Γ-aminobutyric Acid Subunit Research Articles

Contraception counseling for women with premenstrual dysphoric disorder (PMDD): current perspectives.

Premenstrual Dysphoric Disorder (PMDD) is a severe form of premenstrual syndrome (PMS) affecting up to 7% of reproductive age women. Women with PMDD are of reproductive age; therefore, contraception and treatment of PMDD are important considerations. The disorder as described in the DSM-V is characterized by moderate to severe psychological, behavioral and physical symptoms beginning up to two weeks prior to menses, resolving soon after the onset of menstruation and significantly interfering with daily functioning. PMDD develops in predisposed individuals after they are exposed to progesterone at the time of ovulation. It has been hypothesized that PMDD is in part attributable to luteal phase abnormalities in serotonergic activity and to altered configuration of ℽ-aminobutyric acid subunit A (GABAA) receptors in the brain triggered by the exposure to the neuroactive steroid progesterone metabolite, allopregnanolone (Allo). A large body of evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can be effective in the treatment of PMDD. Combined hormonal contraceptive (CHC) pills, specifically the 20 mcg ethinyl estradiol/3mg drospirenone in a 24/4 extended cycle regimen has been shown to significantly improve the emotional and physical symptoms of PMDD. Other combined monophasic, extended cycle hormonal contraceptive pills with less androgenic progestins may also be helpful, although not well studied. Copper intrauterine devices (IUDs) are recommended for those not seeking hormonal contraceptives. Progestin-only methods including the progestin-only pill (POP), levonorgestrel (LNG) IUD, etonorgestrel implant or depot medroxyprogesterone acetate (DMPA) have the potential to negatively affect mood symptoms for women with or without baseline mood disorders, including PMDD. Careful counseling and close follow-up is recommended for patients with PMDD seeking these contraceptive methods.

Anxiolytic effect of the GPR103 receptor agonist peptide P550 (homolog of neuropeptide 26RFa) in mice. Involvement of neurotransmitters

The GPR103 receptor is a G protein-coupled receptor, which plays a role in several physiological functions. However, the role of the GPR103 receptor in anxiety has not been clarified. The first aim of our study was to elucidate the involvement of the GPR103 receptor in anxious behavior. Mice were treated with peptide P550, which is the mouse homolog of neuropeptide 26RFa and has similar activity for the GPR103 receptor as neuropeptide 26RFa. The anxious behavior was investigated using an elevated plus-maze paradigm. The second aim of our study was to investigate the underlying neurotransmissions. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a γ-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a nonselective β-adrenergic receptor antagonist, propranolol. Our results demonstrated that peptide P550 reduces anxious behavior in elevated plus maze test in mice. Our study shows also that GABAA-ergic, α- and β-adrenergic transmissions are all involved in this action, whereas 5-HT1 and 5-HT2 serotonergic, muscarinic cholinergic and D2, D3, D4 dopaminergic mechanisms may not be implicated.

The action of orexin B on passive avoidance learning. Involvement of neurotransmitters

The extensive projection of orexigenic neurons and the diffuse expression of orexin receptors suggest that endogenous orexins are involved in several physiological functions of the central nervous system, including learning and memory. Our previous study demonstrated that orexin A improves learning, consolidation and retrieval processes, which involves α- and β-adrenergic, cholinergic, dopaminergic, GABA-A-ergic, opiate and nitrergic neurotransmissions. However, we have little evidence about the action of orexin B on memory processes and the underlying neuromodulation. Therefore, the aim of the present study was to investigate the action of orexin B on passive avoidance learning and the involvement of neurotransmitters in this action in rats. Accordingly, rats were pretreated with the selective orexin 2 receptor (OX2R) antagonist, EMPA; the γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, the bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; the nonselective opioid receptor antagonist, naloxone; the non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; the nonselective α-adrenergic receptor antagonist, phenoxybenzamine and the β-adrenergic receptor antagonist, propranolol. Our results demonstrate that orexin B can improve learning, consolidation of memory and retrieval. EMPA reversed completely the action of orexin B on memory consolidation. Bicuculline blocked fully; naloxone, nitro-l-arginine, phenoxybenzamine and propranolol attenuated the orexin B-induced memory consolidation, whereas haloperidol was ineffective. These data suggest that orexin B improves memory functions through OX2R and GABA-ergic, opiate, nitrergic, α- and β-adrenergic neurotransmissions are also involved in this action.

