Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats

Goeders, Nicholas E.; Clampitt, David M.; Keller, Courtney M.; Sharma, Mukesh; Guerin, Glenn F.

doi:10.1007/s00213-008-1326-1

Cited by 26 publications

(13 citation statements)

References 37 publications

(48 reference statements)

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“…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]. However, unlike benzodiazepines, neuroactive steroids do not engender tolerance to rate-altering effects or anticonvulsant effects [44–47], findings that further support their clinical use.…”

Section: Discussionsupporting

confidence: 85%

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: 85%

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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“…The dose of cocaine selected (0.5 mg/kg/infusion) is a moderate dose of cocaine that engenders high rates of responding in rats (Baird et al, 2000). We previously obtained robust degrees of cocaine-primed and cue-induced reinstatement after training with this dose (Smith et al, 2012), although other investigators have reported equally robust effects with lower doses (Bespalov et al, 2000; Goeders et al, 2009). The 20-day period of training is similar to those used in previous studies reporting robust reinstatement of responding following extinction (Anderson et al, 2006; Anker et al, 2009).…”

Section: Discussionmentioning

confidence: 81%

The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior

Smith

Zhang

Robinson

2016

Front. Behav. Neurosci.

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Social partners influence the likelihood of using drugs, developing a substance use disorder and relapse to drug use after a period of abstinence. Preclinical studies report that social cues influence the acquisition of cocaine use, the escalation of cocaine use over time, and the compulsive patterns of cocaine use that emerge during an extended binge. The purpose of this study was to examine the effects of social cues on the reinstatement of cocaine-seeking behavior after a period of abstinence. Male rats were obtained at weaning, assigned to triads (three rats/cage), reared to adulthood and implanted with intravenous catheters. Rats from each triad were then assigned to one of three conditions: (1) test rats were trained to self-administer cocaine and were tested for reinstatement; (2) cocaine partners were trained to self-administer cocaine and were predictive of response-contingent cocaine delivery; and (3) abstinent partners were not given access to cocaine and were predictive of extinction. The test rats alternated social partners every 5 days for 20 days such that responding was reinforced with cocaine in the presence of the cocaine partner (S+) for 10 days and not reinforced with cocaine in the presence of the abstinent partner (S−) for 10 days. Responding of the test rats was then extinguished over 7 days under isolated conditions. Tests of reinstatement were then conducted in the presence of the cocaine partner and abstinent partner under extinction conditions. Neither social partner reinstated responding relative to that observed on the final day of extinction; however, responding was greater in the presence of the cocaine partner (S+) than the abstinent partner (S−) during the reinstatement test. These data fail to demonstrate that a social partner reinstates cocaine-seeking behavior after a period of abstinence, but they do indicate that social partners can serve as either excitatory or inhibitory discriminative stimuli to influence drug-seeking responses.

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“…Although alprazolam has known abuse potential, 35–37 the prior research described above demonstrated its ability to reduce the abuse-related effects of stimulants, 11,24,27,30,31,38 so it was selected for initial proof-of-concept testing in an attempt to demonstrate the initial efficacy of maintenance on naltrexone and a potent GABA A positive allosteric modulator to attenuate the response to methamphetamine.…”

Section: Introductionmentioning

confidence: 99%

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine

Marks

Lile

Stoops

et al. 2016

Journal of Clinical Psychopharmacology

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Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric acid type A (GABAA) receptors (e.g., alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of d-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and “positive” subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone. Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6–7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like “positive” subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10 mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

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Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats

Abstract: These data suggest that benzodiazepines may be useful in blocking the ability of environmental cues to stimulate cocaine seeking.

Cited by 26 publications

References 37 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

The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine

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