Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice.

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3-36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism.

In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats.

Anxiety may play an important role in the onset of smoking, particularly in young girls. This study examined whether there were sex differences in the effects of nicotine on anxiety in adolescent rats and whether social isolation modified these effects. Male and female adolescent rats were housed in groups of the same sex or in social isolation for seven days prior to testing in the social interaction test of anxiety. Nicotine increased social interaction in both males and females, and because there was no concomitant change in locomotor activity, this indicated anxiolytic effects. However, there was a 5-fold sex difference in the lowest dose required to enhance social interaction, with an anxiolytic effect in females at 0.05 mg/kg, but in males only at 0.25mg/kg. Furthermore, in males the anxiolytic effect was seen only in socially isolated animals, whereas in the females it was present in both housing conditions. The depressant effect of nicotine on locomotor activity also depended on both the sex of the animal and on their housing conditions, with greater effects in singly housed animals and in males. This sex difference in sensitivity to nicotine's anxiolytic effects suggests there may be sex differences in the factors initiating and maintaining teenage smoking.

Different treatment regimens and the development of tolerance to nicotine's anxiogenic effects.

The effects of different treatment regimens were investigated on the development of tolerance to the anxiogenic effect of nicotine (0.45 mg/kg) in the social interaction test of anxiety. Rats received nicotine (0.45 mg/kg/day) by intravenous injections (5 days/week), subcutaneous injections (5 or 7 days/week) or continuous infusion by osmotic minipump. In all groups, 4 days of nicotine treatment resulted in significant decreases in social interaction compared with the vehicle control groups, without changes in locomotor activity, indicating a specific anxiogenic effect. These significant anxiogenic effects persisted even after 4 weeks of treatment although they were less marked, indicating development of partial tolerance. No significant changes in the time spent in social interaction were found when rats were tested undrugged 24 and 72 h after the termination of nicotine treatment. There was no evidence that the treatment regimen affected the rate of development of tolerance, despite very different peak plasma nicotine concentrations.

The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses.

RATIONALE: Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking, and this may be one factor which contributes to nicotine dependence. OBJECTIVE: The aim of this study was to investigate the role of the dorsal raphé nucleus (DRN) in mediating the acute anxiolytic effect of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. METHODS: The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5-4000 ng) following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN nicotine (2.5-7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. RESULTS: Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5-10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100-1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 micrograms). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). CONCLUSIONS: The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic 5-HT1A autoreceptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and because there is an anxiogenic response 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.

Tolerance to midazolam's anxiolytic effects after short-term nicotine treatment.

In the social interaction test of anxiety, microinjections of midazolam (2-8 microg) into the dorsal hippocampus or dorsal raphé nucleus significantly increased the time spent in active social interaction, without changing locomotor activity, thus indicating specific anxiolytic effects. However, tolerance developed to these effects in rats that had been pre-treated for 6 days with (-)-nicotine (0.1 mg/kg/day; subcutaneous). Thus, cross-tolerance to the anxiolytic effects of midazolam develops rapidly following a short period of treatment with a low dose of nicotine, which contrasts with the more slowly developing tolerance (about 3 weeks) that develops after benzodiazepine treatment. Following 6 days of nicotine treatment there was a significant reduction in [(3)H]flunitrazepam binding at 2 and 10 nM in the hippocampus, but no change in the midbrain. The decrease in benzodiazepine binding could explain tolerance to the effects of midazolam when administered to the dorsal hippocampus, but other mechanisms, such as indirect effects on the serotonergic (5-HT) system, might be involved in tolerance to the effects of dorsal raphé nucleus administration.

Development of tolerance to nicotine's anxiogenic effect in the social interaction test.

The purpose of the present experiment was to explore the role of the dorsal hippocampus in mediating the development of tolerance to the anxiogenic effect of nicotine in the social interaction test of anxiety, and to determine whether tolerance develops to the effects of nicotine on [3H]-5-HT release in this area. Nicotine (1 microg) administered bilaterally into the dorsal hippocampus significantly reduced the time spent in social interaction in vehicle pre-treated rats, indicating an anxiogenic effect, but tolerance to this effect was seen in the rats pre-treated for 6 days with s.c. nicotine (0.1 mg/kg/day). In rats that had been pre-treated with vehicle for 6 days, nicotine (50-200 microM), significantly stimulated [3H]-5-HT release from dorsal hippocampal slices. This stimulation was significantly reduced in rats pre-treated with nicotine (0.1 mg/kg/day) for 6 days, indicating the development of tolerance to the effects of nicotine on 5-HT release. This suggests that tolerance to the anxiogenic effect of nicotine administered into the dorsal hippocampus could be mediated by a reduction in the nicotine enhancement of 5-HT release in this area.

Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats.

RATIONALE: Most smokers report smoking has an anxiolytic effect, which may contribute to nicotine dependence. OBJECTIVE: To examine effects in the social interaction test (SI) of anxiety after 4 weeks' self-administered nicotine (15 infusions of 0.03 mg/kg, totalling 0.45 mg/kg per day), and after 24 and 72 h of withdrawal. The effect of exposure to the operant chamber on withdrawal responses was also examined. METHODS: Animals were trained to self-administer saline or nicotine and after 4 weeks they were tested in SI after their daily self-administration session. Animals were retested after 24 and 72 h withdrawal, when they were either taken directly from the home cage or were tested 5 min after a 30-min exposure to the operant chamber. RESULTS: Compared with the saline control group, the animals that had been self-administering nicotine for 4 weeks showed decreased social interaction with no decrease in locomotor activity, indicating a significant anxiogenic effect of the nicotine infusions. There was no change in social interaction after 24 and 72 h withdrawal from chronic nicotine, regardless of whether or not the rats were exposed to the operant chamber just prior to being tested. CONCLUSIONS: Nicotine self-administration is not maintained because of its anxiolytic effect, but despite, or because of, its anxiogenic effect. There was no evidence of an anxiogenic response after either 24 or 72 h of withdrawal and thus increased anxiety on withdrawal from nicotine does not seem to contribute to nicotine self-administration.

