Effects of nicotine and a cannabinoid receptor agonist on negative contrast: distinction between anxiety and disappointment?

RATIONALE: Animals trained to lick for a sucrose solution of a given incentive value that subsequently encounter an incentive downshift (i.e. 32-4% sucrose) display an exaggerated decrease in the amount consumed, relative to unshifted controls. This change has been classified as a successive negative contrast (SNC) effect. The emotional component to this robust behavioural change is dynamic and changes from post-shift day (PSD) 1 to 2. Anxiolytics block SNC, but the possible link between anxiety and SNC needs further exploration. Both nicotine and a cannabinoid receptor agonist have been reported to change anxiety and both have actions on the reward process, but their effects on SNC have not been investigated. OBJECTIVES: To determine: (1) whether exposure to SNC evokes an anxiogenic response; (2) whether an anxiolytic dose of nicotine has the same effects on SNC as those of chlordiazepoxide; (3) the effects of a low (anxiolytic) and a high (anxiogenic) dose of the cannabinoid receptor agonist CP 55,940 on SNC. METHODS: Two groups of animals were given access to high (32%) or low (4%) sucrose solutions for 5 min per day for 10 days. On PSD 1 and 2, the shifted group had access to a devalued incentive (from 32 to 4% sucrose) and the unshifted group remained at 4% sucrose. The volumes (ml) of sucrose solution consumed were measured pre-shift and on PSD 1 and 2. In experiment 1, immediately after SNC testing on PSD 1 and 2, the rats were tested in the social interaction and elevated plus-maze tests of anxiety. In experiment 2, the effects of chlordiazepoxide (5 and 7.5 mg/kg) and nicotine (0.1 mg/kg) were examined on PSD 1 and 2. In experiment 3, the effects of CP 55,940 (5 and 40 microg/kg) were examined on PSD 1 and 2. RESULTS: There were no anxiogenic effects of shift in either test of anxiety on either test day. However, on PSD 1, the shifted group had significantly higher locomotor activity and spent a higher percentage of time on the open arms, perhaps reflecting search strategies. Nicotine was without significant effect on SNC on either test day. On PSD 1, chlordiazepoxide (5 mg/kg) and CP 55,940 (5 and 40 microg/kg, IP) blocked SNC. On PSD 2, both doses of chlordiazepoxide and the low, anxiolytic dose of CP 55,940 (5 microg/kg) blocked SNC, the high dose of CP 55,940 was without effect. CONCLUSIONS: The pattern of results allows for the separation between effects on anxiety and SNC. The block of contrast on PSD 1 was independent of changes in anxiety, since both anxiolytic and anxiogenic drug doses were effective. It is suggested that this may provide an animal model of disappointment in which the cannabinoid system plays an important role. An anxiolytic action would seem to be a necessary, but not a sufficient, action to block SNC on PSD 2.

Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats.

We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 microg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist.

Gincosan (a combination of Ginkgo biloba and Panax ginseng): the effects on mood and cognition of 6 and 12 weeks' treatment in post-menopausal women.

As memory and concentration impairments are a frequent complaint in post-menopausal women, this well-defined population was selected to investigate the effect on mood and cognition of chronic treatment with Gincosan. In a double-blind placebo controlled study, post-menopausal women aged 51-66 were randomly assigned to 12 weeks' treatment with Gincosan (320mg/day), containing 120mg Ginkgo biloba, and 200mg Panax ginseng (n = 30), or matched placebo (n = 27). They were given measurements of mood, somatic anxiety, sleepiness, and menopausal symptoms and a battery of cognitive tests before treatment and after 6 and 12 weeks of treatment. There were no significant effects of Gincosan treatment on ratings of mood, bodily symptoms of somatic anxiety, menopausal symptoms, or sleepiness or on any of the cognitive measures of attention, memory or frontal lobe function. Thus, after chronic administration, Gincosan appeared to have no beneficial effects in post-menopausal women.

Oestrogen receptor-beta and neurohypophysial hormones: functional interaction and neuroanatomical localisation.

