Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats

Quinton, Maria S.; Gerak, Lisa R.; Moerschbaecher, Joseph M.; Winsauer, Peter J.

doi:10.1007/s00213-005-2241-3

Cited by 8 publications

(13 citation statements)

References 42 publications

(37 reference statements)

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“…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: 53%

“…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). For instance, Quinton et al (2005) found that pregnanolone and lorazepam in combination produced greater disruptions in learning than either drug alone when administered to rats responding under a repeated-acquisition procedure.…”

Section: Discussionmentioning

confidence: 99%

“…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). For instance, Quinton et al (2005) found that pregnanolone and lorazepam in combination produced greater disruptions in learning than either drug alone when administered to rats responding under a repeated-acquisition procedure. Taken together, these results emphasize the importance of GABA A modulation in the effects produced by pregnanolone on memory.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…7-ketoDHEA (kindly provided by Dr. Henry Lardy, Department of Biochemistry and Institute for Enzyme Research, University of Wisconsin-Madison) was dissolved in a vehicle consisting of 80% (v/v) propylene glycol, 8% polyethylene glycol, and 2% benzyl alcohol. Vehicles for both drugs have been found to be behaviorally inactive in previous studies (Quinton et al, 2005; Quinton et al, 2006; Gurkovskaya and Winsauer 2009). All drugs and control injections were administered intraperitoneally 15 minutes prior to the experimental sessions.…”

Section: Methodsmentioning

confidence: 80%

Effects of 7-keto dehydroepiandrosterone on voluntary ethanol intake in male rats

Worrel

Gurkovskaya

Leonard

et al. 2011

Alcohol

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Administration of dehydroepiandrosterone (DHEA), a neurosteroid that can negatively modulate the GABAA receptor, has been shown to decrease voluntary intake of ethanol in rats. In vivo, DHEA can be metabolized to a variety of metabolites, including 7-keto DHEA, a metabolite without the prohormonal effects of DHEA. This study compared the effectiveness of 7-keto DHEA to DHEA for reducing ethanol intake in the same group of rats. The subjects, previously trained to drink ethanol using a saccharin-fading procedure, had access to ethanol for thirty minutes daily, and the amount consumed was recorded. Subjects were administered 10 and 56 mg/kg of DHEA or 7-keto DHEA intraperitoneally 15 minutes prior to drinking sessions. Subjects received each particular dose daily until one of two criteria was met; that is, either ethanol intake did not differ by more than 20% of the mean for three consecutive days, or for a maximum of eight days. Both 10 and 56 mg/kg of 7-keto DHEA significantly reduced the dose of ethanol consumed. While 10 mg/kg of 7-keto DHEA produced decreases similar to those found with DHEA, the 56-mg/kg dose of 7-keto DHEA was significantly more effective at decreasing the dose of ethanol consumed than the same dose of DHEA. These results show that 7-keto DHEA is comparable to, or possibly more effective than, DHEA at decreasing ethanol consumption in rats, and that 7-keto DHEA is a compound deserving further investigation as a possible clinical treatment for alcohol abuse without the prohormonal effects of DHEA.

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“…Repeated acquisition is a well-established technique for assessing the effects of drugs on learning, and when combined with a performance component under a multiple schedule, can determine the capacity of a drug to disrupt learning apart from it capacity to produce more general psychomotor effects (Moerschbaecher et al 1979; Winsauer et al 2002; Winsauer et al 2003; Quinton et al 2005). Finally, assessing the cardiovascular effects of mephedrone seemed essential given the reports of mephedrone-related cardiovascular events (Nicholson et al 2010; Regan et al 2010; Wood et al 2010), and the well known association between stimulant use and cardiovascular and cardiac toxicity (Badon et al 2002; Shenouda et al 2010; Lord et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the behavioral and cardiovascular effects of mephedrone with other drugs of abuse in rats

et al. 2012

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Rationale Exceedingly little experimental research exists on the popular recreational drug mephedrone (4-methylmethcathinone) despite clinical reports concerning its behavioral and cardiovascular toxicity. Objective To characterize mephedrone preclinically by examining its capacity to: 1) serve as a discriminative stimulus, 2) disrupt the acquisition of response sequences, and 3) disrupt mean arterial pressure (MAP) and heart rate (HR). Methods and Results In one group of subjects that reliably discriminated 3.2 mg/kg of mephedrone from saline (n=9), substitution tests indicated that stimulants (cocaine, MDMA and methamphetamine) more closely approximated the mephedrone discriminative stimulus than non-stimulants (fenfluramine, morphine, and phencyclidine), although none fully substituted. In a second group (n=6), mephedrone (0.56–10 mg/kg, i.p.) dose-dependently decreased response rate and increased errors in both components of a procedure in which subjects either acquired a new response sequence each session (repeated acquisition) or completed the same response sequence each session (performance). Finally, in a third group (n=12), radio telemetry probes were used to measure the changes in MAP and HR elicited by mephedrone and then compared them to a known stimulant, methamphetamine. In these studies, mephedrone (0.01–9 mg/kg, i.v.) elicited increases in MAP and HR that were very similar to those elicited by methamphetamine (0.01–9 mg/kg, i.v.). The tachycardia and pressor responses to mephedrone (3 mg/kg) were blocked by the β-blocker atenolol (1 mg/kg, i.v.) and the α1, α2-blocker phentolamine (3 mg/kg, i.v.), respectively. Conclusions Mephedrone produces behavioral and cardiovascular responses that are similar to other stimulants; however, differences from the classical stimulants were also apparent.

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Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats

Abstract: The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.

Cited by 8 publications

References 42 publications

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

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

Effects of 7-keto dehydroepiandrosterone on voluntary ethanol intake in male rats

Comparison of the behavioral and cardiovascular effects of mephedrone with other drugs of abuse in rats

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