Involvement of neurotransmitters in the action of the nociceptin/orphanin FQ peptide-receptor system on passive avoidance learning in rats.

The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-receptor system induces impairment in memory and learning. However, we have little evidence about the underlying neuromodulation. The aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan G protein-coupled receptor (GPCR) SP9155 P550 on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase inhibitor, nitro-L-arginine, a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol. Atropine, bicuculline, naloxone and phenoxybenzamine reversed the orphan GPCR SP9155 P550-induced memory impairment, whereas propranolol, haloperidol and nitro-L-arginine were ineffective. Our results suggest that the NOP system-induced impairment of memory consolidation is mediated through muscarinic cholinergic, GABA-A-ergic, opioid and α-adrenergic receptors, whereas β-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms are not be implicated.

Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice

Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the underlying neuromodulation. Therefore, the aim of the present study was to investigate the involvement of neurotransmitters in the orexin A-induced anxiety-like behavior in elevated plus maze (EPM) test in mice. Accordingly, mice were pretreated with a non-selective muscarinic cholinergic antagonist, atropine; a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; a non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol 30min prior to the intracerebroventricular administration of orexin A. The EPM test started 30min after the i.c.v. injection of the neuropeptide. Our results show that orexin A decreases significantly the time spent in the arms (open/open+closed) and this action is reversed by bicuculline, phenoxybenzamine and propranolol, but not by atropine, haloperidol or nitro-l-arginine. Our results provide evidence for the first time that the orexin A-induced anxiety-like behavior is mediated through GABA-A-ergic, α- and β-adrenergic neurotransmissions, whereas muscarinic cholinergic, dopaminergic and nitrergic neurotransmissions may not be implicated.

Urocortin 3 administration impairs fear motivated learning in mice is mediated by transmitters

Urocortin 3 (Ucn 3) was found to impair passive avoidance learning in male and female mice. The possible involvement of transmitters in the action, the animals were pretreated with the following receptor antagonists in doses which alone could not influence the measurement. Haloperidol (a D2, dopamine receptor antagonist), phenoxybenzamine (a nonselective α1-adrenergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), bicuculline (a γ-aminobutyric acid subunit A receptor antagonist), nitro-l-arginine (a nitric oxide synthase inhibitor), antalarmin (a CRF1 receptor antagonist) and astressin 2B (a CRF2 receptor antagonist). Haloperidol, phenoxybenzamine, bicuculline, atropine, nitro-l-arginine and astressin 2B prevented the action of Ucn 3, in both sexes, whereas antalarmin exerted no action in either male or female animals.

Transmitter mediation of the anxiolytic action of apelin-13 in male mice

The widespread distribution of apelin-13 and apelin receptors in the brain and periphery suggests an important function of this neuropeptide in regulatory processes in the organism. In previous work we found that apelin-13 facilitates the consolidation of passive avoidance learning in rats. In the present work we demonstrate that apelin-13 exerts anxiolytic action in an elevated plus maze in mice. In order to assess the possible involvement of transmitters in this action, the animals were pretreated with the following receptor blockers in doses which themselves did not influence the behavioral paradigm: atropine (a nonselective muscarinic acetylcholine receptor antagonist), haloperidol (a D2, D3, D4 dopamine receptor antagonist), phenoxybenzamine (a nonselective α1-adrenergic receptor antagonist), methysergide (a nonselective 5-HT2 serotonergic receptor antagonist), propranolol (a β-adrenergic receptor antagonist), naloxone (a nonselective opioid receptor antagonist) and bicuculline (a γ-aminobutyric acid subunit A receptor antagonist. Phenoxybenzamine, haloperidol, propranolol and methysergide prevented the action of apelin-13, whereas atropine, naloxone and bicuculline were ineffective. The data suggest that apelin-13 elicits its anxiolytic action via α-adrenergic, dopaminergic, β-adrenergic and 5-HT2 serotonergic mediation.

