[COMPARISON BETWEEN THE METABOLISM OF 5-ALPHA-PREGNANOLONE AND 5-BETA-PREGNANOLONE IN MAN AND THE RABBIT].
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Acute and chronic effects of the neuroactive steroid pregnanolone on schedule-controlled responding in rhesus monkeys.
This study used schedule-controlled responding to examine the acute and chronic effects of the neuroactive steroid and positive -aminobutyric acid A (GABA ) modulator pregnanolone. Pregnanolone, the positive GABA modulator triazolam, the GABA chloride channel site antagonist pentylenetetrazol (PTZ) and the -methyl-d-aspartate (NMDA) antagonist ketamine were administered to monkeys ( = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus shock termination (SST), before, during and after daily treatment with pregnanolone (3.2 mg/kg subcutaneously). Pregnanolone decreased responding in a dose- and time-related manner, with a duration of action of <2 h. Mutual antagonism occurred between pregnanolone and PTZ in the food component, and PTZ antagonized pregnanolone in the SST component. Daily treatment with pregnanolone increased the sensitivity to PTZ 24 h but not 2 h after daily pregnanolone administration, and daily pregnanolone treatment did not alter the sensitivity to pregnanolone, triazolam or ketamine. Baseline responding in the food component was decreased in some monkeys 24 h after daily pregnanolone administration and in all monkeys 48 h after discontinuation of daily pregnanolone treatment. These results suggest that positive GABA modulation is one mechanism by which pregnanolone decreases FR responding, and that dependence resulting from daily pregnanolone treatment is not necessarily accompanied by tolerance to pregnanolone. Failure of pregnanolone to confer tolerance under these conditions might suggest that neuroadaptations at the GABA receptor complex vary according to the site at which positive GABA modulation occurs.
Animals↗
Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.
Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.
Animals↗
Mechanisms of modulation of pregnanolone on glycinergic response in cultured spinal dorsal horn neurons of rat.
The glycine receptors and neurosteroids in spinal cord are both implicated in nociceptive signal processing. However, the modulatory effects of neurosteroid pregnanolone (5beta-pregnan-3alpha-ol-20-one) on native glycine receptors remain unclear. In the present study, we examined the effects of pregnanolone and its three isomers on glycine receptors by using whole-cell patch-clamp technique. Our results showed that pregnanolone reversibly inhibited the amplitude of glycine-induced current mediated by native glycine receptors and recombinant alpha1-, alpha2-, alpha3- and alpha1beta-glycine receptors. In cultured spinal dorsal horn neurons of rats, pregnanolone inhibited the glycine-induced current in dose-dependent manner, with an antagonist concentration inducing half-maximal response of 1.0+/-0.3 microM. The inhibitory effect of pregnanolone on glycine-induced current was voltage-independent and pregnanolone shifted the concentration-response curve for glycine-induced current rightward in a parallel manner without altering the maximal value and Hill coefficient. The isomer of pregnanolone, allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) slightly enhanced glycine-induced current, whereas iso-pregnanolone (5beta-pregnan-3beta-ol-20-one) and iso-allopregnanolone (5alpha-pregnan-3beta-ol-20-one) did not affect the glycine-induced current significantly in cultured spinal dorsal horn neurons. Thus, our results suggest that the inhibitory effect of pregnanolone on glycine-induced current is of a competitive type and depends on the stereo structure of pregnanolone. Furthermore, pregnanolone decreased the amplitude and frequency of the glycinergic miniature inhibitory postsynaptic currents. Through modulating the glycinergic inhibitory neurotransmission, pregnanolone may affect the nociceptive sensory processing under physiological and pathological conditions.
Anesthetics↗
Characterization of discriminative stimulus effects of the neuroactive steroid pregnanolone.
