Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression

Dixon, Claire I.; Walker, Sophie; Swinny, Jerome D.; Belelli, Delia; Lambert, Jeremy J.; King, Sarah L.; Stephens, David

doi:10.1097/fbp.0000000000000466

Cited by 3 publications

(2 citation statements)

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“…In cocaine-dependent individuals, GABRA2 SNPs were associated with cocaine cue reactivity ( 192 ). The involvement of α2GABAARs in some, but not all, effects of cocaine has also been confirmed in rodent studies ( 191 , 193 , 194 ). Finally, long-term exposure to cocaine was found to cause changes in the expression of α2GABAARs in the hippocampi of rodents ( 195 ), however, this finding was not confirmed in postmortem studies of hippocampi from individuals with cocaine use disorder ( 187 ).…”

Section: Gabaars In Alcohol and Other Substance Use Disordersmentioning

confidence: 63%

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

Engin

2023

Front. Psychiatry

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Benzodiazepines have been in use for over half a century. While they remain highly prescribed, their unfavorable side-effect profile and abuse liability motivated a search for alternatives. Most of these efforts focused on the development of benzodiazepine-like drugs that are selective for specific GABAA receptor subtypes. While there is ample evidence that subtype-selective GABAA receptor ligands have great potential for providing symptom relief without typical benzodiazepine side-effects, it is less clear whether subtype-selective targeting strategies can also reduce misuse and abuse potential. This review focuses on the three benzodiazepine properties that are relevant to the DSM-5-TR criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder, namely, reinforcing properties of benzodiazepines, maladaptive behaviors related to benzodiazepine use, and benzodiazepine tolerance and dependence. We review existing evidence regarding the involvement of different GABAA receptor subtypes in each of these areas. The reviewed studies suggest that α1-containing GABAA receptors play an integral role in benzodiazepine-induced plasticity in reward-related brain areas and might be involved in the development of tolerance and dependence to benzodiazepines. However, a systematic comparison of the contributions of all benzodiazepine-sensitive GABAA receptors to these processes, a mechanistic understanding of how the positive modulation of each receptor subtype might contribute to the brain mechanisms underlying each of these processes, and a definitive answer to the question of whether specific chronic modulation of any given subtype would result in some or all of the benzodiazepine effects are currently lacking from the literature. Moreover, how non-selective benzodiazepines might lead to the maladaptive behaviors listed in DSM and how different GABAA receptor subtypes might be involved in the development of these behaviors remains unexplored. Considering the increasing burden of benzodiazepine abuse, the common practice of benzodiazepine misuse that leads to severe dependence, and the current efforts to generate side-effect free benzodiazepine alternatives, there is an urgent need for systematic, mechanistic research that provides a better understanding of the brain mechanisms of benzodiazepine misuse and abuse, including the involvement of specific GABAA receptor subtypes in these processes, to establish an informed foundation for preclinical and clinical efforts.

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Section: Gabaars In Alcohol and Other Substance Use Disordersmentioning

confidence: 63%

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

Engin

2023

Front. Psychiatry

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“…In rodents, maternal separation (MS) with early weaning (MSEW) is a reliable animal model of ELS and depression‐like behaviour 6‐8 . Other studies have reported changes in brain‐derived neurotrophic factor (BDNF) expression in the hippocampus, ventral tegmental area (VTA), and prefrontal cortex of maternally separated rats 9 . Moreover, increased BDNF in the VTA of rats induces a higher vulnerability to drug abuse, turning the GABA inhibitory system to excitatory signalization 10 …”

Section: Introductionmentioning

confidence: 99%

Maternal separation increases cocaine intake through a mechanism involving plasticity in glutamate signalling

et al. 2020

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Early‐life stress (ELS) is associated with negative consequences, including maladaptive long‐lasting brain effects. These alterations seem to increase the likelihood of developing substance use disorders. However, the molecular consequences of ELS are poorly understood. In the present study, we tested the impact of ELS induced by maternal separation with early weaning (MSEW) in CD1 male mice at different phases of cocaine self‐administration (SA). We also investigated the subsequent alterations on GluR2, GluR1, cAMP response element‐binding (CREB), and CREB‐phosphorylation (pCREB) in ventral tegmental area (VTA) and nucleus accumbens (NAc) induced by both MSEW and cocaine SA. Our results show that MSEW animals expressed a higher cocaine intake, an increased vulnerability to the acquisition of cocaine SA, and incapacity to extinguish cocaine SA behaviour. MSEW mice showed decreased GluR2 and increased GluR1 and pCREB in NAc. Also, results displayed reduction of basal levels of GluR1 and CREB and an elevation of GluR1/GluR2 ratio in the VTA. Such results hint at an enhanced glutamatergic function in NAc and increased excitability of VTA DA neurons in maternally separated mice. Altogether, our results suggest that MSEW induces molecular alterations in the brain areas related to reward processing, increasing the vulnerability to depression and cocaine‐seeking behaviour.

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Prophylactic effect of Tongxieyaofang polysaccharide on depressive behavior in adolescent male mice with chronic unpredictable stress through the microbiome-gut-brain axis

Chen¹,

Kan²,

Zhao³

et al. 2023

Biomedicine & Pharmacotherapy

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Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression

Abstract: N (2019) Early life stress influences acute and sensitised responses of adult mice to cocaine by interacting with GABAA α2 receptor expression. Behavioural Pharmacology, 30 (2-3). pp. 272-281.

Cited by 3 publications

References 54 publications

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

Maternal separation increases cocaine intake through a mechanism involving plasticity in glutamate signalling

Prophylactic effect of Tongxieyaofang polysaccharide on depressive behavior in adolescent male mice with chronic unpredictable stress through the microbiome-gut-brain axis

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