Elaine E Irvine

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.

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 0.05mg/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 nicotines anxiolytic effects suggests there may be sex differences in the factors initiating and maintaining teenage smoking.

Social isolation modifies nicotine's effects in animal tests of anxiety

These experiments determined whether the housing conditions of rats influenced the effects of nicotine in two animal tests of anxiety, social interaction and elevated plus‐maze tests. In animals housed singly for 7 days, (−)nicotine (0.025 mg kg−1 s.c.) was ineffective, but 0.05, 0.1 and 0.25 mg kg−1 (s.c.) significantly increased the time spent in social interaction, without changing locomotor activity, thus indicating anxiolytic actions. (−)Nicotine (0.45 mg kg−1 s.c.) significantly reduced social interaction, indicating an anxiogenic effect. However, in group‐housed animals, (−)nicotine (0.025 mg kg−1 s.c.) had a significant anxiolytic effect in the social interaction test, but 0.01, 0.05, 0.1, 0.25 and 0.45 mg kg−1 were ineffective. (−)Nicotine (1 mg kg−1) reduced motor activity and social interaction in the group‐housed animals. In the elevated plus‐maze, the time‐course and the dose‐response curve to nicotine were investigated. In both singly‐ and group‐housed rats, (−) nicotine (0.1 – 0.45 mg kg−1 s.c.) decreased the per cent entries into, and per cent time spent on, the open arms, indicating anxiogenic effects. The housing condition influenced the time course, with significant effects at 5 and 30 min after injection in group‐housed rats, and significant effects at 30 and 60 min in singly‐housed rats. In the social interaction test there was no difference in the scores of the first and last rats removed from group cages, whereas the order of removal from the cages did affect the scores in the elevated plus‐maze. These results provide further evidence that the two animal tests model distinct states of anxiety, and show how social isolation powerfully modifies both anxiolytic and anxiogenic effects of nicotine.

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

Abstract 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.

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.

Mood differences between male and female light smokers and nonsmokers

In an open study, we determined whether there were sex differences in the mood ratings of non-deprived light smokers and nonsmokers under baseline conditions and after completing a battery of cognitive tests that were mildly stressful. Male and female students who were light smokers (5-12 cigarettes a day) were tested immediately after smoking their usual cigarette, at a time that they normally smoked. They were compared with a group of male and female students who were nonsmokers and did not differ on age, IQ, personality measures, anxiety or depression. Compared with the nonsmokers, both male and female smokers felt overall significantly more discontented, troubled, tense, quarrelsome, furious, impatient, hostile, annoyed and disgusted and experienced greater dizziness. The performance of distracting cognitive tasks did not reveal anxiolytic effects of smoking, and after performance of these tasks, both smokers and nonsmokers became more discontented and anxious. In addition, after the cognitive testing, both male and female smokers showed greater increases than nonsmokers in feeling spiteful, rebellious, incompetent and in sweating, suggesting that they experienced greater mood changes in response to cognitive stress. There were no overall differences between the smokers and nonsmokers in the performance of divided or sustained attention tasks or in episodic memory. It is unlikely that either nicotine withdrawal or differences in cognitive performance could account for the greater anxiety, discontent and aggressive mood that was found in smokers.

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.

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.