Neurotransmissions of antidepressant-like effects of neuromedin U-23 in mice

Neuromedin U (NmU) is a widely distributed and multifunctional peptide in the central nervous system and the peripheral tissues. Little is know about the mechanisms of NmU on brain functions. The rodent isoform of the NmU, NmU-23, has been shown to have anxiolytic effects involved in the β-adrenergic and cholinergic nervous systems in elevated plus maze test. NmU-23 was tested for antidepressant-like effects in modified forced swimming test (FST) in mice and furthermore, the involvement of the adrenergic, serotonergic, cholinergic, dopaminergic or gaba-ergic receptors in the antidepressant-like effect of NmU-23 was studied in modified mice FST. Mice were pretreated with a non-selective α-adrenergic receptor antagonist phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist, prazosin, an α2-adrenergic receptor antagonist, yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, nonselective muscarinic acetylcholine receptor antagonist, atropine, D2,D3,D4 dopamine receptor antagonist, haloperidol or γ-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline.NmU-23 showed the antidepressant-like effects by decreasing the immobility time and increasing the climbing and swimming time. Prazosin, haloperidol, and bicuculline prevented the effects of NmU-23 on the climbing and swimming time. Methysergide and cyproheptadine prevented the effects of NmU-23 on the immobility, swimming and climbing time. Atropine prevented the effects of NmU-23 on the climbing time. Phenoxybenzamine, yohimbine and propranolol did not change the effects of NmU-23.The results demonstrated that the antidepressant-like effect of NmU-23 is mediated, at least in part, by an interaction of the α2-adrenergic, 5-HT1–2 serotonergic, D2,D3,D4 dopamine receptor, muscarinic acetylcholine receptors and γ-aminobutyric acid subunit A (GABAA) receptor in a modified mouse FST.

The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters

Kisspeptins are G protein-coupled receptor ligands originally identified as human metastasis suppressor gene products that have the ability to suppress melanoma and breast cancer metastasis and recently found to play an important role in initiating the secretion of gonadotropin-releasing hormone at puberty. Kisspeptin-13 is an endogenous isoform that consists of 13 amino acids.The action of kisspeptin in the regulation of gonadal function has been widely studied, but little is known as concerns its function in limbic brain structures.In the brain, the gene is transcribed within the hippocampal dentate gyrus.This paper reports on a study the effects of kisspeptin-13 on passive avoidance learning and the involvement of the adrenergic, serotonergic, cholinergic, dopaminergic and GABA-A-ergic, opiate receptors and nitric oxide in its action in mice. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α2-adrenergic receptor antagonist, yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, D2, D3, D4 dopamine receptor antagonist, haloperidol, a γ-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, naloxone, a nonselective opioid receptor antagonist and nitro-l-arginine, a nitric oxide synthase inhibitor. Kisspeptin-13 facilitated learning and memory consolidation in a passive avoidance paradigm. Phenoxybenzamine, yohimbine, propranolol, methysergide, cyproheptadine, atropine, bicuculline and nitro-l-arginine prevented the action of kisspeptin-13 on passive avoidance learning, but haloperidol and naloxone did not block the effects of kisspeptin-13. The results demonstrated that the action of kisspeptin-13 on the facilitation of passive avoidance learning and memory consolidation is mediated, at least in part, through interactions of the α2-adrenergic, beta-adrenergic, 5-HT2 serotonergic, muscarinic cholinergic and GABA-A-ergic receptor systems and nitric oxide.

Involvement of neurotransmitters in the action of apelin-13 on passive avoidance learning in mice

The widespread distribution of apelin-13 and apelin receptors in the brain suggests an important function of this neuropeptide in the brain that has not been explored extensively so far. In the present work, apelin-13 was found to facilitate the consolidation of passive avoidance learning in mice. In order to assess the possible involvement of transmitters in this action, the animals were pretreated with the following receptor blockers in doses which themselves did not influence the behavioral paradigm: phenoxybenzamine (a nonselective α-adrenergic receptor antagonist), propranolol (a β-adrenergic receptor antagonist), cyproheptadine (a nonselective 5-HT2 serotonergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), haloperidol (a D2, D3 and D4 dopamine receptor antagonist), bicuculline (a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist), naloxone (a nonselective opioid receptor antagonist), and nitro-l-arginine (a nitric oxide synthase inhibitor). Phenoxybenzamine, cyproheptadine, atropine, haloperidol, bicuculline and nitro-l-arginine prevented the action of apelin-13. Propranolol and naloxone were ineffective. The data suggest that apelin-13 elicits its action on the consolidation of passive avoidance learning via α-adrenergic, 5-HT2 serotonergic, cholinergic, dopaminergic, GABA-A-ergic and nitric oxide mediations.

Neurotransmissions of antidepressant-like effects of kisspeptin-13

Kisspeptins are G protein-coupled receptor ligands originally identified as human metastasis suppressor gene products that have the ability to suppress melanoma and breast cancer metastasis and which have recently been found to play an important role in initiating the secretion of gonadotropin-releasing hormone at puberty. In the brain, the gene is transcribed within the hippocampal dentate gyrus. Kisspeptin-13, one of the endogenous isoforms, consists of 13 amino acids. In this work, antidepressant-like effects of kisspeptin-13 were studied and the potential involvement of the adrenergic, serotonergic, cholinergic, dopaminergic and gabaergic receptors in its antidepressant-like effects was investigated in a modified forced swimming test (FST) in mice. The mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist, prazosin, an α2-adrenergic receptor antagonist, yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, a D2,D3,D4 dopamine receptor antagonist, haloperidol, or a γ-aminobutyric acid subunit A receptor antagonist, bicuculline.The FST revealed that kisspeptin-13 reversed the immobility, climbing and swimming times, suggesting antidepressant-like effects. Phenoxybenzamine, yohimbine and cyproheptadine prevented the effects of kisspeptin-13 on the immobility, climbing and swimming times, whereas prazosin, propranolol, methysergide, atropine, haloperidol and bicuculline did not modify the effects of kisspeptin-13.The results demonstrated that the antidepressant-like effects of kisspeptin-13 in a modified mouse FST are mediated, at least in part, by an interaction of the α2-adrenergic and 5-HT2 serotonergic receptors.

Involvement of neurotransmitters in the action of growth hormone-releasing hormone antagonist on passive avoidance learning

The antagonist MZ-4-71 of growth hormone-releasing hormone (GH-RH) has been shown to suppress the secretion of GH and insulin-like growth factor-1 (IGF-1), suggesting that this class of analogs could be used for the therapy of disorders characterized by excessive GH secretion. Numerous GH-RH antagonists has been synthetized and shown to suppress the growth of various tumors. MZ-4-71 facilitates the consolidation of passive avoidance learning. Beta-amyloid 25–35 impairs the consolidation of passive avoidance learning and MZ-4-71 fully blocks this impairment. However, little is known about the possible mechanism of action of GR-RH antagonists on these actions. In the present work, the possible effects of different neurotransmitters on the action of MZ-4-71 were studied in the memory consolidation of passive avoidance behavior. The involvement of cholinergic, serotonergic, dopaminergic, GABA-ergic, adrenergic and opiate receptors was tested. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, or a nonselective opioid receptor antagonist, naloxone. Atropine, methysergide, cyproheptadine and naloxone prevented the effects of MZ-4-71 on passive avoidance learning, whereas haloperidol, phenoxybenzamine, propranolol and bicuculline did not change the effects of MZ-4-71. The results demonstrate that the muscarinic acetylcholine receptor, the 5-HT1/5-HT2 serotonergic receptor and opioid receptors are involved as mediators in the action of MZ-4-71 on the consolidation of passive avoidance learning.

Neurotransmitter-mediated action of an antagonist of growth hormone-releasing hormone on anxiolysis in mice

Antagonists of growth hormone-releasing hormone (GH-RH), such as MZ-4-71 suppress the secretion of GH. These findings suggest that GH-RH antagonists could be used for the therapy of disorders characterized by excessive GH secretion. It has been also demonstrated that MZ-4-71 displays antidepressant effects in a modified forced swimming test in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by β-amyloid (25–35) in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions.In the present work, the involvement of the adrenergic, serotonergic and GABA-ergic receptors in the anxiolytic action of MZ-4-71 was studied in an elevated plus maze. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist, prazosin, an α2-adrenergic receptor antagonist, yohimbine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, and a γ-aminobutyric acid subunit (GABA-A) receptor antagonist, bicuculline.Phenoxybenzamine, prazosin, yohimbine, methysergide, cyproheptadine and bicuculline prevented the effects of MZ-4-71 on the elevated plus maze revealing that the anxiolytic actions of MZ-4-71 in this test are mediated, at least in part, by the an interaction of the α1/α2-adrenergic, 5-HT1/5-HT2 serotonergic and GABA-A-ergic receptors.

