Effects of pregnanolone alone and in combination with other positive GABA A modulators on complex behavior in rats

Gerak, Lisa R.; Stevenson, Michael W.; Winsauer, Peter J.; Moerschbaecher, Joseph M.

doi:10.1007/s00213-003-1717-2

Cited by 16 publications

(10 citation statements)

References 21 publications

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“…These findings corroborate earlier work investigating the acute effects of triazolam and clonazepam administration alone in preclinical behavioral models. Our results also confirm the findings of other studies showing that neuroactive steroids have response-altering effects similar to benzodiazepines, presumably due to their actions as modulators of the GABA A receptor [35–37]. Furthermore, neuroactive steroids also have been shown to elicit similar discriminative stimulus effects as benzodiazepines [14, 38] and can alter effects of cue-induced reinstatement in models of ethanol and cocaine seeking [39–41] in a manner similar to benzodiazepines [42, 43].…”

Section: Discussionsupporting

confidence: 91%

“…Finally it is important to note that while assessing mixtures of drugs is highly dependent on the behavioral endpoint [20, 37, 48, 54], the present findings clearly indicate that the nature of a drug interaction can vary dramatically within a single endpoint. In fact, schedule-controlled behavior was chosen in the present study because operant lever pressing is common to many other procedures, such as drug discrimination, self-administration, and conflict procedures.…”

Section: Discussionmentioning

confidence: 66%

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Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Gunter

Platt

Rowlett

2015

Pharmacology Biochemistry and Behavior

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Gunter

Platt

Rowlett

2015

Pharmacology Biochemistry and Behavior

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“…Combinations of pregnanolone and flunitrazepam also produced decreases in retention that did not affect response rate or percent error, which is indicative of a selective effect on retention because these doses did not produce motor impairments or disrupt working memory. These findings were also reminiscent of the results in a study by Gerak et al (2004) in which doses of pregnanolone potentiated the disruptive effects of flunitrazepam and pentobarbital (two positive GABA A modulators), but not of the NMDA receptor antagonist ketamine, on a repeated-acquisition task in rats. There are also several studies from this laboratory implicating GABAergic mechanisms in the behavioral effects of the neuroactive steroids, and pregnanolone in particular (Amato et al , 2010; Gerak et al , 2004; Gerak et al , 2008; Quinton et al , 2005).…”

Section: Discussionsupporting

confidence: 67%

“…Thus, the doses required to disrupt the weaker stimulus control established under within-session performance conditions tend to be lower than those required disrupt the strong stimulus control established under between-session performance conditions. The same potency relationship seems to hold for pregnanolone when pregnanolone's effects on retention in this study are compared with its effects on repeated acquisition and performance under a multiple schedule in two previous studies (Gerak et al, 2004; Quinton et al, 2005). …”

Section: Discussionsupporting

confidence: 54%

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

Amato¹,

Moerschbaecher²,

Winsauer

2011

Pharmacology Biochemistry and Behavior

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With increasing interest in using neuroactive steroids therapeutically, greater understanding of the effects of these substances on learning and memory is needed. Neuroactive steroids have effects at both the NMDA and GABAA receptor complexes, and therefore, may have the capacity to alter memory processes. To specifically assess the effects of a neurosteroid on memory, male Long‐Evans rats responding under a retention procedure were administered pregnanolone (1 ‐ 18 mg/kg). During the procedure, a tandem response sequence was acquired and then retested after delays of 30 (n=12) or 180 (n=12) minutes. Responding during both sequence acquisition and retest was maintained under a second‐order fixed‐ratio (FR) 2 schedule of food reinforcement and incorrect responding (errors) produced a 5‐sec timeout. Retention of the sequence was quantified as percent savings in errors to criterion and the 180‐min delay interval alone produced a time‐dependent decrease in retention. Pregnanolone produced a dose‐dependent decrease in the response rate, accuracy, and percent savings. However, decreases in retention occured at doses lower than those that disrupted response rate and accuracy. These data indicate that the neurosteroid pregnanolone potently disrupts retention and that this effect may be an important consideration in the evaluation of neuroactive steroids as therapeutics. Supported by DA 019625

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“…Particularly, it has been known barbiturates including the pentobarbital activate the channel directly (Cottrell et al ., 1987; Paul and Purdy, 1992; Lambert et al ., 2001). Regardless of that, GABA A receptors agonists generally make similar behavioral effects (Gerak et al ., 2004). Therefore, from this result for the increase of Cl − influx, it can derive that RA may be useful for inducing sedation or sleep.…”

Section: Discussionmentioning

confidence: 99%

Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABA_A-ergic Systems

Kwon

Hong

2016

Biomol Ther (Seoul)

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It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through γ-aminobutyric acid (GABA)A-ergic systems in rodents. RA (0.5, 1.0 and 2.0 mg/kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in δ-waves and the decrease in α-waves. On the other hand, RA (0.1, 1.0 and 10 μg/ml) increased intracellular Cl− influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase (GAD65/67) and GABAA receptors subunits except β1 subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through GABAA-ergic transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.

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Effects of pregnanolone alone and in combination with other positive GABA A modulators on complex behavior in rats

Cited by 16 publications

References 21 publications

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABA_A-ergic Systems

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Effects of pregnanolone alone and in combination with other positive GABA A modulators on complex behavior in rats

Cited by 16 publications

References 21 publications

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABAA-ergic Systems

Contact Info

Product

Resources

About

Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABA_A-ergic Systems