Reduced pregnane neurosteroids such as allopregnanolone and pregnanolone are potent neuromodulators able to affect a number of membrane receptors, including gamma-aminobutyric acid (GABA)(A), N-methyl-D-aspartate (NMDA), 5-hydroxytryptamine (5-HT)(3), and sigma(1) receptors. The present study used a drug discrimination procedure to assess further the receptor effects of pregnanolone in vivo. Rats were trained to discriminate 5 mg/kg pregnanolone from saline in a two-lever operant task maintained by food reinforcement. The opiate agonist morphine and the negative GABA(A) modulator dehydroepiandrosterone sulfate did not substitute for pregnanolone. All of the GABA(A) positive modulators tested (allopregnanolone, epipregnanolone, androsterone, pentobarbital, midazolam, and zolpidem) dose dependently substituted for pregnanolone. The direct GABA-site agonists 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol and muscimol failed to substitute for pregnanolone. Ethanol and the sigma(1) receptor agonist SKF 10047 fully substituted for pregnanolone, and the NMDA antagonist MK-801 partially substituted for pregnanolone. The 5-HT(3) antagonist tropisetron did not substitute at any dose tested. The 5-HT(3) agonist SR 57227A reached full substitution, whereas the other 5-HT(3) agonist tested, m-chlorophenylbiguanide, produced partial substitution. These results suggest that positive GABA(A) modulation, but not direct agonism, confers a discriminative stimulus effect similar to pregnanolone. Additionally, antagonism of NMDA receptors and activation of 5-HT(3) and sigma(1) receptors modulate stimulus effects similar to the pregnanolone cue. Overall, the data suggest that pregnanolone produces discriminative stimulus effects representative of a wide-spectrum sedative hypnotic.
Animals↗
The interaction between ethanol and pregnanolone at induction of anaesthesia investigated with a threshold method in male rats.
1. An anaesthesia threshold was used to investigate the pharmacodynamic and pharmacokinetic interactions between ethanol and pregnanolone in male rats. 2. The criterion to determine threshold doses of pregnanolone was the first burst suppression of 1 s in the EEG. 3. Ethanol (0.5, 1.0, 1.5 and 2.0 g kg(-1)) was injected i.p. 15 min before pregnanolone infusion. Trunk blood, serum, cortex, cerebellum, hippocampus, striatum, brain stem, fat and muscle tissues obtained at criterion were used to determine ethanol (blood) and pregnanolone. Ethanol reduced threshold doses in a dose dependent linear manner. A similar reduction of pregnanolone tissue concentrations was only found in brain stem and striatum. Deviations consisted of larger decreases in serum, cerebellum and hippocampus after 0.5 g kg(-1) ethanol and in cerebellum, cortex and hippocampus after 2.0 g kg(-1) of ethanol. Positive correlations between dose and concentration of pregnanolone was recorded in brain stem, hippocampus, cerebellum and cortex. A kinetic component influenced the concentration in cortex. There was a correlation between dose and serum concentration of pregnanolone only after ethanol. In the muscle 0.5 g kg(-1) ethanol had no influence on pregnanolone concentration. 4. The linear, additive pharmacodynamic interaction could involve the GABA ionophore. A pharmacokinetic interaction was found in cortex. The retained high uptake of pregnanolone in muscle (after 0.5 g kg(-1)) corresponded to losses in other tissues (including serum). The reduced uptake of pregnanolone in cerebellum, cortex and hippocampus (after 2.0 g kg(-1)) was not due to a corresponding change in serum concentration. It was probably due to a reduced blood flow.
Anesthesia↗
Multiple modulatory effects of the neuroactive steroid pregnanolone on GABAA receptor in frog pituitary melanotrophs.
1. The effects of the neuroactive steroid pregnanolone (5 beta-pregnan-3 alpha-ol-20-one) on the electrical response to GABA were investigated in cultured frog pituitary melanotrophs using the patch-clamp technique. 2. Low concentrations of pregnanolone (0.01-1 microM) in the extracellular solution enhanced the current evoked by submaximal concentrations of GABAA receptor agonists and prolonged the GABA-induced inhibition of the spontaneous action potentials in a dose-dependent manner. 3. Pregnanolone augmented the opening probability of the single GABA-activated channels but did not modify the conductance levels. 4. Pregnanolone (1 microM) shifted the GABA dose-response curve towards the low GABA concentrations, reducing the EC50 from 4.2 to 1.8 microM. 5. Internal cell dialysis with pregnanolone (1 or 10 microM) did not alter the GABA-evoked current. 6. Pregnanolone accelerated the desensitization of both the current and conductance increases caused by GABA. 7. High concentrations of pregnanolone (30 microM) markedly and reversibly diminished the current evoked by 10 microM GABA. 8. At high concentrations (10-30 microM), pregnanolone induced an outward current which reversed at the chloride equilibrium potential. 9. It is concluded that, in frog pituitary melanotrophs, pregnanolone exerts a dual inverse modulation and a direct activation of the GABAA receptor-channel depending on the concentrations of both GABA and steroid. Pregnanolone acts on an extracellular site on the GABAA receptor inducing conformational changes of the receptor-channel complex, resulting in a desensitized less-conducting state.
