous neuroactive steroids that potentiate the action of GABA at GABA A receptors with high potency both in vitro (Majewska et al 1986;Puia et al 1990;Paul and Purdy 1992;Lambert et al 1995) and in vivo (Concas et al 1996;Pinna et al 2000). The brain concentrations of AP and THDOC are increased by convulsant and anxiogenic drugs, such as isoniazid and negative allosteric modulators of GABA A receptors (Barbaccia et al 1996b(Barbaccia et al , 1997, that reduce GABA-mediated transmission; this action is possibly mediated through a decrease in the GABAergic inhibition of the hypothalamic-pituitaryadrenal axis.…”

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confidence: 99%

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Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

Barbaccia

Affricano

Purdy

et al. 2001

Neuropsychopharmacology

104

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The extrapyramidal side effects of typical antipsychotics, which are induced to a markedly reduced extent by clozapine, have been linked to a dysfunction of central ␥ -aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3 ␣ -hydroxy-5 ␣ AP) and 3 ␣ , THDOC)Clozapine, the prototype of atypical antipsychotic drugs, exhibits the clinical efficacy of classical antipsychotics but lacks or induces to a greatly reduced extent most of the motor side effects of these latter drugs. The molecular mechanisms that underlie the pharmacological profile of clozapine remain unclear. Emphasis has been placed on the purported "selective" action of clozapine on mesocortical and mesolimbic dopaminergic pathways thought to result from its higher affinity for D 4 dopamine receptors than for D 2 receptors (Seeman 1992), as well as on its mixed antagonistic/agonistic action at D 2 and D 1 receptors (Coward et al. 1989;Brunello et al., 1995;Gerlach et al. 1996) and its high affinity for different subtypes of serotonin receptors (Brunello et al. 1995). More recently, the ratios of the affinities of clozapine for D 2 and 5HT 1a , D 2 and 5HT 1b or 5HT 1d , and D 2 and ␣ 2 -adrenergic receptors have been suggested to play a role in the anticata-

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

Barbaccia

Affricano

Purdy

et al. 2001

Neuropsychopharmacology

104

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“…At concentrations higher than 100nM, positive neurosteroids can directly gate the GABA A receptor (for review, Belelli et al, 2006), although such actions are unlikely to have physiological effects except, perhaps, during pregnancy when neurosteroids are reported to reach such levels (see Section 4). A-ring reduction at the 3 position, as well as a D-ring C 20 or C 17 keto group, are believed to be critical for positive neurosteroid binding (for review, Lambert et al, 1995) (Figure 1). …”

Section: Mechanisms Of Steroid Modulation Of Gaba a Receptorsmentioning

confidence: 99%

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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“…3a-reduced neuroactive steroids such as 3a, 5a-tetrahydroprogesterone (3a, 5a-THP), 3a, 5b-THP and 3a, 5a-tetrahydrodeoxycorticosterone (3a, 5a-THDOC) (Figure 1) have been identified as potent positive allosteric modulators of g-aminobutyric acid type A (GABA A ) receptors (Paul and Purdy, 1992;Rupprecht and Holsboer, 1999;Rupprecht, 2003;Lambert et al, 1995). In line with their GABAenhancing potential, a pronounced anxiolytic activity has been shown for 3a-reduced neuroactive steroids in various animal studies (Paul and Purdy, 1992;Rupprecht and Holsboer, 1999;Rupprecht, 2003).…”

Section: Introductionmentioning

confidence: 99%

Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3α, 5α Tetrahydrodeoxycorticosterone (3α, 5α-THDOC) in Healthy Volunteers

Eser

Michele

Zwanzger

et al. 2004

Neuropsychopharmacol

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3a-reduced neuroactive steroids such as 3a, 5a-tetrahydroprogesterone (3a, 5a-THP) and 3a, 5a-tetrahydrodeoxycorticosterone (3a, 5a-THDOC) are potent positive allosteric modulators of g-aminobutyric acid type A (GABA A ) receptors and display pronounced anxiolytic activity in animal models. Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) and sodium lactate is accompanied by a decrease in 3a, 5a-THP concentrations in patients with panic disorder, but not in healthy controls. However, no data are available on 3a, 5a-THDOC concentrations during experimental panic induction. Therefore, we quantified 3a, 5a-THDOC concentrations in 10 healthy volunteers (nine men, one woman) before and after panic induction with CCK-4 by means of a highly sensitive and specific gas chromatography/mass spectrometry analysis. CCK-4 elicited a strong panic response as assessed by the Acute Panic Inventory. This was accompanied by an increase in 3a, 5a-THDOC, ACTH and cortisol concentrations. This increase in 3a, 5a-THDOC might be a consequence of hypothalamic-pituitary-adrenal (HPA) axis activation following CCK-4-induced panic, and might contribute to the termination of the anxiety/stress response following challenge with CCK-4 through enhancement of GABA A receptor function.

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Neurosteroids and GABAA receptor function

Cited by 681 publications

References 26 publications

Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3α, 5α Tetrahydrodeoxycorticosterone (3α, 5α-THDOC) in Healthy Volunteers

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