Stress, alcohol and infection during early development: A brief review of common outcomes and mechanisms.

Although stress is an adaptive physiological response to deal with adverse conditions, its occurrence during the early stages of life, such as infancy or adolescence, can induce adaptations in multiple physiological systems, including the reproductive axis, the hypothalamic-pituitary-adrenal (HPA) axis, the limbic cortex and the immune system. These early changes have consequences in adult life, as seen in the physiological and behavioural responses to stress. This review highlights the impact of several stress challenges incurred at various stages of development (perinatal, juvenile, adolescent periods) and how the developmental timing of early-life stress confers unique physiological adaptations that may persist across the lifespan. In doing so, we emphasise how intrinsic sex differences in the stress response might contribute to sex-specific vulnerabilities, the molecular processes underlying stress in the adult, and potential therapeutic interventions to mitigate the effects of early stage stress, including the novel molecular mechanism of SUMOylation as a possible key target of HPA regulation during early-life stress.

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

Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 µL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1ß increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration.