Synthesis, σ1, σ2-receptors binding affinity and antiproliferative action of new C1-substituted adamantanes.

The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ(1), σ(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain.

Neonatal handling on the first postnatal day leads to increased maternal behavior and fos levels in the brain of the newborn rat.

In the present work we employed Fos expression, an index of neuronal activity, to identify brain areas activated by a single exposure to "neonatal handling" on postnatal Day 1. Eight hours following "handling" there was an increase in the number of Fos positive cells in the hippocampus, the parietal and occipital cortex. We also recorded maternal behavior during the 8 hr following "handling." "Handled" pups received increased maternal licking during the 4 hr following the end of "handling." Furthermore, the number of Fos positive cells detected in each of the three brain areas 8 hr following "handling" was positively correlated with the amount of licking up to 8 hr following "handling." These results indicate that the increased maternal care could underlie the handling-induced increase in Fos. The Fos protein, acting as a transcription factor, controls the expression of downstream genes, whose products may mediate the effects of "neonatal handling" on the developing rat brain.

Cellular mechanisms underlying the effects of an early experience on cognitive abilities and affective states.

In the present study we investigated the effects of neonatal handling, an animal model of early experience, on spatial learning and memory, on hippocampal glucocorticoid (GR), mineralocorticoid (MR) and type 1A serotonin (5-HT1A) receptors, as well as brain derived neurotrophic factor (BDNF), and on circulating leptin levels, of male rats. METHOD: Spatial learning and memory following an acute restraint stress (30 min) were assessed in the Morris water maze. Hippocampal GR, MR and BDNF levels were determined immunocytochemically. 5-HT1A receptors were quantified by in vitro binding autoradiography. Circulating leptin levels, following a chronic forced swimming stress, were measured by radioimmunoassay (RIA). Data were statistically analyzed by analysis of variance (ANOVA). RESULTS: Neonatal handling increased the ability of male rats for spatial learning and memory. It also resulted in increased GR/MR ratio, BDNF and 5-HT1A receptor levels in the hippocampus. Furthermore, leptin levels, body weight and food consumption during chronic forced swimming stress were reduced as a result of handling. CONCLUSION: Neonatal handling is shown to have a beneficial effect in the males, improving their cognitive abilities. This effect on behavior could be mediated by the handling-induced increase in hippocampal GR/MR ratio and BDNF levels. The handling-induced changes in BDNF and 5-HT1A receptors could underlie the previously documented effect of handling in preventing "depression". Furthermore, handling is shown to prevent other maladaptive states such as stress-induced hyperphagia, obesity and resistance to leptin.

Rat dams exposed repeatedly to a daily brief separation from the pups exhibit increased maternal behavior, decreased anxiety and altered levels of receptors for estrogens (ERα, ERß), oxytocin and serotonin (5-HT1A) in their brain.

In the present study we investigated the neurobiological mechanisms underlying expression of maternal behavior. Increased maternal behavior was experimentally induced by a brief 15-min separation between the mother and the pups during postnatal days 1 to 22. On postnatal days (PND) 12 and 22, we determined in experimental and control dams levels of anxiety in the elevated plus maze (EPM) as well as the levels of receptors for estrogens (ERα, ERß), oxytocin (OTR) and serotonin (5-HT1AR) in areas of the limbic system (prefrontal cortex-PFC, hippocampus, lateral septum-SL, medial preoptic area-MPOA, shell of nucleus accumbens-nAc-Sh, central-CeA and basolateral-BLA amygdala), involved in the regulation of maternal behavior. Experimental dams, which showed increased maternal behavior towards their offspring, displayed reduced anxiety in the EPM on both PND12 and PND22. These behavioral differences could be attributed to neurochemical alterations in their brain: On both PND12 and PND22, experimental mothers had higher levels of ERα and OTRs in the PFC, hippocampus, CeA, SL, MPOA and nAc-Sh. The experimental manipulation-induced increase in ERß levels was less widespread, being localized in PFC, the hippocampal CA2 area, MPOA and nAc-Sh. In addition, 5-HT1ARs were reduced in the PFC, hippocampus, CeA, MPOA and nAc-Sh of the experimental mothers. Our results show that the experience of the daily repeated brief separation from the pups results in increased brain ERs and OTRs, as well as decreased 5-HT1ARs in the dam's brain; these neurochemical changes could underlie the observed increase in maternal behavior and the reduction of anxiety.