Oestrogens affect fluid balance, influencing both ingestive behaviour and renal excretion. The renal effects are partly due to altered release of vasopressin and oxytocin. This study was designed to explore the role of oestrogen receptor-beta (ERbeta) in neurohypophysial hormonal function. Following dietary administration, soya isoflavones reach the brain in sufficient concentration to activate ERbeta, but not oestrogen receptor-alpha (ERalpha). ERbeta function was therefore manipulated by feeding rat diets differing in soya isoflavone content. Fluid balance and neurohypophysial hormone release were measured in male rats maintained for 14 days on a soya isoflavone-free diet or one containing 150 microg/g genistein+daidzein. Food and water intake, body weight, urine flow, osmolality and sodium concentrations were determined daily. After 14 days, plasma and urine osmolality and sodium, vasopressin and oxytocin concentrations were determined. There was no significant difference in weight gain between the two groups or in their excretion of sodium and water or plasma sodium and plasma oxytocin. However, plasma vasopressin was significantly lower in the iso-free group. Double-label immunocytochemistry was used to assess colocalisation of ERbeta with the neurohypophysial hormones in male rats. Cell nuclei showing ERbeta immunoreactivity were abundant in the posterior magnocellular paraventricular nucleus (PVNpm) and in the supraoptic nucleus (SON). Vasopressin-immunoreactive neurones were similarly distributed, forming the core of the PVNpm and the ventral portion of the SON; majority were positive for ERbeta. Cells with oxytocin immunoreactivity were located mainly at the periphery of the PVNpm and in the dorsal SON; only approximately a quarter of these cells showed ERbeta immunoreactivity. Thus, the difference in the effects of the soya diet on vasopressin and oxytocin release may be related to the ERbeta-activating properties of this diet and to the preponderance of this receptor in vasopressin as opposed to oxytocin cells.

Do different mechanisms underlie two anxiogenic effects of systemic nicotine?

Alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and 5-hydroxytryptamine 1A (5-HT1A) receptors have been implicated in the anxiogenic effects of centrally administered nicotine, but the receptors that mediate the anxiogenic effects of systemic nicotine are not known. This study explored whether competitive nAChR antagonists [dihydro-beta-erythroidine (DHbetaE), 4 mg/kg, and methyllycaconitine (MLA), 5 mg/kg], and a 5-HT1A receptor antagonist (WAY 100635, 0.5 and 1 mg/kg) could block the effects of two anxiogenic doses of nicotine in the social interaction test of anxiety. The anxiogenic effect of 0.1 mg/kg nicotine, given 5 min before the test, was blocked by DHbetaE and WAY 100635, establishing roles for alpha4beta2 nAChRs and 5-HT1A receptors. None of the antagonists could block the effect of 0.45 mg/kg nicotine, given 30 min before the test, precluding firm conclusions about the mechanisms underlying this anxiogenic effect. However, there was evidence for a role of alpha7 nAChRs in mediating an endogenous anxiogenic tone, since MLA itself had an anxiolytic effect that was blocked by both doses of nicotine. Thus, both alpha7 and alpha4beta2 nAChRs might have a role in mediating the anxiogenic effects of nicotine.

Methyllycaconitine (MLA) blocks the nicotine evoked anxiogenic effect and 5-HT release in the dorsal hippocampus: possible role of alpha7 receptors.

