Acute diazepam administration has been shown to decrease plasma cortisol levels consistent with decreased activity of the hypothalamic-pituitary-adrenal axis, especially in individuals experiencing stress. However, the effects of chronic diazepam treatment on cortisol have been less studied, and the relationship to age, anxiety, duration of treatment, and dose are not well understood.
This double-blind placebo-controlled study examined acute and chronic effects of diazepam on plasma cortisol levels in young (19-35 years) and elderly (60-79 years) individuals with and without generalized anxiety disorder (GAD). Subjects received single oral challenges of placebo or diazepam (2.5 mg or 10 mg) in a placebo-controlled cross-over design, followed by 3 weeks of chronic daily treatment with 2.5 mg or 10 mg diazepam or placebo taken at 10 p.m., and then by a final acute challenge with a single oral dose of the same study medication received during chronic treatment.
The elderly experienced significant reductions in plasma cortisol levels compared to placebo both in the initial challenge and during chronic treatment, but the young did not. However, cortisol response to drug was comparable in both groups. Final challenge did not produce any significant cortisol effects in either group and the cortisol response in the elderly was significantly reduced compared to the initial challenge. GAD status was not a factor in plasma cortisol responses to diazepam.
Diazepam reduced cortisol both acutely and during chronic treatment, but not during final challenge, consistent with some tolerance development. This effect was most apparent in the elderly compared with the young adults and was not modulated by GAD status or dosage, and was not related to drug effects on performance and on self-ratings of sedation and tension.
"The effects of diazepam and fluoxetine on cortisol levels have been previously reported in other species. For example, diazepam has been shown to decrease plasma cortisol levels, especially in humans experiencing stress . Another study in elephant seals (Mirounga angustirostris) found that when animals were sedated with a combination of drugs ([tiletamine hydrochloride 50 mg/mL, zolazepam hydrochloride 50 mg/mL], ketamine, and diazepam) in the field, they did not exhibit a cortisol stress response. "
[Show abstract][Hide abstract] ABSTRACT: The presence of pharmaceutical products in the aquatic environment has been reported in several studies. However, the impact of these drugs on living organisms is still uncharacterized. Here, we investigated the effects of acute exposure to either diazepam or fluoxetine on the stress response in Danio rerio. We showed that diazepam and fluoxetine inhibited the stress axis in zebrafish. Intermediate concentrations of diazepam suppressed the stress response as measured by cortisol levels, whereas fluoxetine inhibited cortisol increase at concentrations similar to those found in the environment. These data suggest that the presence of psychoactive drugs in aquatic ecosystems could cause neuroendocrine dysfunction in fish.
PLoS ONE 07/2014; 9(7):e103232. DOI:10.1371/journal.pone.0103232 · 3.23 Impact Factor
"Taken together, these findings suggest that cortisol may indeed play an important role in the facilitation of extinction learning. A major consideration in furthering the development of glucocorticoids as an adjunct to extinction-based therapies is the notion that many anxiolytic medications suppress cortisol or hinder cortisol reactivity (Fries et al., 2006; Pomara et al., 2005). Therefore, the attenuation of glucocorticoid activity by anxiolytic medications may actually interfere with extinction learning during exposure-based treatments, which may reduce the benefits of combining treatment modalities between CBT and medications (Otto, McHugh et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Traditional treatments for anxiety disorders include cognitive-behavioral therapy and anxiolytic medications. Although these treatments are more effective than placebo, there is still considerable room for further improvement. Unfortunately, combining these different modalities is generally not substantially better than monotherapies. Recently, researchers have turned their attention toward translating preclinical research on the neural circuitry underlying fear extinction to clinical applications for the treatment of anxiety disorders with the goal to augment the learning process during exposure-based procedures with cognitive enhancers. This review examines d-cycloserine, cortisol, catecholamines, yohimbine, oxytocin, modafinil, as well as nutrients and botanicals as agents to augment treatment for anxiety disorders. D-cycloserine shows the most empirical support. Other promising agents include cortisol, catecholamines, yohimbine, and possibly oxytocin. Less support comes from studies that examined nutrients and botanicals, such as caffeine, nicotine, and omega-3 fatty acid. Limitations of the exiting literature and future research directions are discussed.
"The observed inhibitory effect of 2.0 mg/kg diazepam on the HPA axis activity agrees with our previous studies that used the same (21) or similar (20,26) doses and timing of diazepam administration, but disagrees with some results which demonstrated no changes in the levels of corticosterone induced by diazepam treatment (23). Some of the discrepancies considering the effects of diazepam on the basal HPA activity (stimulation, inhibition, or no effect) could be ascribed to the differences in sex (15,20,28,38), age (13,39), basal vs stressful conditions (10,13,38), or the strain of the animals used (40). "
[Show abstract][Hide abstract] ABSTRACT: To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.
Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α(2)-adrenoreceptor agonist), yohimbine (α(2)-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine.
Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity.
The results suggest that α(2)-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.
Croatian Medical Journal 06/2012; 53(3):214-23. DOI:10.3325/cmj.2012.53.214 · 1.31 Impact Factor
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