A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats

Schmoutz, Christopher D.; Guerin, Glenn F.; Runyon, Scott P.; Dhungana, Suraj; Goeders, Nicholas E.

doi:10.1016/j.bbr.2015.05.019

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…The neuroactive steroid system is one of the most potent neuroendocrine pathways that plays a critical role in many vital functions of the human body, including direct modulation of GABAergic neurotransmission [ 16 ] and regulation of the physiologic arousal response to stress [ 9 , 10 , 11 , 12 ]. There is also mounting preclinical evidence that neuroactive steroids may play a role in reducing relapse to cocaine use in rats [ 12 , 31 , 32 , 33 ], confirming our findings observed here in a clinical population of individuals with CUD. We have also previously observed that chronic cocaine use is associated with decreased endogenous levels of pregnenolone [ 48 ].…”

Section: Discussionsupporting

confidence: 90%

“…On the other hand, chronic drug use and related neuroadaptations down-regulate GABAergic transmission [ 8 ] and decrease neuroactive steroid levels in the brain and periphery [ 10 , 14 , 28 ], arguing that increasing endogenous neuroactive steroids may improve drug-related outcomes. For example, chronic alcohol exposure reduced both plasma and brain levels of ALLO [ 28 ], and ALLO administration attenuated drug-primed reinstatement of cocaine [ 12 ] and cue-induced reinstatement [ 31 ] in cocaine dependent animals. Moreover, ALLO administration decreased cocaine primed reinstatement in female, but not in male rats [ 32 ], and decreased yohimbine-induced cocaine reinstatement in female rats only [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

et al. 2022

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Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

et al. 2022

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“…The rationale for 3α,5α-THP treatment of substance use disorders, such as cocaine and alcohol, is restoring the normal HPA axis response to stress as well as the glutamatergic/GABAergic signaling imbalance in the brain. Indeed, the efficacy of 3α,5α-THP administration to reduce cocaine reinstatement was observed in cocaine-dependent animals [ 48 , 49 ], and female rats were more sensitive to this effect [ 50 , 51 ]. Other findings showed that pregnenolone and its GABAergic metabolites regulate alcohol motivation by reducing alcohol seeking and intake in rodents [ 52 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats

Boero,

McFarland,

Tyler

et al. 2023

Biomolecules

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The neurosteroid 3α,5α-THP is a potent GABAA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation.

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“…Using GABAergic drugs to blunt the cocaine amplification of dopamine signals has been proposed as a strategy to counteract the rewarding and motivational effects of cocaine (Ashby et al, 1999; Quinones‐Jenab & Jenab, 2010). Indeed, benzodiazepines block cocaine self‐administration in animal models (Barrett et al, 2005; Goeders et al, 1993; Schmoutz et al, 2015; Weerts et al, 2005; but see Maier et al, 2008) and prolong abstinence in rat cocaine self‐administration (Augier et al, 2012). Benzodiazepines can also decrease cue‐induced cocaine seeking and reinstatement, cocaine‐induced conditioned place preference, and cocaine‐evoked hyperlocomotion and sensitization in rats (Dewey et al, 1997; Goeders et al, 2009; Keller et al, 2013; Meririnne et al, 1999; Quinton et al, 2005) and can attenuate cocaine discrimination in rhesus monkeys (Negus et al, 2000; Quinton et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Diazepam attenuates the effects of cocaine on locomotion, 50‐kHz ultrasonic vocalizations and phasic dopamine in the nucleus accumbens of rats

Sanchez

Pochapski

Jessen

et al. 2021

British J Pharmacology

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Background and Purpose: Currently, there is no effective drug to treat cocaine-use disorder, which affects millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine concentrations in the nucleus accumbens of rodents and block the increase in dopamine levels and appetitive 50-kHz ultrasonic vocalizations (USVs) induced by amphetamine in rats.Experimental Approach: Here, we tested whether administration of 2.5-mgÁkg À1 diazepam (i.p.) in adult male rats could block the effects of 20-mgÁkg À1 cocaine (i.p.) on electrically evoked phasic dopamine signals in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity.Key Results: Cocaine injection increased evoked dopamine signals up to threefold within 5 min, and the increase was significantly higher than baseline for at least 75 min. The injection of diazepam, 5 min after cocaine, attenuated the cocaine effect by nearly 50%, and this attenuation was maintained for at least 40 min. Behaviourally, cocaine increased the number of appetitive 50-kHz calls by about 12-fold. Diazepam significantly blocked this effect for the entire duration of the session. Also, cocainetreated rats were more active than controls and diazepam significantly attenuated cocaine-induced locomotion, by up to 50%. Conclusion and Implications:These results suggest that the neurochemical and psychostimulant effects of cocaine can be mitigated by diazepam.LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.

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A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats

Cited by 10 publications

References 23 publications

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats

Diazepam attenuates the effects of cocaine on locomotion, 50‐kHz ultrasonic vocalizations and phasic dopamine in the nucleus accumbens of rats

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