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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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Hypothetical mechanisms involved in the inhibitory effect of diazepam on the hypothalamic-pituitary-adrenal (HPA) axis activity – modified from Carrasco et al (12). The γ-amino-butyric acid (GABA) system is involved in the regulation of the HPA activity via inhibition of corticotrophin-releasing hormone (CRH) and noradrenergic neurons (A). The diazepam-enhanced GABAergic neurotransmission results in the increased inhibition of CRH neurons in the hypothalamic paraventricular nucleus (PVN) and consequently in the decrease of plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels (B). However, this inhibitory effect of diazepam could be achieved, besides direct GABAergic inputs to CRH neurons, also by the interaction of GABAergic neurons from the surrounding hypothalamic regions and noradrenergic neurons in the locus coeruleus (LC), which also exhibit reciprocal neural connections with CRH neurons in PVN (C). This hypothesis is supported by our results demonstrating that intact noradrenergic function is essential for the diazepam-induced suppression of the HPA axis activity, while activation of postsynaptic or blockade of presynaptic α2-noradrenergic receptors reduces inhibitory effect of diazepam.
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Figure 5: Hypothetical mechanisms involved in the inhibitory effect of diazepam on the hypothalamic-pituitary-adrenal (HPA) axis activity – modified from Carrasco et al (12). The γ-amino-butyric acid (GABA) system is involved in the regulation of the HPA activity via inhibition of corticotrophin-releasing hormone (CRH) and noradrenergic neurons (A). The diazepam-enhanced GABAergic neurotransmission results in the increased inhibition of CRH neurons in the hypothalamic paraventricular nucleus (PVN) and consequently in the decrease of plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels (B). However, this inhibitory effect of diazepam could be achieved, besides direct GABAergic inputs to CRH neurons, also by the interaction of GABAergic neurons from the surrounding hypothalamic regions and noradrenergic neurons in the locus coeruleus (LC), which also exhibit reciprocal neural connections with CRH neurons in PVN (C). This hypothesis is supported by our results demonstrating that intact noradrenergic function is essential for the diazepam-induced suppression of the HPA axis activity, while activation of postsynaptic or blockade of presynaptic α2-noradrenergic receptors reduces inhibitory effect of diazepam.

Mentions: To our knowledge, the present study was the first to demonstrate that besides central benzodiazepine receptors, the part of GABAA receptor complex (21), α2-adrenoreceptors activity, and intact presynaptic noradrenergic function were required for the suppressive effect of 2.0 mg/kg diazepam on the activity of the HPA axis in female rats. The suggestion that diazepam affects the HPA axis via noradrenergic system (Figure 5) also agrees with the previously shown interactions between diazepam and noradrenergic function (48-50).


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)

Hypothetical mechanisms involved in the inhibitory effect of diazepam on the hypothalamic-pituitary-adrenal (HPA) axis activity – modified from Carrasco et al (12). The γ-amino-butyric acid (GABA) system is involved in the regulation of the HPA activity via inhibition of corticotrophin-releasing hormone (CRH) and noradrenergic neurons (A). The diazepam-enhanced GABAergic neurotransmission results in the increased inhibition of CRH neurons in the hypothalamic paraventricular nucleus (PVN) and consequently in the decrease of plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels (B). However, this inhibitory effect of diazepam could be achieved, besides direct GABAergic inputs to CRH neurons, also by the interaction of GABAergic neurons from the surrounding hypothalamic regions and noradrenergic neurons in the locus coeruleus (LC), which also exhibit reciprocal neural connections with CRH neurons in PVN (C). This hypothesis is supported by our results demonstrating that intact noradrenergic function is essential for the diazepam-induced suppression of the HPA axis activity, while activation of postsynaptic or blockade of presynaptic α2-noradrenergic receptors reduces inhibitory effect of diazepam.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Hypothetical mechanisms involved in the inhibitory effect of diazepam on the hypothalamic-pituitary-adrenal (HPA) axis activity – modified from Carrasco et al (12). The γ-amino-butyric acid (GABA) system is involved in the regulation of the HPA activity via inhibition of corticotrophin-releasing hormone (CRH) and noradrenergic neurons (A). The diazepam-enhanced GABAergic neurotransmission results in the increased inhibition of CRH neurons in the hypothalamic paraventricular nucleus (PVN) and consequently in the decrease of plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels (B). However, this inhibitory effect of diazepam could be achieved, besides direct GABAergic inputs to CRH neurons, also by the interaction of GABAergic neurons from the surrounding hypothalamic regions and noradrenergic neurons in the locus coeruleus (LC), which also exhibit reciprocal neural connections with CRH neurons in PVN (C). This hypothesis is supported by our results demonstrating that intact noradrenergic function is essential for the diazepam-induced suppression of the HPA axis activity, while activation of postsynaptic or blockade of presynaptic α2-noradrenergic receptors reduces inhibitory effect of diazepam.
Mentions: To our knowledge, the present study was the first to demonstrate that besides central benzodiazepine receptors, the part of GABAA receptor complex (21), α2-adrenoreceptors activity, and intact presynaptic noradrenergic function were required for the suppressive effect of 2.0 mg/kg diazepam on the activity of the HPA axis in female rats. The suggestion that diazepam affects the HPA axis via noradrenergic system (Figure 5) also agrees with the previously shown interactions between diazepam and noradrenergic function (48-50).

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