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Lisa R. Gerak - One of the best experts on this subject based on the ideXlab platform.
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using drug combinations to assess potential contributions of non gabaa receptors in the discriminative stimulus effects of the neuroactive steroid Pregnanolone in rats
Physiology & Behavior, 2014Co-Authors: Amy K. Eppolito, Hanna R Kodeih, Lisa R. GerakAbstract:Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as Pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of Pregnanolone. Separate groups of rats discriminated either 3.2mg/kg Pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, Pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of Pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of Pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of Pregnanolone.
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Discriminative stimulus effects of Pregnanolone in rhesus monkeys
Psychopharmacology, 2014Co-Authors: Lisa R. Gerak, Charles P. FranceAbstract:Rationale Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA_A receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA_A, N -methyl- d -aspartate (NMDA), σ_1, or 5-HT_3 receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators. Objective The current study established the neuroactive steroid Pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA_A receptors might contribute to its discriminative stimulus effects. Methods Four rhesus monkeys discriminated 5.6 mg/kg Pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination. Results Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % Pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA_A receptors, such as extrasynaptic GABA_A, NMDA, σ_1, and 5-HT_3 receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and p A_2 values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of Pregnanolone. Conclusion While these results do not exclude the possibility that Pregnanolone acts at receptors other than synaptic GABA_A receptors, they indicate a primary and possibly exclusive role of synaptic GABA_A receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA_A receptors.
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acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and Pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam
European Journal of Pharmacology, 2013Co-Authors: Claudio Zanettini, Seong Shoon Yoon, Lisa R. GerakAbstract:Benzodiazepines and neuroactive steroids act at distinct binding sites on γ-aminobutyric acidA (GABAA) receptors where they positively modulate GABA, resulting in similar acute behavioral effects. Tolerance to benzodiazepines can develop with repeated treatment; however, cross tolerance to neuroactive steroids does not develop, perhaps due to conformational changes in benzodiazepine, and not neuroactive steroid, binding sites. Three monkeys discriminated 0.178 mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination. On separate occasions, dose-effect curves for midazolam and Pregnanolone were determined when monkeys had not received chlordiazepoxide and when they received 10 mg/kg chlordiazepoxide 46 hours earlier; for some tests, flumazenil was given before determination of dose-effect curves. Midazolam and Pregnanolone produced ≥80% midazolam-lever responding. When administered 46 h before sessions, chlordiazepoxide did not produce Pregnanolone-lever responding; under those treatment conditions, midazolam dose-effect curves were shifted 2.8-fold rightward and Pregnanolone dose-effect curves were not changed. Flumazenil antagonized midazolam; Schild (linear) analyses yielded slopes that were not different from unity and pA2 values of 7.46 when monkeys had not received chlordiazepoxide and 7.44 when they received chlordiazepoxide 46 h earlier. Flumazenil did not alter the effects of Pregnanolone in chlordiazepoxide-treated monkeys. Thus, interactions between flumazenil and midazolam were not qualitatively or quantitatively changed in monkeys acutely tolerant to chlordiazepoxide, suggesting that mechanisms other than alterations of benzodiazepine binding sites account for the development of acute tolerance.
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Discriminative stimulus effects of Pregnanolone in rats: role of training dose in determining mechanism of action
Psychopharmacology, 2012Co-Authors: Amy K. Eppolito, Xiang Bai, Lisa R. GerakAbstract:Rationale Positive γ-aminobutyric acid_A (GABA_A) modulators acting at different binding sites often produce similar behavioral effects; however, their effects are not identical. Actions of neuroactive steroids at other receptors, in addition to GABA_A receptors, might account for some differences between neuroactive steroids and other positive modulators, like benzodiazepines. Objective Multiple mechanisms of other drugs (e.g., ethanol) have been elucidated by comparing their discriminative stimulus effects across different training doses; the current study used that approach to examine the mechanisms of action of the neuroactive steroid Pregnanolone. Methods Separate groups of rats ( n = 6–8/group) discriminated Pregnanolone from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Two groups initially discriminated 3.2 mg/kg; once stimulus control was established, the training dose was systematically decreased to 1.33 mg/kg in one group and increased to 7.5 mg/kg in the other group. Other rats discriminated either 1.33 or 7.5 mg/kg without training at another dose. Results Stimulus control was established in 24–28 sessions in all groups. Positive GABA_A modulators produced ≥80 % Pregnanolone-lever responding, regardless of training dose; rank-order potency was flunitrazepam > midazolam > Pregnanolone = pentobarbital. Ethanol produced some drug-lever responding (42 %) only in rats discriminating 1.33 mg/kg, whereas the N -methyl- d -aspartate receptor antagonist ketamine and the serotonin receptor agonist 1-( m -chlorophenyl)-biguanide occasioned predominantly vehicle-lever responding in all rats. Conclusions There was little difference in discriminative stimulus effects of Pregnanolone across different training conditions, confirming a predominant, if not exclusive, role of GABA_A receptors in these effects of Pregnanolone.
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quantitative analyses of antagonism combinations of midazolam and either flunitrazepam or Pregnanolone in rhesus monkeys discriminating midazolam
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Lisa R. GerakAbstract:Adverse effects of benzodiazepines limit their clinical use; these effects might be reduced without altering therapeutic effects by administering other positive GABAA modulators (i.e., neuroactive steroids) with benzodiazepines. One concern with this strategy involves reversing these combined effects in case of overdose. The current study examined whether flumazenil can attenuate the combined effects of two benzodiazepines, midazolam and flunitrazepam, and the combined effects of midazolam and the neuroactive steroid Pregnanolone, in four monkeys discriminating midazolam. Each positive modulator produced ≥80% midazolam-lever responding. Interactions between midazolam and either flunitrazepam or Pregnanolone were additive. Flumazenil antagonized the benzodiazepines when they were administered alone or in combination. Schild analyses yielded slopes that did not deviate from unity, regardless of whether benzodiazepines were administered alone or together; the pA2 value for flumazenil was 7.58. In contrast, flumazenil enhanced the effects of Pregnanolone with 0.32 mg/kg flumazenil shifting the Pregnanolone dose-effect curve 2-fold leftward. Flumazenil attenuated the combined effects of midazolam and Pregnanolone, although antagonism was not dose-dependent. Thus, the interaction between two benzodiazepines was similar to that of a benzodiazepine and a neuroactive steroid; however, flumazenil more efficiently attenuated a combination of two benzodiazepines compared with a combination of a benzodiazepine and a neuroactive steroid. Although the magnitude of antagonism of a benzodiazepine combined with a neuroactive steroid was reduced, these results support continued exploration of the use of combinations of positive modulators to enhance therapeutic effects while reducing adverse effects.
James K Rowlett - One of the best experts on this subject based on the ideXlab platform.
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Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats.
Pharmacology biochemistry and behavior, 2015Co-Authors: Barak W. Gunter, Donna M. Platt, James K RowlettAbstract:Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid Pregnanolone can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects. In the present study, we investigated these same combinations as well as combinations of two clinically-relevant drugs from different chemical classes, the 1, 4 substituted (7-nitro) benzodiazepine clonazepam and the synthetic neuroactive steroid ganaxolone, in rats trained under a 10-response, fixed ratio (FR) schedule of food reinforcement. All four drugs induced a significant and dose-dependent suppression of food-maintained responding. From the dose-response functions, ED50s (i.e., the doses that engendered 50% of the maximum rate-decreasing effect) were generated for each drug. Dose-response functions for combinations of triazolam/Pregnanolone, clonazepam/ganaxolone, triazolam/ganaxolone, and clonazepam/Pregnanolone were then determined. Isobolographic analysis of the rate-decreasing effects of these combinations revealed that the potencies of the triazolam/Pregnanolone combinations were supra-additive while the clonazepam/ganaxolone combinations were additive or infra-additive in relation to predicted values based on dose-additive effects. Furthermore, mixtures of clonazepam/Pregnanolone were supra-additive while triazolam/ganaxolone combinations were additive, infra-additive and supra-additive. These results suggest that the ability of benzodiazepine and neuroactive steroid combinations to attenuate rates of food-maintained responding depends critically on both the constituent drugs and the dose of drug in the mixtures.
