O. Malkesman

Stress hormones and emotion-regulation in two genetic animal models of depression

Children of depressed parents often exhibit emotion-regulation deficits, characterized by either excessive withdrawal or approach strategies toward the mother. The current study examined behavioral and physiological emotion-regulation in preweanling pups (postnatal day 17-19) belonging to two different genetic animal models of depression, Wistar-Kyoto (WKY) and Flinders Sensitive-Line (FSL) rats. The study also examined the effects of stress on the two animal models, hypothesizing an interactive effect of hereditary vulnerability and exposure to stress. Chronic-stress was simulated by providing limited bedding to the dam and litter for a week, in the early postnatal period. Acute-stress was generated by exposure to an adult male rat, an ethologically valid stressor. Emotion-regulation of the pups was examined using a Y-maze preference test and radioimmunoassay of Hypothalamic-Pituitary-Adrenal (HPA) axis hormones (corticosterone & adreno-corticotropin/ACTH). WKY and FSL pups exhibited reduced approach-behavior toward the dam, an emotion-regulation profile reminiscent of avoidant attachment evident in many children of depressed parents. In contrast, the two animal models did not show similar HPA axis activity. FSL pups exhibited markedly lower ACTH levels compared to controls, while WKY pups did not differ from controls. With regard to the stress manipulations, the limited-bedding condition had no effect, while the acute-stressor induced overall effects on all groups, with more pronounced reactivity evident in the WKY and FSL pups. Taken together, the experiments indicate a similar behavioral profile of the two strains at the preweanling period, while suggesting HPA dysfunction in only one of the strains.

Dehydroepiandrosterone in the nucleus accumbens is associated with early onset of depressive-behavior : A study in an animal model of childhood depression

Although the monoamine theory of depression is well studied, regarding childhood depression it is poorly supported. Antidepressant treatments affecting the monoaminergic system fail to ameliorate childhood depression in the same manner that they affect adult depression. The present study used the Flinders sensitive line (FSL) rat, a well-investigated genetic animal model of depression and Sprague-Dawley (SD) rats as controls. We co-measured monoamines and dehydroepiandrosterone (DHEA) levels in the nucleus accumbens on postnatal day 1, in prepubertal rats (35 days), and adult rats (4 months) in order to examine developmental characteristics in the monoamine systems. The results suggest that there are different ontogenetic patterns of monoaminergic activity in FSL and SD rats. While monoamine levels were different only in adulthood, FSL rats exhibited lower DHEA levels already in prepubertal childhood. These differences may be relevant to the poor response to antidepressant drugs observed in depressed children and suggest DHEA as a new marker for childhood depression.

Effects of CCK-8 on independent ingestion and central c-Fos-like immunoreactivity in rats on postnatal days 10 and 11.

Controls of the independent ingestion of food in the preweanling rat emerge in the second postnatal week. We investigated the effects of CCK-8 (0, 1, 5, or 10 microg/kg IP) on intake and c-Fos-like immunoreactive (CFLI) cells in hindbrain and forebrain on postnatal days 10 and 11. Five micrograms per kilogram decreased intake and increased the number of CFLI cells in four subnuclei of the nucleus tractus solitarius (NTS), in arcuate nucleus (ARC), and in central nucleus of the amygdala (CeA). Ten micrograms per kilogram decreased intake and increased CFLI in three NTS subnuclei as much as 5 microg/kg did, but was more potent than 5 microg/kg in the medial NTS subnucleus. Ten micrograms per kilogram increased CFLI in paraventricular (PVN) and supraoptic (SON) nuclei, but 5 microg/kg did not. Thus, reduction of intake by CCK-8 on days 10 and 11 is associated with increased hindbrain and forebrain CFLI.

Stress and pain responses in rats lacking CCK1 receptors

UNLABELLED CCK involvement in stress- and pain-responsiveness was examined by studying the behavior of infant (11-12-days-old) and adult OLETF rats that do not express CCK1 receptors. Infant odor- and texture-preferences were also assessed. We hypothesized that OLETF rats will show behavioral patterns similar to those previously observed after CCK1 antagonist administration. Rate of separation-induced ultrasonic vocalization was significantly greater in OLETF compared to controls, in two separate studies. Infant pups of the two strains did not differ in odor- and texture-preference tests. OLETF rats showed consistently longer hot-plate paw-lift (as infants, in two separate studies) and paw-lick (as adults) latencies. SUMMARY OLETF pups vocalized in isolation more than controls and showed relative hypoalgesic responses, evident also in adulthood, in concordance with the pharmacological literature.

Gastric preloads of corn oil and mineral oil produce different patterns of increases of c-Fos-like immunoreacitve cells in the brain of 9-12 day-old rats.

Equivolumetric gastric preloads of corn oil and mineral oil administered to rats on postnatal day 12 (P12) inhibited intake equally during a 30-min test of independent ingestion (II), but preloads of corn oil inhibited intake significantly more than preloads of mineral oil on P15 and P18 [Weller, A., Gispan, I.H., Armony-Sivan, R., Ritter, R.C., Smith, G.P., 1997. Preloads of corn oil inhibit independent ingestion on postnatal day 15 in rats. Physiol. Behav. 62, 871-874]. It is possible that the equivalent inhibition of intake by the oil preloads on P12 resulted from the failure of the preabsorptive sensory properties of the preloads to be discriminated by peripheral or central sensory mechanisms. To investigate this possibility, we administered equivolumetric gastric preloads of 25% corn oil and 25% mineral oil to pups on P9-12 and counted the number of c-Fos-like immunoreactive (CFLI) cells in central sites that are activated by food intake and postingestive preabsortive mechanisms in adult rats and in pups on P10-11. The major result was that preloads of 25% corn oil and 25% mineral oil that produced equivalent inhibition of II intake produced differential increases of CFLI cells in the forebrain and hindbrain. Specifically, preloads of corn oil increased the number of CFLI cells in the caudal Nucleus Tractus Solitarius significantly more than preloads of mineral oil. Furthermore, preloads of corn oil increased the number of CFLI cells in the Paraventricular and Supraoptic nuclei, but preloads of mineral oil did not. This differential pattern of increases of CFLI cells is evidence that the brain discriminates the preabsorptive sensory properties of preloads of corn oil and mineral oil on P9-12.