Action Potentials↗
Anaesthetic properties of pregnanolone in mice in an emulsion preparation for intravenous administration: a comparison with thiopentone.
The anaesthetic properties of pregnanolone emulsion, which is a new pharmaceutically and clinically acceptable preparation of pregnanolone, have been evaluated and compared with those of thiopentone in the mouse. "Loss of the righting reflex" for 15 sec. was used as a criterion for the anaesthetic effect. The range for the optimal infusion rate to reach the threshold anaesthetic dose was 0.25-1.0 mg/kg/min. for pregnanolone and 10-40 mg/kg/min. for thiopentone. Potency, measured at the optimal infusion rate as the mean anaesthetic dose, AD50, or as the threshold anaesthetic dose, was about six times higher for pregnanolone than for thiopentone. The induction of anaesthesia, which ensured directly after a complete dose was given, and the duration of anaesthesia were similar for pregnanolone and thiopentone in equipotent doses. The approximate therapeutic index for pregnanolone was about four times higher than that for thiopentone. The range for the time of anaesthesia was about 150 min. for pregnanolone emulsion but only about 50 min. for thiopentone. Recovery of the mice from anaesthesia occurred within minutes after pregnanolone, whereas it took hours following thiopentone. In conclusion, these results show that the advantage of pregnanolone emulsion over thiopentone include a higher therapeutic index, a wider range for the duration of anaesthesia and a shorter recovery period.
Anesthetics↗
Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice.
Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.
Animals↗
Endocrine response to pregnanolone.
Neuroendocrine effects of the neurosteroids, pregnanolone and allopregnanolone have been demonstrated in rats. The endocrine effects of pregnanolone in humans have so far not been fully elucidated. This study has evaluated the effects of pregnanolone administration on part of the hypothalamus-pituitary-gonadal (HPG) axis throughout the menstrual cycle in control subjects and patients with premenstrual syndrome (PMS). Intravenous pregnanolone and vehicle were given to eight women with, and eight women without, PMS during the mid-follicular and late luteal phase. Following the drug administrations, progesterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin plasma levels were measured. Intravenous pregnanolone induced a rise in progesterone levels in the follicular phase. In the luteal phase progesterone levels decreased in response to pregnanolone provocation. Pregnanolone did not induce any changes in estradiol, LH, FSH or prolactin plasma levels in either cycle phase. PMS patients and control subjects did not differ with respect to the endocrine effects of pregnanolone. In conclusion, our data show that pregnanolone, in moderate doses, appears not to have any adverse effects on the HPG axis, irrespective of cycle phase.
Adult↗
Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice.
GABA-potentiating neuroactive steroids such as pregnanolone have potent protective effects in the pentylenetetrazol seizure test. We sought to determine if tolerance develops to the anticonvulsant activity of pregnanolone with chronic administration. Mice were treated with two daily injections of a 2 x ED50 dose of pregnanolone (25 mg/kg, i.p.) for 7 days. On the day after the chronic treatment protocol, the dose-response relationship for protection in the pentylenetetrazol seizure test was obtained. The ED50 value after the chronic treatment protocol was not significantly different from that in naive mice (12 mg/kg), indicating that tolerance does not develop to the anticonvulsant activity of pregnanolone. In subsequent experiments, we extended the chronic treatment protocol to 14 days with three daily injections of pregnanolone (25 mg/kg, i.p.). Again, no tolerance was observed (ED50, 13 mg/kg). The anticonvulsant activity of pregnanolone was well correlated with plasma levels in both the naive and chronically (14 day) treated mice. The estimated plasma concentrations of pregnanolone representing threshold (10%) protection (125-150 ng/ml) and 50% protection (575-700 ng/ml) were similar in naive and chronically treated animals. In both chronically treated and naive animals, plasma levels of pregnanolone declined rapidly (t1/2, 16-19 min) and there was a corresponding reduction in the anticonvulsant activity. Our results with pregnanolone suggest that tolerance does not develop to the anticonvulsant activity of neuroactive steroids as it does with other GABA potentiating drugs such as benzodiazepines, supporting the potential clinical utility of neuroactive steroids in chronic seizure therapy.
