Review

Proto-oncogenes in the nervous system

Repeated exposure to anabolic/androgenic steroids (AAS) during adolescence stimulates high levels of offensive aggression in Syrian hamsters. The current study investigated whether adolescent AAS exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent AAS-treated hamsters and sesame oil-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, oil-treated controls, aggressive AAS-treated hamsters showed persistent increases in the number of FOS-ir cells in select aggression regions, namely the anterior hypothalamus and lateral septum. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the ventrolateral hypothalamus, bed nucleus of the stria terminals, central and/or medial amygdala or in non-aggression areas, such as the samatosensory cortex and the suprachiasmatic nucleus. These results suggest that adolescent AAS exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the anterior hypothalamus) may facilitate the development of the aggressive phenotype in adolescent-AAS exposed animals is presented.

We examined the effects of dexamethasone on the expression of the inducible transcription factor c-fos in 4-aminopyridine (4-AP) seizures. Induction of c-fos mRNA due to 4-AP-elicited convulsion was detected by means of the polymerase chain reaction (PCR) in samples from the neocortex. Adult male rats were pretreated with different doses of dexamethasone (0.5, 1, 3, 5 mg/kg body weight); 1 h later 5 mg/kg 4-AP was injected intraperitoneally. Controls received the solvent of dexamethasone. Pretreatment with dexamethasone provided significant symptomatic protection against 4-AP-induced convulsions. Immunohistochemistry was used to evaluate the presence of the c-fos protein. The number of Fos-immunoreactive nuclei per section area was measured in the neocortex and hippocampus. Pretreatment with dexamethasone resulted in a dose-dependent, significant decrease of seizure-induced Fos-protein immunoreactivity in the neocortex, in the hilum of the dentate fascia, as well as in regions CA1-3 of the hippocampus, compared to control animals. Brains processed for mRNA isolation and PCR, displayed a significant increase of c-fos mRNA following the 4-AP treatment, while pretreatment with dexamethasone did not prevent or decrease this boosted c-fos mRNA expression. We conclude that seizure-induced c-fos expression and intracellular Fos-protein localization are mediated by transmitter and receptor systems, and dexamethasone significantly decreases Fos immunoreactivity, probably by regulating the intracellular traffic of the protein. We also conclude that dexamethasone does not interfere with the genomic regulation of c-fos mRNA synthesis.

Galanin and the N-terminal fragment Galanin(1–15) are involved in central cardiovascular regulation. The present paper reviews the recent cardiovascular results obtained by intracisternal injections of Galanin and Galanin(1–15) showing that: (A) the Galanin antagonist M40 blocks the central cardiovascular responses induced by Galanin(1–15) but not those elicited by Galanin; (B) both Galanin and Galanin(1–15) induce the expression of c-Fos in cardiovascular nuclei of the medulla oblongata with different temporal and spatial profiles; (C) the cardiovascular action of Galanin(1–15), but not Galanin, is mediated by peripheral β-receptor stimulation; (D) and it is demonstrated an antagonistic Galanin/α2-adrenoceptors interaction as well as a differential modulation of central cardiovascular responses of Angiotensin II by Galanin or Galanin(1–15). All these data strengthen the involvement of both Galanin molecules as neuromodulators on central cardiovascular regulation.

Hamsters repeatedly exposed to cocaine throughout adolescence display highly escalated offensive aggression compared to saline-treated littermates. The current study investigated whether adolescent cocaine exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent cocaine-treated hamsters and saline-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, saline-treated controls, aggressive cocaine-treated hamsters showed persistent increases in the number of FOS-ir cells in several aggression regions, including the anterior hypothalamus, nucleus circularis, lateral hypothalamus (i.e., the hypothalamic attack area), lateral septum, and medial and corticomedial amygdaloid nuclei. Conversely, aggressive cocaine-treated hamsters showed a significant decrease in FOS-ir cells in the medial supraoptic nucleus, bed nucleus of the stria terminalis, and central amygdala when compared with controls. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the paraventricular hypothalamic nucleus, or in a number of non-aggression areas. These results suggest that adolescent cocaine exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the hypothalamus) may facilitate the development of the aggressive phenotype in adolescent cocaine-exposed animals is presented.

The purpose of this study was to describe the pain experience of children with sickle cell disease who were hospitalized for vaso-occlusive painful episodes. The pain experience, and signs and symptoms prior to admission and during hospitalization, are presented in the context of whether there is evidence to support the existence of phases to a vaso-occlusive painful episode. Children were interviewed about the onset of the painful episode and were asked to describe their pain from the day of admission to the day of discharge from the hospital. They were also observed for the absence or presence of signs and symptoms associated with the painful vaso-occlusive episode. Findings from this study provide some evidence to support previous observations related to changes during the evolution of painful episodes that may be occurring in phases (e.g., evolving, inflammatory, resolving), as previously described in adults and children. These phases had different names, although the concepts were similar.

We investigated the causative role of testosterone in copulatory disorder and the expression of c-fos messenger (m)RNA in the medial preoptic area in rats after social stress.

To generate copulatory disorder rats in the experimental defeated group were attacked by residents for 10 minutes daily for 7 consecutive days (social stress). We then investigated the effect of repeat defeat on the frequency of mounting behavior and plasma testosterone levels. The effects of testosterone replacement and/or apomorphine (100 μg./kg. subcutaneously), a dopamine receptor agonist, on the frequency of mounting behavior were also studied. After experiencing social stress the brain area within the medial preoptic area was removed for analysis of c-fos and androgen receptor mRNA expression. Real-time reverse transcription-polymerase chain reaction was done to analyze gene expression.

Rats in the defeated group showed a reduced frequency of mounting behavior and a decrease in plasma testosterone levels compared with values in control rats (p <0.01). After testosterone replacement the frequency of mounting behavior became significantly higher than that of socially stressed rat (p <0.05) but did not achieve control levels. The frequency of mounting behavior by socially stressed rats after apomorphine treatment was significantly higher than that of vehicle treated rats (p <0.05) but the frequency produced by the combination of testosterone replacement and apomorphine injection did not achieve control levels. After the social stress experience c-fos mRNA expression was significantly increased compared with that in control rats (p <0.05). The expression of androgen receptor mRNA was not affected by social stress. Testosterone replacement significantly reduced the expression of c-fos mRNA in the medial preoptic area (p <0.05).

Our results indicate that a reduction in plasma testosterone may have a causative role in copulatory disorder induced by social stress. Changes in c-fos mRNA expression in the medial preoptic area correlated with copulatory disorder and, thus, they are suitable for monitoring that disorder.