Diazepam enhances conditioned defeat in hamsters (Mesocricetus auratus)

Hebert, Mark; Potegal, Michael; Moore, Timothy O.; Evenson, Amy; Meyerhoff, James L.

doi:10.1016/s0091-3057(96)00110-4

Cited by 25 publications

(7 citation statements)

References 31 publications

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“… 36 Note that the effects on social competence were so far reported for low doses; in fact, the opposite effect has been reported for high doses. 37 This is probably related to the fact that at higher doses benzodiazepines induce sedation; an effect mediated by overstimulation of the alpha-1 type GABAa receptors. 38 We also report that intra-VTA diazepam treatment enhances mitochondrial respiration in the NAc, which is in line with causal evidence implicating mitochondrial respiration in the NAc in the social rank attainment in rats.…”

Section: Discussionmentioning

confidence: 99%

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

et al. 2017

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Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines’ effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

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Section: Discussionmentioning

confidence: 99%

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

et al. 2017

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“…In a previous study, diazepam (6 mg/kg i.p.) increased anticipatory flight in response to a nonaggressive intruder and reduced the number of defensive postures observed in previously defeated subjects (Hebert et al 1996). Differences in the number of exposures to the aggressive hamsters, the dose and timing of pharmacological manipulations as well as the dependent measure assessed may account for differences between the studies.…”

Section: Differential Effects Of Urb597 and Diazepam In The Elevated mentioning

confidence: 95%

“…The conditioned defeat model has been described as an ethologically relevant model of social anxiety and social stress (Hebert et al 1996;Young 2002). However, more work is necessary to validate this claim pharmacologically.…”

Section: Differential Effects Of Urb597 and Diazepam In The Elevated mentioning

confidence: 99%

An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters

Moise¹,

Eisenstein²,

Astarita

et al. 2008

Psychopharmacology

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Rationale-An endocannabinoid signaling system has not been identified in hamsters.Objective-We examined the existence of an endocannabinioid signaling system in Syrian hamsters using neuroanatomical, biochemical and behavioral pharmacological approaches.Method-The distribution of cannabinoid receptors was mapped and membrane fatty-acid amide hydrolase (FAAH) activity and levels of fatty-acid amides were measured in hamster brain. The impact of cannabinoid CB 1 receptor blockade and inhibition of FAAH was evaluated in the elevated plus maze, rota-rod test and models of unconditioned and conditioned social defeat.Results-A characteristic heterogeneous distribution of cannabinoid receptors was detected in hamster brain using [ 3 H]CP55,940 binding and autoradiography. The FAAH inhibitor URB597 inhibited FAAH activity (IC 50 = 12.8 nM) and elevated levels of fatty-acid amides (N-palmitoyl ethanolamine (PEA) and N-oleoyl ethanolamine (OEA)) in hamster brain. Anandamide levels were not reliably altered. The cannabinoid agonist WIN55,212-2 (1-10 mg/kg i.p.) induced CB 1 -mediated motor ataxia. Blockade of CB 1 with rimonabant (5 mg/kg i.p.) induced anxiogenic-like behavior in the elevated plus maze. URB597 (0.1-0.3 mg/kg i.p.) induced CB 1 -mediated anxiolytic-like effects in elevated plus maze, similar to the benzodiazepine diazepam (2 mg/kg i.p.). Diazepam (2-6 mg/ kg i.p.) suppressed the expression, but not the acquisition, of conditioned defeat. By contrast, neither URB597 (0.3-3.0 mg/kg i.p.) nor rimonabant (5 mg/kg i.p.) altered unconditioned or conditioned social defeat or rota-rod performance.Conclusions-Endocannabinoids engage functional CB 1 receptors in hamster brain to suppress anxiety-like behavior and undergo enzymatic hydrolysis catalyzed by FAAH. Our results further suggest that neither unconditioned nor conditioned social defeat in the Syrian hamster is dependent upon cannabinoid CB 1 receptor activation.

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“…It seems patients are much more adept at detecting the immediate impact of a BZD on anxiety symptoms as opposed to detecting the long-term deterioration in mood or worsening of anxiety. Potential explanations for BZD-induced anxiety disorder include: Rebound or withdrawal anxiety (i.e., after tolerance develops to the anxiolytic effects of BZDs, they no longer treat baseline anxiety but only treat discontinuation symptoms at best returning anxiety levels back to their pre-BZD baseline) [ 1 , 8 ]; BZDs increasing fear responses after stressful exposures likely by fear-sensitization and generalizing conditioneddefeat [ 60 , 61 , 103 , 104 ]; BZDs being associated with a loss of self-confidence in one’s ability to cope with stressors without medications [ 83 ]; and BZDs indirectly worsening anxiety by promoting avoidance, preventing fear extinction, inhibiting cognitive processing of past traumas and present risk assessment, and inhibiting the process of desensitizing individuals to anxiety through both therapeutic and natural exposure [ 7 , 17 , 23 , 25 , 27 , 39 , 58 , 59 ]. During the 1980s, many behavioral therapists and researchers began realizing that BZDs reduce the therapeutic effects of exposure.…”

Section: Evidence Against Benzodiazepine Prescriptionmentioning

confidence: 99%

Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives

Guina

Merrill

2018

JCM

185

139

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Benzodiazepines are some of the most commonly prescribed medications in the world. These sedative-hypnotics can provide rapid relief for symptoms like anxiety and insomnia, but are also linked to a variety of adverse effects (whether used long-term, short-term, or as needed). Many patients take benzodiazepines long-term without ever receiving evidence-based first-line treatments (e.g., psychotherapy, relaxation techniques, sleep hygiene education, serotonergic agents). This review discusses the risks and benefits of, and alternatives to benzodiazepines. We discuss evidence-based indications and contraindications, and the theoretical biopsychosocial bases for effectiveness, ineffectiveness and harm. Potential adverse effects and drug-drug interactions are summarized. Finally, both fast-acting/acute and delayed-action/chronic alternative treatments for anxiety and/or insomnia are discussed. Response to treatment—whether benzodiazepines, other pharmacological agents, or psychotherapy—should be determined based on functional recovery and not merely sedation.

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Diazepam enhances conditioned defeat in hamsters (Mesocricetus auratus)

Cited by 25 publications

References 31 publications

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors

An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters

Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives

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