Animals↗
Anxiolytic effects of the neuroactive steroid pregnanolone (3 alpha-OH-5 beta-pregnan-20-one) after microinjection in the dorsal hippocampus and lateral septum.
The anxiolytic effects of the neuroactive steroid, 3 alpha-OH-5 beta-pregnan-20-one (pregnanolone), were determined after injection into the dorsal hippocampus or lateral septum in adult male rats. An increase in the proportion of time spent on the open arms of the elevated plus-maze was found after 2.5 and 5 micrograms of pregnanolone in the hippocampus, but not in the lateral septum. Intrahippocampal injection of 2.5 micrograms of the 3 beta-epimer of pregnanolone did not affect behavior in the plus-maze; a higher dose of 5 micrograms produced an anxiogenic effect. In the shock-probe burying test latency to burying behavior was increased by intrahippocampal or intraseptal injection of 2.5 and 5 micrograms of pregnanolone; the duration of burying behavior was decreased by 0.5, 2.5 and 5 micrograms of pregnanolone injection in the dorsal hippocampus or lateral septum. The number of contacts with the shock probe was not affected by any dose of pregnanolone in either intracranial site of injection. The anxiolytic effects of intrahippocampal or intraseptal injection of pregnanolone were blocked by intracranial pretreatment with 20 ng of picrotoxin, but not by microinjection of 5 micrograms of flumazenil or 200 ng of PK 11195. Thus, inhibition of the hippocampus, mediated by the pregnanolone's action at the GABAA receptor, produces a general anxiolytic effect. However, similar inhibition in the lateral septum attenuates active avoidance of anxiogenic stimuli (i.e., decreased burying behavior), but not passive avoidance of aversive stimuli (i.e., exploration of open arms of the plus-maze and number of shocks in the probe burying test).
Animals↗
Dipole potential and head-group spacing are determinants for the membrane partitioning of pregnanolone.
The membrane interactions of pregnanolone, an intravenous general anesthetic steroid, were characterized using fluorescence spectroscopy and monolayer technique. di-8-ANEPPS [4-[2-[6-(dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-pyridinium], a membrane dipole potential (Psi)-sensitive probe, revealed pregnanolone to decrease Psi similarly as reported previously for other anesthetics. The decrement in Psi was approximately 16 and 10 mV in dipalmitoylphosphatidylcholine (DPPC) and DPPC/cholesterol (90:10, mol/mol) vesicles, respectively. Diphenylhexatriene anisotropy indicated pregnanolone to have a negligible effect on the acyl chain order. In contrast, substantial changes were observed for the fluorescent dye Prodan, thus suggesting pregnanolone to reside in the interfacial region of lipid bilayers. Langmuir balance studies indicated increased association of pregnanolone to DPPC monolayers containing cholesterol or 6-ketocholestanol at surface pressures pi > 20 mN/m as well as to monolayers of the unsaturated 1-palmitoyl-2-oleoylphosphatidylcholine. In the same surface pressure range, the addition of phloretin, which decreases Psi, reduced the penetration of pregnanolone into the monolayers. These results suggest that membrane partitioning of pregnanolone is influenced by the spacing of the phosphocholine head groups as well as by membrane dipole potential. The latter can be explained in terms of electrostatic dipole-dipole interactions between pregnanolone and the membrane lipids with their associated water molecules. Considering the universal nature of these interactions, they are likely to affect membrane partitioning of most, if not all, weakly amphiphilic drugs.
