A role for endocannabinoids in acute stress-induced suppression of the hypothalamic-pituitary-gonadal axis in male rats

Abstract

ObjectiveStress is known to be an inhibitor of the reproductive hypothalamic-pituitary-gonadal (HPG) axis. However, the neural and molecular connections between stress and reproduction are not yet understood. It is well established that in both humans and rodents, kisspeptin (encoded by the kiss1 gene) is a strong stimulator of the HPG axis. In the present study we hypothesized that endocannabinoids, an important neuromodulatory system in the brain, can act on the HPG axis at the level of kiss1 expression to inhibit reproductive function under stress.MethodsAdult male Wistar rats were unilaterally implanted with an intracerebroventricular cannula. Afterwards, the animals were exposed to immobilization stress, with or without the presence of the cannabinoid CB1 receptor antagonist AM251 (1 µg/rat). Blood samples were collected through a retro-orbital plexus puncture before and after stress. Five hours after the stress, brain tissue was collected for reverse transcriptase-quantitative polymerase chain reaction measurements of kiss1 mRNA.ResultsImmobilization stress (1 hour) resulted in a decrease in the serum luteinizing hormone concentration. Additionally, kiss1 gene expression was decreased in key hypothalamic nuclei that regulate gonadotrophin secretion, the medial preoptic area (mPOA), and to some extent the arcuate nucleus (ARC). A single central administration of AM251 was effective in blocking these inhibitory responses.ConclusionThese findings suggest that endocannabinoids mediate, at least in part, immobilization stress-induced inhibition of the reproductive system. Our data suggest that the connection between immobilization stress and the HPG axis is kiss1 expression in the mPOA rather than the ARC.

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge

“…administration of kisspeptin . Furthermore, in acute immobilisation stress experiments performed in rats, AM251 prevented the reduced expression of kiss1 mRNA, suggesting that kisspeptinergic neurones might be influenced by CB1 activation . For the first time, the present study shows the response of these neurones to the modulation of CB1 under LPS‐induced immune challenge.…”

“…31,65 Furthermore, in acute immobilisation stress experiments performed in rats, AM251 prevented the reduced expression of kiss1 mRNA, suggesting that kisspeptinergic neurones might be influenced by CB1 activation. 66 For the first time, the present study shows the response of these neurones to the modulation of CB1 under LPS-induced immune challenge. Kisspeptinergic neurones responded by decreasing the mRNA expression of this neurotransmitter at 180 minutes post-LPS, and this effect was blocked by i.c.v.…”

2-Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation

“…In this way, OX hyperactivity might be responsible for the spontaneous increase in W observed in MS rats, as these lateral hypothalamic neurons have been involved in facilitating waking [12] and are activated in a variety of paradigms that involve stressors such as cold exposure, food deprivation, foot shock, and immobilization (for an extensive review, see Tsujino et al [17]). In agreement with this, it has also been demonstrated that eCBs regulate stress (for an extensive review, see Crowe et al [18]); for example, infusion of the CB1R antagonist AM251 into the ventricles of rats blocks the expression of biomarkers associated with immobilization-induced acute stress [19]. Likewise, in-vitro evidence has suggested that CB1R stimulation hyperpolarizes OX neurons and depolarizes MCH neurons in rodent brain slices [20].…”

Endocannabinoids

“…Stress elevates hypothalamic endocannabinoid concentrations , likely through glucocorticoid receptor activation (Evanson et al 2010), leading to the hypothesis that ECS mediates stress-induced inhibition of the HPG axis. In support of this hypothesis, recent data demonstrate that immobilization stress-induced decrease in LH release in male rats is reversed by CB 1 R antagonist treatment (Karamikheirabad et al 2013).…”