Nicotine has bimodal effects on anxiety, with low doses having an anxiolytic effect and high doses having an anxiogenic effect. The dorsal hippocampus is one of the brain areas that mediate the anxiogenic effect of nicotine through enhanced 5-HT release, but the nAChR subtype(s) that mediate these effects are not known. Intrahippocampal administration of a high dose of nicotine (1 micro g, 4.3 mM) had an anxiogenic effect in the social interaction test that was reversed by co-administration of a behaviourally inactive dose (1.9 ng, 4.3 micro M) of methyllycaconitine (MLA), which is an antagonist at alpha7 and alpha3 nAChR subunits. At a dose (0.8 ng, 4.3 micro ;M) at which its actions would be specific to alpha4beta2 and alpha3beta2 nAChRs dihydro-beta-erythroidine (DHbetaE) was unable to reverse nicotine's anxiogenic effect. Reversal was obtained with a 10-fold higher, but receptor non-specific concentration of DHbetaE (7.8ng, 43 micro M), suggesting that the DHbetaE reversal might have been due to action at alpha7 nAChRs. Exposure of hippocampal slices to MLA (0.25, 05, 1 and 10 micro M) significantly reduced the increase in [(3)H]5-HT release evoked by nicotine (100 micro M). DHbetaE (0.1-0.5 micro M) failed to reverse this effect of nicotine on [(3)H]5-HT release, although higher concentrations (1 and 10 micro M), at which alpha7 subunits would also be affected, were able to do so. Because of the lack of effects of low, receptor specific concentrations of DHbetaE, it is more likely that the MLA reversal of both nicotine's anxiogenic effect and its stimulation of [(3)H]5-HT release is due to action at alpha7 than at alpha3 units. This is perhaps also more likely because the alpha7 receptors are highly expressed in the dorsal hippocampus, whereas the alpha3 subunits are much less abundant. However, what is most important is that, in the dorsal hippocampus, nicotine's anxiogenic effect and induced release of [(3)H]5-HT are mediated by non alpha4beta2 nAChRs, which contrasts with the previously reported anxiolytic effect of a low dose of nicotine which is mediated by alpha4beta2 nAChRs within the dorsal raphé nucleus. Thus the anxiolytic and anxiogenic effects of nicotine can be distinguished both by brain region and by nicotinic receptor subtype.

Anxiety conditioned to nicotine in the elevated plus-maze is time dependent.

Conditioning to the anxiogenic effects of nicotine has previously been demonstrated in the social interaction test and there was no generalization of conditioning between the social interaction and elevated plus-maze tests. Because the two tests generate distinct states of anxiety, the conditioning could have occurred to the cues associated with the test environment and/or to those associated with the type of anxiety generated by the test. The elevated plus-maze permits separation of these two factors, because quite distinct states of anxiety are generated on trials 1 and 2, whereas the apparatus cues remain the same. Rats that had been tested on day 1 in the plus-maze, 5 min after nicotine (0.45 mg/kg), showed a conditioned anxiogenic response when tested undrugged on day 2. This was shown by significantly lower percentages of open-arm entries and percentage of time spent on the open arms, compared with control groups. Thus, conditioning to apparatus cues is sufficient to mediate a conditioned anxiogenic effect. The importance of the timing of the nicotine-associated cues was demonstrated by the failure to obtain conditioned anxiogenic effects when rats were exposed to the plus-maze on day 1, 30 min after nicotine (0.45 or 0.1 mg/kg).

Eating soya improves human memory.

RATIONALE: Soya foods are rich in isoflavone phytoestrogens with weak agonist activity at oestrogen receptors. Oestrogen treatment has been found to improve memory in men awaiting gender reassignment and in post-menopausal women. OBJECTIVE: To examine the effects of supervised high versus low soya diets on attention, memory and frontal lobe function in young healthy adults of both sexes. METHODS: Student volunteers were randomly allocated to receive, under supervision, a high soya (100 mg total isoflavones/day) or a low soya (0.5 mg total isoflavones/day) diet for 10 weeks. They received a battery of cognitive tests at baseline and then after 10 weeks of diet. RESULTS: Those receiving the high soya diet showed significant improvements in short-term (immediate recall of prose and 4-s delayed matching to sample of patterns) and long-term memory (picture recall after 20 min) and in mental flexibility (rule shifting and reversal). These improvements were found in males and females. In a letter fluency test and in a test of planning (Stockings of Cambridge), the high soya diet improved performance only in females. There was no effect of diet on tests of attention or in a category generation task. Those on the high soya diet rated themselves as more restrained and, after the tests of memory and attention, they became less tense than did those on the control diet. CONCLUSIONS: Significant cognitive improvements can arise from a relatively brief dietary intervention, and the improvements from a high soya diet are not restricted to women or to verbal tasks.