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anticonflict and reinforcing effects of triazolam Pregnanolone combinations in rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid Pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and Pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and Pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and Pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and Pregnanolone were self-administered significantly, and triazolam and Pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and Pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
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Anticonflict and reinforcing effects of triazolam + Pregnanolone combinations in rhesus monkeys.
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid Pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and Pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and Pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and Pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and Pregnanolone were self-administered significantly, and triazolam and Pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and Pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
Peter J Winsauer - One of the best experts on this subject based on the ideXlab platform.
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discriminative stimulus effects of ethanol Pregnanolone and dehydroepiandrosterone dhea in rats administered ethanol or saline as adolescents
Pharmacology Biochemistry and Behavior, 2009Co-Authors: Olga V Gurkovskaya, Peter J WinsauerAbstract:Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol abuse and dependence as an adult. To test this possibility, ethanol (0.18-1.8 g/kg) and two neurosteroids, Pregnanolone (1-10 mg/kg) and dehydroepiandrosterone (DHEA, 1-100 mg/kg), were administered alone and in combination to adult, male Long-Evans rats discriminating 1 g/kg ethanol (15% v/v) under a fixed ratio (FR) 20 schedule of food presentation after adolescent treatment with 15 injections of ethanol (n=9, 2 g/kg, 20% v/v) or saline (n=7). When compared as adults, ethanol-treated adolescents (as opposed to saline-treated adolescents) had higher percentages of ethanol-lever responding at doses smaller than the training dose, and higher response rates after both control and ethanol injections. Neither Pregnanolone nor DHEA substituted for ethanol in either adolescent-treated group up to doses that substantially decreased response rates. When administered with ethanol, 1 and 3.2 mg/kg of Pregnanolone enhanced the discriminative stimulus effects of small ethanol doses more in saline-treated adolescents than ethanol-treated adolescents. Unlike Pregnanolone, 32 and 100 mg/kg of DHEA attenuated the discriminative stimulus effects of ethanol modestly in both adolescent-treated groups. These results in adult rats suggest that adolescent ethanol administration can enhance the discriminative stimulus effects of small ethanol doses and affect the capacity of Pregnanolone, but not DHEA, to interact with ethanol's discriminative stimulus effects.
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overlapping but not identical discriminative stimulus effects of the neuroactive steroid Pregnanolone and ethanol
Pharmacology Biochemistry and Behavior, 2008Co-Authors: Lisa R. Gerak, Joseph M Moerschbaecher, Peter J WinsauerAbstract:Many behavioral effects of neuroactive steroids are mediated by GABAA receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of Pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced > 80% Pregnanolone-lever responding. In contrast, neither morphine nor the negative GABAA modulator β-CCE substituted for Pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced < 20% Pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABAA modulators, and not morphine or β-CCE, for Pregnanolone in all rats suggests that positive modulation of GABAA receptors is important in the discriminative stimulus effects of Pregnanolone. Although Pregnanolone might have actions at other receptors, in addition to actions at GABAA receptors, substitution of ethanol for Pregnanolone only in some rats suggests that the mechanisms of action of Pregnanolone and ethanol overlap, but are not identical.
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effects of Pregnanolone in rats discriminating cocaine
Pharmacology Biochemistry and Behavior, 2006Co-Authors: M. S. Quinton, Lisa R. Gerak, Joseph M Moerschbaecher, Peter J WinsauerAbstract:Abstract The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA A receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaine's discriminative effects and to examine the interaction between cocaine and Pregnanolone, a drug that can modulate the GABA A receptor complex. Rats ( n = 15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d -amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA A modulators Pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D 2 receptor antagonist haloperidol and Pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose–effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA A receptors by Pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.
Torbjorn Backstrom - One of the best experts on this subject based on the ideXlab platform.