Tolerance to nicotine's effects in the elevated plus-maze and increased anxiety during withdrawal.

In the elevated plus-maze test of anxiety, nicotine (0.1 mg/kg sc; 30 min after injection) had a significant anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open-arm entries. Tolerance developed to this anxiogenic effect after 7 days of nicotine treatment (0.1 mg/kg/day). Five minutes after an acute injection, nicotine (0.1 mg/kg) was ineffective, but after 7 days of treatment a significant anxiolytic effect, shown by specific increases in the percentage of time spent on the open arms and in the percentage of open-arm entries, emerged. After 14 days of nicotine treatment, tolerance developed to this anxiolytic effect. There was a complete dissociation between the effects of nicotine on the measures of anxiety, and on the locomotor activity as measured by closed-arm entries. No changes in closed-arm entries were found after acute administration of nicotine, but rats tested 30 min after their 7th injection made significantly fewer, and those tested 5 min after their 14th injection made significantly more, entries than their respective controls. Rats that were tested after 24 h withdrawal from six daily nicotine injections showed a significant anxiogenic effect. A low dose of nicotine (5 ng) injected into the dorsal hippocampus was without effect in vehicle pretreated rats, but it was able to reverse the anxiogenic effect found after 24 h of withdrawal from 6 days of nicotine treatment.

The effect of treatment regimen on the development of tolerance to the sedative and anxiolytic effects of diazepam.

RATIONALE: Chronic treatment with benzodiazepines results in tolerance to their sedative and anxiolytic effects and there is considerable evidence that different mechanisms underlie the development of tolerance to different behavioural effects. OBJECTIVE: The purpose of the present experiment was to compare the behavioural effects of chronic treatment with diazepam (15 mg/kg per day) given as daily subcutaneous injections or by osmotic minipump. Both regimens resulted in continual receptor occupancy, but the daily injections also provided a period of higher brain concentrations. METHODS: Rats were tested in the holeboard, which provides measures of exploration and locomotor activity, and in the elevated plus-maze and social interaction tests of anxiety. For those in the subcutaneous injection group the tests were 2 h after injection, when brain concentrations were highest. RESULTS: Despite a higher brain concentration in the injected group, both groups showed tolerance to diazepam's sedative effects, after 7 days of treatment. In contrast, in the elevated plus-maze, there was tolerance to the anxiolytic effects in the pump group after 14 days, but a persisting anxiolytic effect in the injected group at 14 and 28 days. Whilst higher brain concentrations could explain this result in the plus-maze, they cannot account for the pattern observed in the social interaction test, where the injection group showed a significant anxiogenic effect at 28 days. CONCLUSIONS: Whereas the mechanism underlying tolerance to the sedative effects of diazepam was insensitive to the different treatment regimens, the results suggest that different adaptive mechanisms were triggered in the two tests of anxiety with a differential sensitivity to the treatment regimen. The adaptive mechanism predominating in the social interaction test was favoured by the injection regimen which produced intermittent peak concentrations. This mechanism seems to be an oppositional one, leading to an anxiogenic response, which was manifest despite high brain concentrations of diazepam at the time of testing.

Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine.

The purpose of these experiments was to explore the hypothesis that the effects of nicotine on anxiety depend on the time since administration and the duration of treatment. In the social interaction test of anxiety, acute nicotine administration (0.1 mg/kg, subcutaneously) decreased social interaction when rats were tested 5 min after injection, but increased it when they were tested 30 min after injection. Social interaction was also decreased 1 h post-injection, but levels returned to baseline between 3 and 30 h. As these changes were independent of any changes in locomotor activity, nicotine seemed to be having both anxiogenic and anxiolytic effects at different times after injection. An anxiolytic effect was also observed 30 min after the second nicotine injection, and the anxiogenic effect observed 5 min after injection remained after 4 days of nicotine administration. However, after 7 days of nicotine treatment, tolerance was observed to both these effects. When rats were tested 72 h after the last of 7 or 14 days of nicotine treatment, an anxiogenic withdrawal response was observed. Thus, an oppositional mechanism may underlie tolerance to the anxiolytic effects, whereas there is as yet no evidence for this type of mechanism mediating tolerance to the anxiogenic effects.

Children in Kibbutzim: thirteen years after.

The social system of the kibbutz is briefly described, especially as it affects the young child. Attention is paid to the distribution of parental functions between mother, nurse and father, and the conceptual problems involved in the analysis of this situation. The aspirations of the kibbutz movement for the outcome of "collective education" and the misgivings of various Western commentators are confronted ith (a) clinical reports by two psychiatrists working with kibbutz children of the incidence and type of symptoms and psychopathology found in this population; (b) the findings of several comparative studies of children from the kibbutz and from villages with the family structure traditional in Western societies.