New adamantane phenylalkylamines with σ-receptor binding affinity and anticancer activity, associated with putative antagonism of neuropathic pain.

The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.

New adamantane derivatives with sigma affinity and antiproliferative activity.

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.

Neonatal handling and gender modulate brain monoamines and plasma corticosterone levels following repeated stressors in adulthood.

Neonatal handling affects the response to repeated stress in a sexually dimorphic manner. In order to elucidate the mechanisms underlying these gender-dependent effects, we investigated the consequences of neonatal androgenization and handling on adult stress reactivity by determining: (a) immobility time during repeated forced swimming, (b) plasma corticosterone levels, and (c) brain serotonin and dopamine levels and turnover after either repeated forced swimming, or repeated forced swimming followed by repeated restraint stress. In neonatally androgenized females, immobility time was lower in the handled than in the non-handled rats, a pattern resembling that of the males, suggesting that the sexually dimorphic effect of handling on immobility time can be attributed to the organizational effects of testosterone. No differences were found between androgenized females and females injected neonatally with vehicle, indicating that the gender differences in circulating corticosterone are not due to the organizational effects of testosterone. The stress of a neonatal injection interacted with neonatal handling resulting in lower plasma corticosterone and hypothalamic dopamine and serotonin levels in the neonatally injected handled animals following repeated forced swimming. The serotonergic system appears to be sensitive to both the organizational actions of testosterone and the effects of handling, since handled androgenized females had higher serotonin levels and decreased turnover following repeated forced swimming stress, compared to those injected neonatally with vehicle. Handling resulted in increased hypothalamic and striatal serotonin levels in both males and females following repeated forced swimming. Our results reveal that handling has gender-dependent effects on adult hypothalamic-pituitary-adrenal axis and brain monoaminergic system reactivity to stress and that these effects can be attributed to both the organizational and activational effects of gonadal hormones.

Effect of neonatal handling and sex on basal and chronic stress-induced corticosterone and leptin secretion.

Neonatal handling is an experimental paradigm for early experiences. It affects the programming of hypothalamo-pituitary-adrenal (HPA) axis function, known to be sexually dimorphic. Recently leptin, a hormone related to energy balance and secreted mainly by adipocytes, has been implicated in the stress response. We thus determined the effect of neonatal handling on plasma concentrations of corticosterone and leptin of male and female rats under basal conditions and after two consecutive chronic stressors: chronic forced swimming stress and chronic restraint. Handling resulted in lower basal corticosterone levels in both males and females and in a more efficient HPA response, with a large corticosterone surge following the first chronic stressor and a return to basal levels following the second. Handling also resulted in decreased plasma leptin concentrations in males, thus abolishing the sex difference in leptin levels. Furthermore, handling increased body weight while it decreased food intake under basal conditions. Food intake and body weight gain during chronic forced swimming was lower in handled than in non-handled males, while in females these parameters were not influenced by handling. In both males and females, handling resulted in decreased food intake and increased body weight loss during chronic restraint stress. Body weight loss during chronic restraint stress, which is considered an index of maladaptation and 'depression', was particularly pronounced in the handled females. Our results also showed that non-handled females had higher corticosterone and lower leptin levels than males under basal conditions and following each of the two chronic stressors. The present work suggests that early experiences, such as the mother-infant relationship, interact with endogenous factors, such as gonadal hormones, to determine the organism's response to stressful stimuli during adulthood.