Prenatal Exposure to Betamethasone Decreases Anxiety in Developing Rats: Hippocampal Neuropeptide Y as a Target Molecule

Abstract

Repeated antenatal administration of betamethasone is frequently used as a life-saving treatment in obstetrics. However, limited information is available about the outcome of this therapy in children. The initial prospective studies indicate that there are behavioral impairments in children exposed to repeated courses of prenatal betamethasone during the third trimester of pregnancy. In this study, pregnant rats received two betamethasone injections on day 15 of gestation. Using immunohistochemistry, the expression of a powerful anxiolytic molecule neuropeptide Y (NPY) was determined on postnatal day (PN) 20 in the hippocampus and basolateral amygdala (structures related to anxiety and fear) of the offspring. Prenatal betamethasone exposure induced significant increases in NPY expression in the hippocampus but not in the amygdala. Indeed, behavioral tests in the offspring, between PN20 and PN22 in the open field, on the horizontal bar, and in the elevated plus maze, indicated decreases in anxiety, without impairments in motor performance or total activity. Decreased body weight in betamethasone-exposed rats confirmed long-lasting effects of prenatal exposure. Thus, prenatal betamethasone treatment consistently increases hippocampal NPY, with decreases in anxiety-related behaviors and hippocampal role in anxiety in rats. Animal models may assist in differentiation between pathways of the desired main effect of the antenatal corticosteroid treatment and pathways of unwanted side effects. This differentiation can lead to specific therapeutic interventions directed against the side effects without eliminating the beneficial main effect of the corticosteroid treatment.

Prenatal corticosteroid exposure alters early developmental seizures and behavior

“…In experimental animals, prenatal treatments with betamethasone or dexamethasone have anticonvulsant effects in the kindling model (Velíšek 2005, Young, et al 2006). In developing offspring, prenatal betamethasone increases hippocampal expression of anticonvulsant neuropeptide Y (NPY) (Heilig, et al 1993, Velíšek 2006b), corroborating thus findings of anticonvulsant effects of prenatal betamethasone or dexamethasone exposure in kindling epileptogenesis.…”

“…each) at 08:00 and 18:00 (all drugs were purchased from Sigma, St. Louis, MO, USA, unless stated otherwise). These doses were found effective in previous studies (Velíšek 2006b) and in pilot experiments. Control pregnant rats received two i.p.…”

“…The offspring were used in the experiments starting on P15, which in terms of brain development corresponds to human infants (Avishai-Eliner, et al 2002, Gottlieb, et al 1977). At P15, body weight of the animals was determined as biological control because prenatal exposure to corticosteroids is associated with the decreases in postnatal body weight (Velíšek 2006b, Welberg and Seckl 2001, Young et al, 2006). Each experimental subgroup contained pups from at least three different litters to minimize the “litter effect”.…”

Developmental nicotine exposure induced alterations in behavior and glutamate receptor function in hippocampus

“…Individual rats were placed at the distal end of one open arm, facing away and released, and the latency to enter last the third of a closed arm was measured. This latency, referred to as transfer latency (TL), was chosen to preferably test anxiety than to include simple exploratory activities [25]. Forced swim tests were performed to assess depressive-like behaviors as previously described [26][27][28], with some modifications.…”

The Impact of Prenatal Exposure to Dexamethasone on Gastrointestinal Function in Rats

“…Treatment protocols do not show a preference for one in particular, since meta-analysis of different studies directly comparing DEX with betamethasone found no statistically significant differences [38, 39]. The impact of DEX, prenatally administrated in rodents, has been studied in more detail since it is associated with central nervous system (CNS) negative effects [7, 40, 41]. …”