Influences of gender, gonadectomy 5 and estrous cycle on GABA/BZ receptors and benzodiazepine responses in rats

doi:10.1016/0361-9230(92)90022-P

Brain Research Bulletin

Volume 29, Issue 2, August 1992, Pages 165-172

https://doi.org/10.1016/0361-9230(92)90022-P Get rights and content

Abstract

Benzodiazepines (BZ) and steroid hormone derivatives can potentiate the inhibitory actions of GABA through interactions with the GABA_A/BZ/chloride ionophore complex. The present study examines whether the in vivo hormone milieu of rats modulates GABA/BZ receptors and/or benzodiazepine responses. The influences of gender, estrous cycle, and the diminution of steroid levels on GABA/BZ receptors and BZ anticonvulsant responses were tested by comparing these parameters in groups of intact male, intact female, orchidectomized, and ovariectomized rats. The hormonal milieu appears to modulate the GABA recognition site and possibly GABA-related responses in rats. This is evidenced by the decrease in cortical GABAA receptor affinity seen in females compared with other hormone groups and the gender-related difference observed in susceptibility to seizures induced by the GABA antagonist bicuculline. In cycling females, high circulating levels of progesterone were correlated with heightened seizure thresholds, suggesting that progestins serve a protective role in the control of seizure activity. Although a gender-related difference in cortical BZ binding affinity was observed, BZ receptor parameters in several other brain areas and BZ anticonvulsant responses were unaffected by physiological fluctuations in gonadal hormones.

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In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.
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However, no studies have analyzed the effect of this plant in female rats under different endocrine conditions. Because GABAA receptors mediate MT's anxiolytic-like effect in male rats (Sollozo-Dupont et al., 2015), and ovarian hormonal fluctuations along the estrous cycle can modulate the affinity (Wilson, 1992) and expression of the GABAA receptors subunits (Lovick, 2006). It is feasible that ovarian hormone fluctuations can also influence MT's actions.
Montanoa tomentosa Cerv. (MT) is a native plant from Mexico used in traditional medicine as a remedy for reproductive impairments and relaxing effects. In previous studies, it has been shown that the endocrine state could modify the antianxiety-like actions of anxiolytic compounds. Although women are the primary user of MT, no studies have evaluated the potential impact of the endocrine milieu on its anti-anxiety actions.
Aims of the study:Ascertain the antianxiety effects of M. tomentosa in rats with different hormonal conditions, and to analyze the participation of the GABA_A receptor in ovariectomized rats treated with MT.
The animal model of anxiety used was the elevated plus-maze (EPM). Rats’ endocrine conditions were: a) Low hormone levels (rats in diestrus I and II phases); b) High hormone levels (proestrus/estrus phases); c) No hormones (ovariectomized rats); and d) Rats under progesterone withdrawal (PW). To evaluate the participation of the GABA_A receptor in the anxiolytic-like action of MT the antagonist picrotoxin was used.
Results showed that MT induced dose-dependent anxiolytic-like actions in rats with low hormone level conditions. Also, MT reduced anxiety-like behavior in female rats under PW, in contrast to diazepam which was ineffective. MT's anxiolytic-like effect was blocked by picrotoxin, suggesting the participation of the GABA_A receptor complex. However, increased anxiety-like behavior was observed in rats with a high hormone level condition and low doses of MT.
Beneficial anxiolytic-like actions of MT are observed under low hormone conditions, particularly in the PW challenge (a condition that can be related to a premenstrual period). Furthermore, the participation of the GABA_A receptor is evidenced. However, hormonal variations could induce the opposite effects, hence women should be cautious.
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In the mentioned study, male offspring had higher levels of corticosterone, greater intensity of seizure, and higher mortality rate compared with female offspring. In addition, the study of Finn et al. [49] suggested that the basal seizure risk differs in males and females, as also revealed by other studies on the measurement of seizure susceptibility [50,51]. Thus, prenatal stressors may affect males and females in different ways.
Stressful episodes are common during early-life and may have a wide range of negative effects on both physical and mental status of the offspring. In addition to various neurobehavioral complications induced by prenatal stress (PS), seizure is a common complication with no fully explained cause. In this study, the association between PS and seizure susceptibility was reviewed focusing on sex differences and various underlying mechanisms. The role of drugs in the initiation of seizure and the effects of PS on the nervous system that prone the brain for seizure, especially the hypothalamic–pituitary–adrenal (HPA) axis, are also discussed in detail by reviewing the papers studying the effect of PS on glutamatergic, gamma-aminobutyric acid (GABA)ergic, and adrenergic systems in the context of seizure and epilepsy. Finally, epigenetic changes in epilepsy are described, and the underlying mechanisms of this change are expanded. As the effects of PS may be life-lasting, it is possible to prevent future psychiatric and behavioral disorders including epilepsy by preventing avoidable PS risk factors.
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Progesterone lessens various behavioral indices of anxiety [19]; moreover, fluctuations in many of these endpoints over the course of the cycle are progesterone dependent. These anxiolytic effects are likely mediated by metabolites of progesterone binding to the GABAA receptor, which makes the receptor more sensitive to GABA [16,26]. Thus, were infection with T. gondii to increase progesterone concentrations, the hormone's anxiolytic effects might help explain the parasite's behavioral effects.
The protozoan Toxoplasma gondii (T. gondii) manipulates the behavior of its rodent intermediate host to facilitate its passage to its feline definitive host. This is accomplished by a reduction of the aversive response that rodents show towards cat odors, which likely increases the predation risk. Females on average show similar changes as males. However, behaviors that relate to aversion and attraction are usually strongly influenced by the estrus cycle. In this study, we replicated behavioral effects of T. gondii in female rats, as well as expanded it to two novel behavioral paradigms. We also characterized the role of the estrus cycle in the behavioral effects of T. gondii on female rats. Uninfected females preferred to spend more time in proximity to rabbit rather than bobcat urine, and in a dark chamber rather than a lit chamber. Infected females lost both of these preferences, and also spent more time investigating social novelty (foreign bedding in their environment). Taken together, these data suggest that infection makes females less risk averse and more exploratory. Furthermore, this effect was influenced by the estrus cycle. Uninfected rats preferred rabbit urine to bobcat urine throughout the cycle except at estrus and metestrus. In contrast, infected rats lost this preference at every stage of the cycle except estrus. Commensurate with the possibility that this was a hormone-dependent effect, infected rats had elevated levels of circulating progesterone, a known anxiolytic.
Autoradiographic analysis of GABAA receptor binding in the neural anxiety network of postpartum and non-postpartum laboratory rats
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Postpartum female rats exhibit a suppression of anxiety-related behaviors when compared to diestrous virgin females, pregnant females, and males. This blunted anxiety promotes optimal maternal care and involves elevated GABA neurotransmission, possibly including greater density of GABA_A and benzodiazepine receptors in the postpartum brain. We here examined autoradiographic binding of [³H]muscimol to measure the total population of GABA_A receptors and [³H]flunitrazepam to assess density of benzodiazepine sites in the medial prefrontal cortex, bed nucleus of the stria terminalis, amygdala, hippocampus, and periaqueductal gray of female rats sacrificed on day 7 postpartum, day 10 of pregnancy, or as diestrous virgins. A group of sexually naïve male rats was also included. We found that [³H]muscimol binding did not differ among groups in any site but that diestrous virgin females had greater [³H]flunitrazepam binding in the CA1 and dentate gyrus of the hippocampus compared to mid-pregnant females and males. Notably, postpartum and diestrous virgin females did not significantly differ in binding of either ligand in any site examined. This is the first study to evaluate the densities of GABA_A and benzodiazepine binding sites simultaneously across three female reproductive states and sex with a focus on brain sites influencing anxiety-related behaviors. The results suggest that changes in other GABA_A receptor characteristics such as subunit composition, or increased presynaptic GABA release during interactions with offspring, must instead play a greater role in the postpartum suppression of anxiety in laboratory rats.
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Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA_A receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA_A receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood–brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA_A receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv.