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alloPregnanolone and Pregnanolone are produced by the human corpus luteum
Molecular and Cellular Endocrinology, 2005Co-Authors: Ulrika Ottander, Torbjorn Backstrom, Inger Sundstrom Poromaa, Erik Bjurulf, Asa Skytt, Jan I OlofssonAbstract:Abstract Using a dispersed human luteal cell culture model, progesterone, alloPregnanolone and Pregnanolone release following treatment by incremental doses of human chorionic gonadotrophin (hCG) were evaluated. Corpus luteum tissues, obtained from 48 healthy women scheduled for benign surgery, were grouped according to luteal age and tissue concentration of alloPregnanolone and Pregnanolone was determined. The mRNA expression of 5α-, and 5β-reductase and 3α-HSOR mRNA expressions were evaluated in corpora lutea from the late luteal phase. AlloPregnanolone concentrations in corpus luteum tissue were consistently about three- to four-fold higher than Pregnanolone levels. AlloPregnanolone tissue concentrations significantly decreased between early- and late-luteal phase, p In conclusion, the neurosteroids alloPregnanolone and Pregnanolone are produced in the human corpus luteum and their release is stimulated by trophic hormone.
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the interaction between ethanol and Pregnanolone at induction of anaesthesia investigated with a threshold method in male rats
British Journal of Pharmacology, 2001Co-Authors: Mingde Wang, Torbjorn Backstrom, Di Zhu, Goran WahlstromAbstract:An anaesthesia threshold was used to investigate the pharmacodynamic and pharmacokinetic interactions between ethanol and Pregnanolone in male rats. The criterion to determine threshold doses of Pregnanolone was the first burst suppression of 1 s in the EEG. 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. 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. British Journal of Pharmacology (2001) 134, 1393–1402; doi:10.1038/sj.bjp.0704385
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endocrine response to Pregnanolone
Gynecological Endocrinology, 1999Co-Authors: Inger Sundstrom, Torbjorn BackstromAbstract: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 pha...
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lack of influence of menstrual cycle and premenstrual syndrome diagnosis on Pregnanolone pharmacokinetics
European Journal of Clinical Pharmacology, 1999Co-Authors: Inger Sundstrom, Olav Spigset, Agneta Andersson, P Appelblad, Torbjorn BackstromAbstract:Objective: Pregnanolone is a 3α-hydroxylated-5β-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.
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citalopram increases Pregnanolone sensitivity in patients with premenstrual syndrome an open trial
Psychoneuroendocrinology, 1998Co-Authors: Inger Sundstrom, Torbjorn BackstromAbstract:We have investigated the ability of citalopram, a serotonin reuptake inhibitor, to alter the functional sensitivity to a neuroactive steroid during the late luteal phase in twelve women with premenstrual syndrome. Sensitivity to Pregnanolone was assessed by comparing the effect of three increasing doses of intravenous Pregnanolone on saccadic eye velocity (SEV) and self-rated sedation. Testings were performed in two consecutive menstrual cycles; without treatment and during citalopram treatment. During citalopram treatment, Pregnanolone injections induced a significant SEV reduction compared to vehicle, whereas during the pre-treatment cycle there was no significant change in SEV response between vehicle and Pregnanolone injections. Citalopram treatment did not alter the self-rated sedation response to Pregnanolone compared to vehicle in either study cycle. These findings indicate that treatment with a selective serotonin reuptake inhibitor in the luteal phase increases the Pregnanolone sensitivity in patients with premenstrual syndrome.
Bradford D Fischer - One of the best experts on this subject based on the ideXlab platform.
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anticonflict and reinforcing effects of triazolam Pregnanolone combinations in rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid Pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and Pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and Pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and Pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and Pregnanolone were self-administered significantly, and triazolam and Pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and Pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
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Anticonflict and reinforcing effects of triazolam + Pregnanolone combinations in rhesus monkeys.
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid Pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and Pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and Pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and Pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and Pregnanolone were self-administered significantly, and triazolam and Pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and Pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.