M. Kathleen Gordon

Foster Children’s Diurnal Production of Cortisol: An Exploratory Study

Young children in foster care have often experienced inadequate early care and separations from caregivers. Preclinical studies suggest that early inadequate care and separations are associated with long-term changes in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the daytime pattern of cortisol production was examined among 55 young children who had been placed into foster care and 104 children who had not. Saliva samples were taken at wake-up, in the afternoon, and bedtime for 2 days. Average salivary cortisol values for each time of day were computed. A group (foster vs. comparison) time (morning, afternoon, night) interaction emerged, reflecting less decline in levels across the day for foster than comparison children. Daytime patterns were categorized as typical, low, or high. Children who had been in foster care had higher incidences of atypical patterns of cortisol production than children who had not. These differences suggest that conditions associated with foster care interfere with children’s ability to regulate neuroendocrine functioning.

Intervening to enhance cortisol regulation among children at risk for neglect: Results of a randomized clinical trial

The hypothalamus-pituitary-adrenal axis is particularly sensitive to conditions of maltreatment. In particular, neglected children have shown a flatter slope with lower wake-up values relative to nonneglected children. An intervention, the Attachment and Biobehavioral Catch-Up (ABC), was developed to enhance biological and behavioral regulation in young children at risk for neglect. The effectiveness of the intervention was assessed in a randomized clinical trial for children with involvement with Child Protective Services. Following the intervention, children receiving the ABC intervention (n = 49) showed more typical cortisol production, with higher wake-up cortisol values and a steeper diurnal slope, than children receiving the control intervention (n = 51). These results suggest that the ABC intervention is effective in enhancing biological regulation.

Differential Expression of c-fos and Tyrosine Hydroxylase mRNA in the Adrenal Gland of the Infant Rat: Evidence for an Adrenal Hyporesponsive Period

Rats exhibit a stress hyporesponsive period from postnatal day (PND) 4-14 in which the neonate displays a minimal corticosterone response to stress. We used the maternal deprivation model to test whether this adrenocortical hyporesponsiveness to stress results from a decrease in adrenal sensitivity to ACTH. Neonates (PND 6, 9, and 12) were injected ip with dexamethasone to block endogenous ACTH release, and 4 h later injected with graded doses of ACTH and killed. In another experiment, neonates were injected with isotonic saline and adrenal glands were collected at 30, 60, and 120 min post injection to examine c-fos and tyrosine hydroxylase mRNA levels using in situ hybridization. Maternally deprived pups demonstrated elevated corticosterone levels at the two highest ACTH doses and showed a greater magnitude in glucocorticoid secretion compared with the nondeprived pups. Maternally deprived pups given a saline injection exhibited elevated basal and stress-induced levels of corticosterone, in contrast to the nondeprived pups that showed a minimal response. Strikingly, maternally deprived pups exhibited elevated levels of adrenocortical c-fos mRNA, whereas the nondeprived pups did not. In contrast, the pattern of c-fos gene expression in the adrenal medulla in both groups did not display any correlation with glucocorticoid secretion. Tyrosine hydroxylase gene expression in the adrenal medulla was observed in both nondeprived and maternally deprived pups, with the latter exhibiting an earlier response of greater magnitude. These results demonstrate that the suppression of steroidogenesis occurs directly in the adrenal cortex and provide further evidence for an adrenal hyporesponsive period in the rat.

Lasting effects of repeated cocaine administration on acoustic and fear-potentiated startle in rats

Abstract  Rationale: Following cocaine withdrawal, humans may experience an abstinence syndrome with high levels of anxiety. Studying anxious behavior in animals following repeated cocaine administration may help elucidate important variables that contribute to a withdrawal syndrome. Objectives: This study investigated whether repeated cocaine pre-exposure produced lasting increases in conditioned fear as measured by fear-potentiated startle responses in rats. Methods: Startle was measured in response to 50 ms acoustic stimuli of 95, 105 and 115 dB. Cocaine (20 mg/kg, IP) or saline was administered for 7 days and after each injection rats were either placed in startle chambers for 30 min or returned to the home cage. After a 1-week cocaine-free period, most rats were given ten light-footshock pairings in the startle chamber. Fear-potentiated startle was tested by presenting acoustic startle-eliciting stimuli of 95, 105 and 115 dB in the presence or absence of the light. Rats that were not fear conditioned received acoustic stimuli one week after 7 days of 20 mg/kg cocaine. Results: Startle responses, both in the presence and absence of the light CS, were greater in fear-conditioned rats that received cocaine pre-exposure in the startle chamber than in saline pre-exposed rats. Startle responses in the presence of the light CS were further augmented at 115 dB. In contrast, home-cage exposure to cocaine did not enhance startle responses. In rats that were not fear conditioned, cocaine pre-exposure reduced acoustic startle. Conclusions: Repeated cocaine pre-exposure can increase, decrease or not change acoustic startle depending on whether fear conditioning occurred and whether cocaine was given in the testing chamber. The data suggest that cocaine pre-exposure may act as a contextually conditioned occasion setting stimulus that can facilitate anxious behavior similar to the postulated human cocaine abstinence syndrome.

