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The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats.

Švob Štrac D, Muck-Šeler D, Pivac N - Croat. Med. J. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.

ABSTRACT

Aim: To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.

Methods: 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.

Results: 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.

Conclusion: 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.

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The effect of clonidine on diazepam-induced decrease of plasma corticosterone (A) and adrenocorticotropic hormone (ACTH) (B) concentrations. Clonidine (0.01 and 0.5 mg/kg) or its vehicle and diazepam (2.0 mg/kg) or its vehicle were injected ip 35 and 30 minutes, respectively, prior to sacrifice. The results are expressed as percents ± standard error of the mean of the values in control animals treated with the corresponding vehicles. The number of animals per group was 12 for determination of corticosterone levels and 7 for determination of ACTH levels. *P < 0.01; †P < 0.001 vs the control vehicles-treated group; ‡P < 0.05 vs diazepam-treated group (one-way ANOVA followed by Tukey test).
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Figure 1: The effect of clonidine on diazepam-induced decrease of plasma corticosterone (A) and adrenocorticotropic hormone (ACTH) (B) concentrations. Clonidine (0.01 and 0.5 mg/kg) or its vehicle and diazepam (2.0 mg/kg) or its vehicle were injected ip 35 and 30 minutes, respectively, prior to sacrifice. The results are expressed as percents ± standard error of the mean of the values in control animals treated with the corresponding vehicles. The number of animals per group was 12 for determination of corticosterone levels and 7 for determination of ACTH levels. *P < 0.01; †P < 0.001 vs the control vehicles-treated group; ‡P < 0.05 vs diazepam-treated group (one-way ANOVA followed by Tukey test).

Mentions: The administration of 2.0 mg/kg of diazepam to female rats significantly reduced plasma corticosterone (P < 0.001) and ACTH (P < 0.01) levels. Both doses of clonidine (0.01 and 0.5 mg/kg) failed to affect plasma corticosterone and ACTH levels in control rats, but clonidine administered in a dose of 0.5 mg/kg antagonized diazepam-induced decrease of both hormones (P < 0.05) (Figure 1A and 1B). The administration of yohimbine in two doses (0.5 mg/kg and 3 mg/kg) elicited no effect on basal plasma corticosterone and ACTH levels. Although diazepam-induced reduction of plasma corticosterone levels (P < 0.001) was reversed already with 0.5 mg/kg yohimbine (P < 0.01) (Figure 2A), the higher (3.0 mg/kg) dose of yohimbine was required to counteract (P < 0.001) the effect of diazepam (P < 0.01) on plasma ACTH levels (Figure 2B). The administration of α-MPT significantly increased (P < 0.001) plasma corticosterone and ACTH levels (Figure 3A and 3B). Although diazepam significantly decreased (P < 0.001) plasma corticosterone and ACTH levels in control rats, it was unable to diminish the increase of corticosterone and ACTH in the rats pretreated with α-MPT (Figure 3A and 3B). Plasma corticosterone levels were similar between rats treated with α-MPT alone or α-MPT in combination with diazepam, but the combination of α-MPT and diazepam had an additive effect on plasma ACTH levels (P < 0.01). The combined treatment with reserpine and yohimbine induced a significant increase (P < 0.001) in plasma corticosterone and ACTH levels (Figure 4A and 4B). Diazepam significantly decreased plasma corticosterone and ACTH levels in control rats (P < 0.01), but could not suppress the elevated concentrations of both hormones in the rats pretreated with reserpine and yohimbine (Figure 4A and 4B).


The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats.

Švob Štrac D, Muck-Šeler D, Pivac N - Croat. Med. J. (2012)

The effect of clonidine on diazepam-induced decrease of plasma corticosterone (A) and adrenocorticotropic hormone (ACTH) (B) concentrations. Clonidine (0.01 and 0.5 mg/kg) or its vehicle and diazepam (2.0 mg/kg) or its vehicle were injected ip 35 and 30 minutes, respectively, prior to sacrifice. The results are expressed as percents ± standard error of the mean of the values in control animals treated with the corresponding vehicles. The number of animals per group was 12 for determination of corticosterone levels and 7 for determination of ACTH levels. *P < 0.01; †P < 0.001 vs the control vehicles-treated group; ‡P < 0.05 vs diazepam-treated group (one-way ANOVA followed by Tukey test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368292&req=5

Figure 1: The effect of clonidine on diazepam-induced decrease of plasma corticosterone (A) and adrenocorticotropic hormone (ACTH) (B) concentrations. Clonidine (0.01 and 0.5 mg/kg) or its vehicle and diazepam (2.0 mg/kg) or its vehicle were injected ip 35 and 30 minutes, respectively, prior to sacrifice. The results are expressed as percents ± standard error of the mean of the values in control animals treated with the corresponding vehicles. The number of animals per group was 12 for determination of corticosterone levels and 7 for determination of ACTH levels. *P < 0.01; †P < 0.001 vs the control vehicles-treated group; ‡P < 0.05 vs diazepam-treated group (one-way ANOVA followed by Tukey test).
Mentions: The administration of 2.0 mg/kg of diazepam to female rats significantly reduced plasma corticosterone (P < 0.001) and ACTH (P < 0.01) levels. Both doses of clonidine (0.01 and 0.5 mg/kg) failed to affect plasma corticosterone and ACTH levels in control rats, but clonidine administered in a dose of 0.5 mg/kg antagonized diazepam-induced decrease of both hormones (P < 0.05) (Figure 1A and 1B). The administration of yohimbine in two doses (0.5 mg/kg and 3 mg/kg) elicited no effect on basal plasma corticosterone and ACTH levels. Although diazepam-induced reduction of plasma corticosterone levels (P < 0.001) was reversed already with 0.5 mg/kg yohimbine (P < 0.01) (Figure 2A), the higher (3.0 mg/kg) dose of yohimbine was required to counteract (P < 0.001) the effect of diazepam (P < 0.01) on plasma ACTH levels (Figure 2B). The administration of α-MPT significantly increased (P < 0.001) plasma corticosterone and ACTH levels (Figure 3A and 3B). Although diazepam significantly decreased (P < 0.001) plasma corticosterone and ACTH levels in control rats, it was unable to diminish the increase of corticosterone and ACTH in the rats pretreated with α-MPT (Figure 3A and 3B). Plasma corticosterone levels were similar between rats treated with α-MPT alone or α-MPT in combination with diazepam, but the combination of α-MPT and diazepam had an additive effect on plasma ACTH levels (P < 0.01). The combined treatment with reserpine and yohimbine induced a significant increase (P < 0.001) in plasma corticosterone and ACTH levels (Figure 4A and 4B). Diazepam significantly decreased plasma corticosterone and ACTH levels in control rats (P < 0.01), but could not suppress the elevated concentrations of both hormones in the rats pretreated with reserpine and yohimbine (Figure 4A and 4B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.

ABSTRACT

Aim: To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.

Methods: 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.

Results: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus