The Effects of Early Rearing Environment on the Development of GABAA and Central Benzodiazepine Receptor Levels and Novelty-Induced Fearfulness in the Rat

Abstract

We compared the effects of handling or maternal separation from the day following birth until postnatal day 14 on behavioral responses to novelty and on GABA A and central benzodiazepine (CBZ) receptor levels in the rat. As adults, handled animals showed reduced startle responsivity, increased exploration in a novel open field, and decreased novelty-induced suppression of feeding relative to the handled (H) and/or maternal separation (MS) groups. As compared with handled animals, both nonhandled (NH) and MS animals displayed: (1) reduced GABA A receptor levels in the locus coeruleus (LC) and the n. tractus solitarius (NTS); (2) reduced CBZ receptor sites in the central and lateral n. of the amygdala, the frontal cortex, and in the LC and NTS; and (3) The development of behavioral and endocrine responses to acute stress is greatly influenced by the early postnatal rearing environment (for reviews see Levine 1975;Denenberg 1964;Meaney et al. 1996). These environmental effects persist throughout the life of the animal, resulting in stable individual differences in stress reactivity. Indeed, there is considerable plasticity in the development of these systems. Postnatal handling during the first week of life greatly decreases behavioral fearfulness and hypothalamic-pituitary-adrenal (HPA) responses to stress; whereas, repeated periods of prolonged maternal separation produce enhanced reactivity. Increased stress reactivity has been associated with an enhanced risk for several forms of illness, including affective disorders, diabetes, autoimmune disorders, and coronary heart disease (Chrousos and Gold 1992;Higley et al. 1991;McEwen and Steller 1993;Seckl and Meaney 1994). Thus, in determining the magnitude of behavioral and endocrine responses to stress, early life events NO . 3 contribute to vulnerability to disease in later life (Seckl and Meaney 1994). The critical question, then, concerns the mechanisms for these early environmental effects on the development of behavioral and endocrine responses to stress.Postnatal handling has been shown to decrease fearfulness to novelty (Levine 1962(Levine , 1957Denenberg 1964;Bodnoff et al. 1987). As adults, handled (H) rats show reduced novelty-induced suppression of appetitive behavior and increased exploration in novel environments. The behavioral effects of repeated maternal separation in rats are less documented, although, in primates, there is considerable evidence for enhanced fearfulness in animals exposed to maternal separation in early life (Sackett 1969).The mechanisms underlying these early environmental effects on behavioral responses to novelty are unclear. Bodnoff et al. (1987) reported that neonatal handling increased forebrain central benzodiazepine (CBZ) receptor levels, with no indication of where in the forebrain such differences might exist. Nevertheless, these data are certainly consistent with the wellestablished, anxiolytic effects of benzodiazepines on behavioral responses to novelty (see File 1995 for a review). Moreover, these findings are a...

Marked for life? Effects of early cage‐cleaning frequency, delivery batch, and identification tail‐marking on rat anxiety profiles

“…3C shows the lack of a negative trend). Power tests showed that our study would have been able to detect an effect size comparable to that reported by Caldji et al (2000). Including marked and unmarked rats (because marking had no significant effect on this test), we would have had a power of .99 to detect the magnitude of difference they report in latency to feed between EH and NH rats (minimum n ¼ 19 per cleaning treatment group; hypothesized effect size (arcsine transformed) ¼ .73; standard deviation ¼ .49; a ¼ .05).…”

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder

“…Animal models support the notion that stress and trauma can alter GABA A -benzodiazepine binding density. 2,6,[36][37][38] In general, these animal models have shown decreased GABA A function and binding in the cerebral cortex and hippocampus. [3][4][5] This is the first benzodiazepine-GABA A receptor binding study in patients with PTSD that supports these preclinical data.…”

Epigenetic mechanisms and the transgenerational effects of maternal care

“…In addition to these HPA effects, offspring of low LG dams have a decreased density of benzodiazepine receptors in the amygdala compared to the offspring of High LG dams [36;38;39;40] and GABA subunit expression is altered by maternal LG with implications for …”

“…Interestingly, in these initial studies, a negative linear correlation was demonstrated between the levels of maternal LG received and adult plasma levels of corticosterone following restraint stress [36]. Behaviorally, these neuroendocrine changes result in decreased exploratory behavior and increased inhibition on tests such as the open-field and elevated plus maze [35].In addition to these HPA effects, offspring of low LG dams have a decreased density of benzodiazepine receptors in the amygdala compared to the offspring of High LG dams [36;38;39;40] and GABA subunit expression is altered by maternal LG with implications for …”