Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 37 records · Page 2Linked to original sources

PubMed2001

Nicotine has calming effects on stress-induced mood changes in females, but enhances aggressive mood in males.

In a double-blind, placebo-controlled study, we examined the effects of nicotine (2 mg administered by inhalator) on the cognitive performance of male and female non-smoking students and on mood changes following a moderately stressful task. The groups were matched for age and IQ, and did not differ in pre-test measures of anxiety, depression, extroversion and neuroticism or in their weekly alcohol or daily caffeine intake. Nicotine did not change performance in tests of attention and memory. Exposure to moderate stress significantly increased ratings of anxiety, discontent and aggression and nicotine blocked these mood changes in females, but enhanced them in males. This suggests that young women may start regular smoking as a form of stress self-medication, which implies that preventative and smoking cessation programmes would be more successful in women if they addressed issues of stress and anxiety, which may be core factors underlying initiation and maintenance of regular smoking.

Adult↗

PubMed2001

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.

Animals↗

PubMed2001

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.

Animals↗

PubMed2001

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.

Adult↗

PubMed2000

Acute nicotine decreases, and chronic nicotine increases the expression of brain-derived neurotrophic factor mRNA in rat hippocampus.

Acute nicotine administration (0.5 mg/kg i.p.) significantly decreased BDNF mRNA levels in dentate gyrus, CA3 and CA1 subfields of the rat hippocampus 2 h and 24 h after administration. However, with 7 days nicotine treatment, tolerance developed to the inhibitory effect of nicotine on BDNF mRNA expression and there was a significant increase in BDNF expression 2 h after the final injection in the CA1 region. These data suggests that changes in expression of hippocampal BDNF may be involved in the behavioural effects of nicotine observed after acute and chronic treatment.

Acetylcholine↗

PubMed2000

Neurobiological mechanisms by which nicotine mediates different types of anxiety.

The effects of nicotine administration into the dorsal hippocampus and lateral septum provide further evidence that different neurochemical and neuroanatomical substrates control behaviour in different animal tests. Thus, in the social interaction test (a model of generalised anxiety disorder), bilateral administration of nicotine (1-4 microg) into both regions has anxiogenic effects in test conditions that generate moderate anxiety. The anxiogenic effects are mediated by a nicotine-evoked increase in 5-hydroxytryptamine (5-HT) release and are reversed by co-administration of the 5-HT(1A) receptor antagonist, N-(2-(6-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohex -ane carboxamide trichloride (WAY 100,635). On trial 1 in the elevated plus-maze (which models the escape components of panic disorder), nicotine is without effect when administered to the dorsal hippocampus, but has anxiogenic effects after lateral septal administration. On trial 2 in the elevated plus-maze (a model of specific phobia), nicotine (1 microg) has anxiolytic effects when administered to the dorsal hippocampus, but is ineffective (4 and 8 microg) in the lateral septum.

Animals↗

PubMed2000

Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food.

BACKGROUND: Thy-1 is a major cell-surface glycoprotein of mature neurons and certain other cells, including those of the lymphoreticular system. Despite being the simplest member of the immunoglobulin superfamily, the biological role of Thy-1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively, without any neurological or behavioural effects being apparent. RESULTS: We show here that Thy-1 null mice are unable to make the appropriate dietary choice in the test for social transmission of food preference, despite showing a normal level of social interaction with the demonstrator mouse, normal neophobia, and normal learning in a T-maze using scented food as cues. The mice also performed normally in tests of anxiety, locomotor activity, exploration of a novel environment, habituation to novelty and spatial learning. This phenotype is maintained on two different strain backgrounds, is rescued by transgenic expression of Thy-1 and by administration of the GABA(A) receptor antagonist pentylenetetrazole. CONCLUSIONS: The test for social transmission of food preference is based on the normal ability of mice in a colony to learn from each other which foods are safe to eat. The lack of this key survival behaviour in Thy-1 null mice could act as an evolutionary pressure point to conserve expression of Thy-1. Furthermore, the specific cognitive defect caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to determine the role of Thy-1 in certain human familial forms of mental retardation that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the nearby ataxia telangiectasia locus.

Animal Communication↗

PubMed2000

Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5-HT1A and not by muscarinic M1 receptors.

After direct administration into the dorsal hippocampus nicotine decreased the time spent in social interaction, without changing locomotor activity, indicating an anxiogenic effect. The possibility that post-synaptic M1 muscarinic receptors mediated this effect was examined by determining whether dorsal hippocampal administration of a specific M1 receptor agonist (McN-A-343) had anxiogenic effects, and whether the anxiogenic effect of nicotine could be reversed by co-administration of the M1 receptor antagonist, pirenzepine. McN-A-343 (0.3, 1.6, 3.2, 15.8 nmol) was without effect on social interaction, and pirenzepine (0.7 and 2.4 nmol) injection into the dorsal hippocampus failed to reverse the decrease in social interaction caused by nicotine (6.3 nmol) injection into this area. However, the decrease in social interaction after nicotine (50 nmol) was completely reversed by the specific 5-HT1A receptor antagonist, WAY 100635 (0.4 nmol) after co-administration of both drugs into the dorsal hippocampus. Thus, the anxiogenic effect of nicotine in this brain region seems to be mediated by 5-HT1A, but not M1, receptors. In contrast to the effect of nicotine in naive animals, those retested after a second injection of 50 nmol did not show a significant anxiogenic effect. The theoretical implications of this are discussed and from a practical point of view this suggests caution in the retesting of animals after central injections.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed2000

Is benzodiazepine-induced amnesia due to deactivation of the left prefrontal cortex?

UNLABELLED: The amnesic properties of benzodiazepines result from an impairment in explicit (conscious) acquisition of new material. RATIONALE: Explicit encoding of new material has consistently resulted in an increase in regional cerebral blood flow (rCBF) in the left prefrontal cortex, as measured by positron emission tomography (PET). OBJECTIVE: PET was used to determine whether an amnesic dose of midazolam (0.075 mg/kg) attenuated activation in this area during explicit memory encoding. METHODS: A second condition (condition A) used a task to control for the automatic processing that occurs during explicit learning (condition E). RESULTS: The subjects who received midazolam (n=7) recognised significantly fewer words than those who received placebo (n=8), but were not impaired with regard to automatic processing. rCBF was significantly increased in the left prefrontal cortex during explicit encoding of word lists in all subjects and in the temporal lobe and parieto-occipital regions during automatic processing. rCBF was significantly decreased in the prefrontal, superior temporal and parieto-occipital regions following midazolam. The midazolam-induced deactivation in the prefrontal cortex did not affect rCBF activations induced by the explicit memory condition (E-A). CONCLUSIONS: These results suggest that a specific interaction with prefrontal cortex activation does not underlie the amnesic effect of midazolam. However, it remains possible that a threshold level of prefrontal rCBF is necessary for encoding and that, after midazolam, this was not reached.

Adult↗

PubMed2000

NKP608, an NK1 receptor antagonist, has an anxiolytic action in the social interaction test in rats.

RATIONALE: Evidence is starting to accumulate that NK1 receptor antagonists might have anxiolytic effects in animal tests and in patients. OBJECTIVE: To examine the effects of NKP608, a substance P antagonist acting at NK1 receptors, in various conditions of the social interaction test of anxiety and to determine its effects after 3 and 6 weeks of treatment. METHODS: Rats were tested after vehicle, 0.01 or 0.1 mg/kg PO in three conditions of the social interaction test that varied in the level of anxiety generated. Thus pairs of rats were tested in an arena with which they were unfamiliar that was lit by high (HU) or low (LU) light and in the condition that generated the lowest level of anxiety, i.e. an arena with which they were familiar, lit by low light (LF). They were also tested after 3 and 6 weeks of treatment with 0.03 mg/kg and after 24 h withdrawal from these chronic treatments. RESULTS: NKP608 had significant anxiolytic effects at 0.01, 0.03 and 0.1 mg/kg PO in the HU and LU test conditions, but was without effect in the LF condition, except for an increased incidence of bite attacks at 0.1 mg/kg. The anxiolytic effect of 0.03 mg/kg remained after 3 weeks of chronic treatment and there was no anxiogenic effect after 24 h of drug withdrawal. Following 6 weeks of chronic treatment (0.03 mg/kg per day), tolerance had developed, but no anxiogenic withdrawal effect was seen 24 h after the last dose. CONCLUSIONS: These results provide further evidence that substance P may play a role in mediating states of anxiety and suggest that the selective NK1 receptor antagonist NKP608 may prove a useful anxiolytic compound.

Aggression↗

PubMed2000

The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety.