Factors controlling measures of anxiety and responses to novelty in the mouse.

This review focuses on factors influencing behaviour in the elevated plus-maze, the holeboard and the social transmission of food preference. The elevated plus-maze provides independent measures of anxiety (percentage of time spent on open arms) and activity (number of closed arm entries) and can be used in both males and females. Important sex differences emerge in factor loadings, and, whereas in males, anxiety is the primary factor, in females it is activity. On trial 2 in the plus-maze, the nature of the anxiety state is changed and thus this maze can be used to screen for possible genetic alterations in two distinct anxiety states. The holeboard provides independent measures of exploration and locomotor activity and habituation between sessions provides a useful measure of learning. Mice display neophobia and avoid novel foods, but information about their safety can be socially transmitted. A mouse that has sampled a novel food will be actively sniffed by others on its return to the colony. It is important to control for possible changes in social investigation, neophobia, olfactory sensitivity, anxiety and exploration, before it is concluded that a changed performance in this task is due to changes in learning.

Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils.

The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.

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.

Nicotine regulates 5-HT(1A) receptor gene expression in the cerebral cortex and dorsal hippocampus.

The 5-HT(1A) receptor has previously been shown to be important in mediating the behavioural effects of nicotine. It is possible that nicotine administration might regulate the levels of 5-HT receptors in limbic and cortical regions, and such regulations may underlie adaptive responses to nicotine in the central nervous system. The effects of acute and chronic systemic (--)-nicotine administration on 5-HT(1A) receptor gene expression were measured by in situ hybridization, in the rat cerebral cortex, dorsal hippocampus and lateral septum. In the cortex, acute nicotine (0.5 mg/kg i.p.) significantly increased the expression of 5-HT(1A) receptor mRNA 2 h and 24 h after injection. Similarly, acute nicotine significantly increased 5-HT(1A) receptor mRNA in the dentate gyrus (DG), CA3 and CA1 regions of the dorsal hippocampus 2 h and 24 h after injection. Acute nicotine was without effect in the lateral septum. Chronic nicotine (0.5 mg/kg i.p; twice daily for 7 days) significantly decreased 5-HT(1A) receptor mRNA in the cortex 2 h after the final injection, but was without effect at 24 h or 72 h. Chronic nicotine caused no changes in 5-HT(1A) mRNA in the lateral septum or dorsal hippocampus. These data demonstrate that nicotine regulates 5-HT(1A) receptor gene expression in the cortex and hippocampus. The rapid regulation of expression of 5-HT(1A) receptor mRNA leads to the hypothesis that nicotine-induced 5-HT release may alter the postsynaptic sensitivity to 5-HT.

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.

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.

Are lorazepam-induced deficits in attention similar to those resulting from aging?

The purpose of this experiment was to compare, in three tasks of attention, the impairment caused by lorazepam (1 and 2.5 mg) administered to young volunteers with the impairment that results from aging. Performance on digit cancellation (DC), digit-symbol substitution (DSS), and Paced Auditory Serial Addition Task (PASAT) was significantly impaired by lorazepam (2.5 mg) and was significantly worse in the middle-aged group (mean +/- SEM, aged 58.9+/-0.8 years) compared with the younger, IQ-matched group (20.7+/-0.2 years). However, there were interesting differences in the extent of impairments among the three tests. In the DC test, lorazepam (2.5 mg) produced a significantly greater impairment than was seen in either the middle-aged men or middle-aged women. However, in the DSS test, the middle-aged women were significantly more impaired than either the middle-aged men or the young volunteers tested after lorazepam (2.5 mg). In the PASAT, both the lorazepam (2.5 mg) group and the middle-aged women were more impaired than the middle-aged men. These results raise the important possibility of gender differences in age-related decline of attentional processes.

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.

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.

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

1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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.