Hormonal and metabolic rhythms associated with the daily scheduled nursing in rabbit pups.

Young rabbits are nursed every 24 h for a period of 3-5 min. As a consequence, pups are synchronized to this nursing event; this synchronization is characterized by increased locomotor activity and a peaking of core temperature and plasma corticosterone in anticipation of the daily meal. Ghrelin is a hormone suggested to play a role in meal initiation and to promote food intake. The present study explored the role of ghrelin in food-entrained conditions. Newborn rabbits were maintained in constant darkness and nursed once daily at 1000 by the lactating dam. On postnatal day 7, rabbits were killed at six different time points to complete a 24-h cycle. All pups developed locomotor rhythms entrained by mealtime and exhibited anticipatory activity. Food-entrained rhythms in plasma corticosterone and free fatty acids were observed even if two meals were omitted. In contrast, daily food-driven rhythms in stomach weight, plasma glucose, liver glycogen, and ghrelin did not persist when two meals were omitted. Peak ghrelin levels were observed at the moment in the cycle when the stomach weight was lowest, i.e., before initiation of anticipation. The present data are in agreement with previous data from rabbit pups maintained in light-dark conditions and provide evidence that 7- to 9-day-old rabbits in constant darkness can exhibit metabolic and hormonal rhythms mainly driven by the restricted daily nursing.

Persistence of hormonal and metabolic rhythms during fasting in 7 to 9 day-old rabbits entrained by nursing during the night

Rabbit does nurse their litter once every 24h during the night. We hypothesized that corticosterone, ghrelin, leptin, and metabolites such as glucose, liver glycogen, and free fatty acids could be affected in the pups by the time at which does nurse them. Therefore, we measured these parameters in pups nursed at 02:00 h (nighttime for the doe) to compare them with results from a previous study where does nursed at 10:00 h, during daytime. From postnatal day 7, pups were sacrificed either just before their scheduled time of nursing or at 4, 8, 12, 16, or 20 h after nursing (n=6 at each time point); additional pups were sacrificed at 4h intervals between 48 and 72 h after nursing to study the persistence of oscillations during fasting. All pups developed locomotor anticipatory activity to nursing. Corticosterone, ghrelin, and free fatty acids exhibited a rhythm that persisted in fasted pups. Glucose concentrations were lower in fasted than in nursed pups, and glycogen was only detected in nursed subjects. Leptin values were stable and low in nursed subjects but increased significantly in fasted subjects up to 72 h after the expected nursing time. The rhythm of ghrelin persisted during fasting, contrary to our previous findings in pups nursed during daytime (i.e., outside the natural time of nursing for this species). Therefore, in 7-day-old rabbit pups, night nursing is a strong zeitgeber for corticosterone, ghrelin, free fatty acids, and energy metabolites but not for leptin.

Measurement of the lowest dosage of phenobarbital that can produce drug discrimination in rats

RationaleAccurate measurement of the threshold dosage of phenobarbital that can produce drug discrimination (DD) may improve our understanding of the mechanisms and properties of such discrimination.ObjectivesThis study aimed to compare three methods for determining the threshold dosage for phenobarbital (D) versus no-drug (N) DD.Materials and methodsRats learned a D versus N DD in two-lever operant training chambers. A titration scheme was employed to increase or decrease dosage at the end of each 18-day block of sessions depending on whether the rat had achieved criterion accuracy during the sessions just completed. Three criterion rules were employed, all based on average percent drug lever responses during initial links of the last six D and six N sessions of a block. The criteria were: D% > 66 and N% < 33; D% > 50, and N% < 50; (D% − N%) > 33. Two squads of rats were trained, one immediately after the other.ResultsAll rats discriminated drug versus no drug. In most rats, dosage decreased to low levels and then oscillated near the minimum level required to maintain criterion performance. The lowest discriminated dosage significantly differed under the three criterion rules. The squad that was trained second may have benefited by partially duplicating the lever choices of the previous squad.ConclusionsThe lowest discriminated dosage is influenced by the criterion of discriminative control that is employed and is higher than the absolute threshold at which discrimination entirely disappears. Threshold estimations closer to absolute threshold can be obtained when criteria are employed that are more permissive of errors and that allow rats to maintain lever preferences.