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Influences of gender, gonadectomy 5 and estrous cycle on GABA/BZ receptors and benzodiazepine responses in rats

Abstract

Eur. J. Pharm.

TINS

Physiol. Behav.

Europ. J. Pharm.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Lancet

J. Biol. Chem.

Eur. J. Pharm.

Life sci.

Eur. J. Pharm.

Life sci.

Steroids

Brain Res.

Brain Res.

Eur. J. Pharm.

Neuropharmacol.

Brain Res.

Brain Res. Bull.

Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle

Acta Neurol. Scandinav.

Studies on the endogenous modulator of GABAA receptors in human brain and CSF

Modulation of the GABAA receptor by progesterone metabolites

GABA[A] receptor level changes in female hamster forebrain following in vivo estrogen progesterone and benzodiazepine treatment: A quantitative autoradiography analysis

Exp. Brain Res.

Longer term progesterone treatment induces changes of GABAA receptor levels in forebrain sites in the female hamster: Quantitative autoradiography study

Exp. Brain Res.

Anticonvulsant activity of steroids: Separability of anticonvulsant from hormonal effects

J. Pharm. Exp. Ther.

Effects of oral contraceptives on diazepam-induced psychomotor impairment

Clin. Pharm. Ther.

Ovarian steroids increase veratridine-induced release of amino acid neurotransmitters in preoptic area synaptosomes

Brain Res.

Chronic benzodiazepine agonist exposure and its consequences for GABA-benzodiazepine interactions

Studies on the endogenous modulator of GABA_A receptors in human brain and CSF

Modulation of the GABA_A receptor by progesterone metabolites

Longer term progesterone treatment induces changes of GABA_A receptor levels in forebrain sites in the female hamster: Quantitative autoradiography study