A review of the literature suggests that the dorsal hippocampal serotonergic system, and, in particular, the postsynaptic 5-HT(1A) receptor, mediates an anxiogenic response, whereas endogenous dorsal hippocampal cholinergic tone mediates an anxiolytic response. Accordingly, it has been shown that direct dorsal hippocampal administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, the nicotinic receptor antagonist, mecamylamine, and the M(1) muscarinic receptor antagonist, pirenzepine, all have anxiogenic effects in rats tested in the social interaction test. It is therefore surprising that nicotine also has an anxiogenic effect in this test following dorsal hippocampal administration. However, the anxiogenic effects of mecamylamine and nicotine in the dorsal hippocampus are blocked by coadministration of the 5-HT(1A) receptor antagonist, WAY 100635, suggesting that both of these compounds act by enhancing hippocampal serotonergic transmission, thereby stimulating postsynaptic 5-HT(1A) receptors. This conclusion is supported by the observation that both nicotine and mecamylamine stimulate basal [3H]-5-HT release from dorsal hippocampal slices. A possible mechanism by which nicotinic receptor ligands modulate hippocampal 5-HT release is discussed, and it is proposed that the dorsal hippocampal serotonergic and cholinergic systems are tightly coupled and function antagonistically in the modulation of anxiety, as measured in the social interaction test. These systems are relatively unimportant in controlling behaviour on trial 1 in the plus-maze. On trial 2 in the elevated plus-maze, a model of specific phobia, the endogenous cholinergic system, nicotine, and the M(1) receptor agonist, McN-A-343, all mediate an anxiolytic effect, whereas stimulation of 5-HT(1A) receptors mediates an anxiogenic effect. It is proposed that the hippocampus may predominantly control the avoidance components of phobic anxiety, with other regions, such as the dorsomedial hypothalamus, controlling the escape components.

Acetylcholine↗

PubMed2000

Kindling induced by pentylenetetrazole in rats is not directly associated with changes in the expression of NMDA or benzodiazepine receptors.

Repeated injections of a subconvulsant dose of pentylenetetrazole (PTZ, 30 mg/kg IP three times weekly for 13 injections) in Wistar and hooded Lister rats resulted in kindled seizures, the extent of which varied between strains. Wistar rats achieved stage 4 of clonic-tonic seizures, whereas hooded Lister rats only reached stage 2 of convulsive waves axially through the body. Rats were killed 10 days after their final injection, and radioligand binding was used to measure the expression of NMDA receptors in cortex and hippocampus using [3H]MK-801 and [3H]L-689,560, the latter binding specifically to the NR1 subunit. [3H]Ro 15-1788 measured expression of GABA(A)-benzodiazepine binding sites containing alpha1, alpha2, alpha3, or alpha5 subunits. Specific analysis of GABA(A) receptors containing the alpha5 subunit, which are preferentially localized in the hippocampus, was assessed with [3H]L-655,708. In the cortex, there was no effect of strain or treatment on the K(D) or B(max) of any of the ligands. Similarly, there was no effect of strain or treatment on hippocampal [3H]L-689,560 or [3H]Ro 15-1788 binding. However, in the hippocampus there was a significant, albeit modest, effect of treatment on the B(max) of [3H]MK-801 binding and the B(max) and K(D) of [3H]L-655,708 binding, i.e., PTZ-treated rats had fewer [3H]MK-801 and [3H]L-655,708 binding sites (NMDA and alpha5-containing GABA(A) receptors, respectively), but, these reductions were significant only in the relatively seizure-insensitive hooded Lister strain. This suggests that the increased susceptibility to kindling in Wistar rats is not directly related to alterations in the expression of NMDA or GABA(A) receptors.

Aminoquinolines↗

PubMed2000

Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety.

1. Different animal tests model different anxiety disorders. Thus, the social interaction test is a model of generalised anxiety disorder, plus-maze Trial 1 models elements of panic disorder and Trial 2 in the elevated plus-maze is a model of specific phobia. 2. Studies of the neuroanatomical and neurochemical pathways controlling behaviour in these different tests provides information on the neurobiological mechanisms modulating anxiety disorders. 3. In the social interaction test, nicotine and 8-OH-DPAT had anxiogenic effects when injected into the dorsal hippocampus or the lateral septum. 4. These ligands were without effect on Trial 1 in the plus-maze when injected into the dorsal hippocampus, but had anxiogenic effects when injected into the lateral septum. 5. On Trial 2 in the elevated plus-maze, nicotine had an anxiolytic effect, but 8-OH-DPAT had an anixiogenic effect when injected into the dorsal hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

The role of 5-HT1A receptors in mediating the anxiogenic effects of nicotine following lateral septal administration.

The purpose of the present study was to determine the role of the 5-HT1A receptors in the lateral septum in the mediation of the anxiogenic effects of nicotine in the social interaction and elevated plus maze tests of anxiety in the rat. Bilateral infusion of (-)-nicotine (4 and 8 microg) and of the 5-HT1A receptor agonist 8-OH-DPAT (200 and 500 ng) into the lateral septum decreased the time spent in social interaction, indicating anxiogenic effects. The anxiogenic effect of 8-OH-DPAT (500 ng) was completely reversed by coadministration of a behaviourally inactive dose of the 5-HT1A receptor antagonist, WAY 100635 (200 ng). The anxiogenic effect of the lower dose of (-)-nicotine (4 microg) was completely reversed by WAY 100635 (200 ng), but the reversal was only partial following administration of 8 microg nicotine. In a second test of anxiety, the elevated plus maze, lateral septal administration of 8-OH-DPAT (500 ng) and nicotine (4 microg) induced anxiogenic effects. In this test, the anxiogenic effect of nicotine (4 microg) was completely reversed by coadministration of WAY 100635 (200 ng). The effects of 8-OH-DPAT demonstrate that stimulation of 5-HT1A receptors in the lateral septum has anxiogenic effects in two animal tests and that the anxiogenic effects of nicotine are mediated at least in part by these 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release.

The effects of nicotine on 5-hydroxytryptamine (5-HT) release from serotonergic nerve endings in rat dorsal hippocampal slices were studied. Nicotine (50-500 microM:) caused a concentration-dependent increase in 5-HT release. This effect was antagonised by mecamylamine (0.5 microM:), indicating an action at nicotinic receptors. Nicotine-evoked 5-HT release was not affected by tetrodotoxin (3 microM:), cadmium chloride (0.1 mM:), or the absence of Ca(2+) or Na(+) in the superfusion medium. Unexpectedly, higher concentrations of mecamylamine alone (1-50 microM:) increased 5-HT release. This suggested the presence of inhibitory input to 5-HT neurones and that these inhibitory neurones possess tonically active nicotinic receptors. The effect of mecamylamine (50 microM:) on 5-HT release was reduced by the muscarinic M(1) receptor agonist, McN-A-343 (100 microM:), but pirenzepine (0.005-1 microM:), which blocks M(1) receptors, alone increased 5-HT release. Hippocampal serotonergic neurones are known to possess both excitatory nicotinic receptors and inhibitory M(1) receptors. Although there may be several explanations for our results, one possible explanation is that nicotine stimulates 5-HT release by activating nicotinic heteroreceptors on 5-HT terminals. Mecamylamine (0.5 microM:) antagonises this effect, but higher concentrations increase 5-HT release indirectly by blocking the action of endogenous acetylcholine on nicotinic receptors situated on cholinergic neurones that provide muscarinic inhibitory input to 5-HT neurones.

Animals↗

PubMed1999

Dizocilpine does not prevent the development of tolerance to the anxiolytic effects of diazepam in rats.

The non-competitive NMDA receptor antagonist, dizocilpine (0.25 mg/kg), has previously been shown to block the development of tolerance to the sedative effects of diazepam (2 mg/kg). Since there is considerable evidence that different mechanisms underlie the development of tolerance to the sedative and anxiolytic effects of diazepam, the present experiment examined whether dizocilpine would block the development of tolerance to diazepam's anxiolytic effects. Rats tested after an acute dose of diazepam (2 mg/kg) showed an anxiolytic effect, measured by an increase in the time spent in social interaction, whereas those tested after 21 days of treatment had scores equal to the control group. This development of tolerance was not blocked by concomitant administration of dizocilpine (0.25 mg/kg). Thus, these results provide further evidence that the mechanism underlying tolerance to the anxiolytic effects of diazepam is different from that underlying tolerance to the sedative effects.

Animals↗

PubMed1999

Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine.

RATIONALE: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (-)-nicotine in the social interaction test. OBJECTIVE: To determine the effects of a wide dose range of (-)-nicotine on trial 1 and 2 in the plus-maze after systemic administration and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. METHODS: (-)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze. Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 microl of artificial CSF or (-)-nicotine (0.1, 1, 4 or 8 microg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial 1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier. RESULTS: Low doses of (-)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses (0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage entries onto the open arms. Infusion of (-)-nicotine (0.1, 1, 4 and 8 microg) bilaterally into the dorsal hippocampus was without effect on trial 1, but 1 microg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms. CONCLUSIONS: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2) showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to be identified.

Analysis of Variance↗

PubMed1999

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.

Animals↗