Neurotransmission of the antidepressant-like effects of the growth hormone-releasing hormone antagonist MZ-4-71

MZ-4-71 is an antagonist of growth hormone–releasing hormone (GH–RH) which suppresses the secretion of GH–RH. It has been shown that MZ-4-71 has antidepressive-like effects in a modified forced swimming test (FST) in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by β-amyloid 25–35in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions.The involvement of the adrenergic, serotonergic, cholinergic, dopaminergic or GABA-ergic receptors in the antidepressant-like action of MZ-4-71 (1.0μg/2μl, intracerebroventricular (i.c.v.)) was studied in a modified mouse forced swimming test (FST). Mice were pretreated with a non-selective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist prazosin, an α2-adrenergic receptor antagonist, yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a non-selective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol or a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist bicuculline.Phenoxybenzamine, prazosin, methysergide, cyproheptadine and atropine prevented the effects of MZ-4-71 on the immobility, the climbing and the swimming times. Yohimbine, propranolol, haloperidol and bicuculline did not change the effects of MZ-4-71.The results demonstrated that the antidepressant-like effects of MZ-4-71 in this modified mouse FST are mediated, at least in part, by the an interaction of the α1-adrenergic, 5-HT1/5-HT2 serotonergic, and muscarinic acetylcholine receptors.

Neurosteroids as Endogenous Regulators of Seizure Suscepibility.

Stress-induced Deoxycorticosterone-derived Neurosteroids Modulate GABAA Receptor Function and Seizure Susceptibility Reddy DS, Rogawski MA J Neurosci 2002;22:3795–3805 Stress affects seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here we provide evidence that γ-aminobutyric acid subunit A (GABAA) receptor-modulating neurosteroids derived from deoxycorticosterone (DOC) play a role in stress-related changes in seizure control. DOC, an adrenal steroid, the synthesis of which is enhanced during stress, undergoes sequential metabolic reduction by 5α-reductase and 3α-hydroxysteroid oxidoreductase to form 5α-dihydrode-oxycorticosterone (DHDOC) and allotetrahydrodeoxycorti-costerone (THDOC), a GABAA receptor-modulating neurosteroid with anticonvulsant properties. Acute swim stress in rats significantly elevated plasma THDOC concentrations and raised the pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC produced comparable increases in THDOC and PTZ seizure thresholds. Pretreatment with finasteride, a 5α-reductase inhibitor that blocks the conversion of DOC to DHDOC, reversed the antiseizure effects of stress. DOC also elevated plasma THDOC levels and protected mice against PTZ, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate, picrotoxin, and amygdala-kindled seizures in mice (ED50 values, 84–97 mg/kg). Finasteride reversed the antiseizure activity of DOC (ED50, 7.2 mg/kg); partial antagonism also was obtained with indomethacin (100 mg/kg), an inhibitor of 3α-hydroxysteroid oxidoreductase. Finasteride had no effect on seizure protection by DHDOC and THDOC, whereas indomethacin partially reversed DHDOC but not THDOC. DHDOC, like THDOC, potentiated GABA-activated Cl– currents in cultured hippocampal neurons (≤1 μ) and directly activated GABAA receptor currents (≤1 μ M), compatible with a role for DHDOC in the antiseizure activity of DOC. DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to neurosteroids with modulatory actions on GABAA receptors including THDOC and possibly also DHDOC. Enhanced Neurosteroid Potentiation of Ternary GABAA Receptors Containing the δ Subunit Wohlfarth KM, Bianchi MT, Macdonald RL J Neurosci 2002;22:1541–1549 Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the γ-aminobutyric acid subunit A [GABA(A)]-receptor δ subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABAA-receptor isoforms in a transient expression system: α1β372L, α1β38, α6β372L, and α6β38. Potentiation of submaximal GABAA-receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the α1β38 isoform. Whole-cell GABA concentration-response curves performed with and without low concentrations (30 n M) of THDOC revealed enhanced peak GABAA-receptor currents for isoforms tested without affecting the GABA EC50. The α1β38 currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15–50%. At a higher concentration (1 μ M), THDOC decreased peak α1β382L-receptor current amplitude evoked by GABA (1 m M) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for α1β382L GABAA receptors. However, the same protocol applied to α1β38 receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing α1β38 receptors. Single-channel recordings obtained from α1β38 receptors indicated that THDOC increased the channel-opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABAA-receptor delta subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of α1β38 GABAA receptors are altered by THDOC.