Anesthetics↗
Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.
Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.
2-Hydroxypropyl-beta-cyclodextrin↗
Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics.
OBJECTIVE: Pregnanolone is a 3alpha-hydroxylated-5beta-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. METHODS: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. RESULTS: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml x min(-1) x kg(-1) and 64.0 ml x min(-1) x kg(-1), depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. CONCLUSION: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects.
Adult↗
Effects of pregnanolone on behavioural parameters and the responses to GABA(A) receptor antagonists in the late gestation fetal sheep.
Placental progesterone metabolites may suppress fetal behaviour by interacting with GABA(A) receptors. In an initial study, the effect of 5beta-pregnan-3alpha-ol-20-one (pregnanolone) given as a bolus (2.5 and 5.0 mg) or infused at a rate of 25 mg/h was investigated in unanaesthetized, catheterized fetal sheep, 127-135 days gestation. The incidence of fetal breathing movements (FBM) and behavioural arousal activity, defined as nuchal muscle electromyographic (EMG) activity during low voltage electrocortical (LV ECoG) activity were suppressed by pregnanolone administered as a bolus, while the pregnanolone infusion produced a significant decrease in arousal and EOG activity, and an increase in the presence of HV ECoG. The effect of pregnanolone on fetal behaviour and arousal induced by the GABA(A) antagonist picrotoxin was also investigated. Picrotoxin was given as a bolus (approximately 300 microg/kg) and pregnanolone was subsequently administered as a bolus (5.0 mg), and behavioural parameters were recorded and analysed. The incidence of arousal and FBM were 1.1 +/- 1.6 min/10 min and 2.5 +/- 2.3 min/10 min, respectively, before picrotoxin treatment and increased during the 10-20 and 20-30 min epochs after picrotoxin treatment (arousal: 5.0 +/- 2.2 and 6.5 +/- 3.6 min/10 min, respectively, n = 6, P < 0.05; FBM: 7.3 +/- 3.2 and 9.3 +/- 1.2 min/10 min, respectively, n = 6, P < 0.05). The picrotoxin-induced increases in arousal and FBM were significantly suppressed (n = 6, P < 0.05) by pregnanolone treatment to 1.6 +/- 1.5 min/10 min and 4.6 +/- 2.3 min/10 min, respectively. We conclude that; (i) the GABA(A) active steroid pregnanolone suppresses basal and picrotoxin-induced fetal arousal and FBM; and (ii) steroid sensitive GABA(A) receptors may regulate fetal behaviour and breathing.
Animals↗
Effects of benzodiazepine receptor ligands and ethanol in rats trained to discriminate pregnanolone.
Although GABA(A) receptor positive modulators share many behavioral effects, subtle differences have been detected among their discriminative stimulus effects. The purpose of the present study was to determine the extent of shared discriminative stimulus effects of pregnanolone with various benzodiazepine receptor ligands and with ethanol. Naive male Sprague-Dawley rats were trained to discriminate the endogenous neuroactive steroid pregnanolone (5.6 or 8.0 mg/kg) from vehicle. The benzodiazepine receptor agonists, triazolam and lorazepam, the benzodiazepine receptor partial agonist, bretazenil, the benzodiazepine1 (BZ1) receptor subtype selective agonists, zolpidem and zaleplon and ethanol were tested. Triazolam, lorazepam and bretazenil substituted for pregnanolone. Lorazepam, but not triazolam or bretazenil, decreased response rates at the highest dose tested. Zaleplon completely substituted for pregnanolone with no effect on response rates. Zolpidem substituted for pregnanolone only at a dose that severely disrupted response rates. Ethanol partially substituted for pregnanolone and decreased response rates. The results are consistent with GABA(A) receptor mediation of the discriminative stimulus effects of pregnanolone. The effects on response rates suggest subtle differentiation among the GABA(A) receptor-mediated cues.
Animals↗
Effects of pregnanolone alone and in combination with other positive GABAA modulators on complex behavior in rats.
RATIONALE: Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators. OBJECTIVE: The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators. METHODS: Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation. RESULTS: Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves. CONCLUSIONS: The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.
Anesthetics↗