SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test.

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

A novel behavioural registration system LABORAS and the social interaction paradigm detect long-term functional deficits following middle cerebral artery occlusion in the rat.

Following stroke, patients suffer a wide range of disabilities including motor impairment, anxiety and depression. However, to date, characterisation of rodent stroke models has concentrated mainly on the investigation of motor deficits. The aim of the present studies was therefore to investigate home cage behaviour (as assessed by a recently developed automatic behavioural classification system, LABORAS) and social behaviour (as a measure of anxiety) in rats following transient middle cerebral artery occlusion (tMCAO). Rats subjected to tMCAO (90 min) showed deficits in general home cage behaviours including locomotion, rearing, grooming and drinking for up to 7 weeks post occlusion, as compared with sham operated controls. In addition, a significant decrease in the total duration of social interaction was also observed in occluded rats compared with shams. The data shows that in addition to motor deficits, animals display changes in home cage behaviour and decreased social behaviour which, in contrast to motor function, are prolonged over time. Transient MCAO in rats may therefore provide a pre-clinical model to investigate agents offering symptomatic relief for ischaemia-induced motor deficits and anxiety over time following injury.

Repeated sensory contact with aggressive mice rapidly leads to an anticipatory increase in core body temperature and physical activity that precedes the onset of aversive responding.

The present study investigated whether the 'psychological threat' induced by sensory contact with an aggressive conspecific would be a sufficient factor in inducing behavioural and physiological disturbances. Repeated sensory contact with an aggressive mouse (social threat) in a partitioned cage was compared with repeated exposure to a novel partitioned cage in male NMRI mice. We first examined parameters of stress responsiveness (body weight, plasma corticosterone levels, frequency of self-grooming and defecation). The temperature and physical activity responses to stress were also recorded during and after the 4 weeks of stress using radiotelemetry. Finally, cognitivo-emotional performance was assessed after acute stress and 2 and 4 weeks of stress by measuring decision making, sequential alternation performance and behaviour in the elevated T-maze. Social threat had a greater impact than novel cage exposure on most parameters of stress responsiveness, although mice did not habituate to either stressor. Social threat rapidly led to an anticipatory rise in core body temperature and physical activity before the scheduled stress sessions. Such anticipation developed within the first week and persisted for 9 days after ending the stress procedure. Some memory impairment in the sequential alternation test was found in stressed mice, independent of the stressor. After 4 weeks of stress, inhibitory avoidance in the elevated T-maze was enhanced in socially stressed mice and reduced in novel cage mice. The sustained anticipation of stress in the social threat group preceded aversive responding. It remains to be established whether anticipation contributes to the development of aversive responses.

LABORAS: Initial pharmacological validation of a system allowing continuous monitoring of laboratory rodent behaviour.

A newly developed apparatus for automated behavioural analysis, Laboratory Animal Behaviour Observation, Registration and Analysis System (LABORAS), has been further validated with respect to the ability of the system to detect the pharmacodynamic effects of standard pharmacological tools. Data were obtained from rats administered with mCPP (reversal with SB242084), 8-OH-DPAT (reversal with WAY100635), amphetamine (reversal with haloperidol) and angiotensin, with the focus on locomotor activity, feeding and drinking behaviours. The data captured and analysed by LABORAS, suggests that the automated system is able to detect pharmacologically induced changes in behaviour, reliably and efficiently, with a significant reduction in the number of animals required, and reduced operator input.

5-HT2C receptor mediation of unconditioned escape behaviour in the unstable elevated exposed plus maze.

RATIONALE AND OBJECTIVES: m-Chlorophenylpiperazine (mCPP) induces panic in humans and dose dependently increases unconditioned escape behaviour in a novel pre-clinical model of extreme anxiety in rats, the unstable elevated exposed plus maze (UEEPM). Numerous studies indicate that the anxiogenic effects of mCPP may be mediated by its action at the 5-HT2C receptor. This study aimed to examine the involvement of the 5-HT2C receptor in the unconditioned fear responses observed in the UEEPM (after an acute dose of mCPP) by pre-treatment with the selective 5-HT2C receptor antagonist SB-242084. METHODS: Male Hooded Lister rats received a single dose of SB-242084 (0.1-1.0 mg/kg IP) or vehicle 40 min pre-test followed by a single dose of mCPP (1.0 mg/kg IP) or saline 30 min before being exposed to the UEEPM for a period of 5 min. Subjects' behaviour was analysed to determine the effects of SB-242084 on mCPP-induced increases in escape behaviour. RESULTS: mCPP alone increased animals' propensity to escape from the UEEPM despite producing marked decreases in locomotor/exploratory behaviour. SB-242084 dose dependently inhibited the increases in escape and hypolocomotor effects induced by mCPP. CONCLUSIONS: These results suggest that the escape-related behaviours exhibited by animals in the UEEPM are mediated, at least in part, by activation of the 5-HT2C receptor subtype.

Ethopharmacological analysis of the unstable elevated exposed plus maze, a novel model of extreme anxiety: predictive validity and sensitivity to anxiogenic agents.

RATIONALE AND OBJECTIVES: The unstable elevated exposed plus maze (UEEPM) has been proposed as a novel model of anxiety which elicits unconditioned escape-related behaviour in rats thought to mimic the persistent "fight/flight" state exhibited by patients suffering from extreme anxiety disorders. This study investigated the predictive validity of the UEEPM by examining the behaviour of rats exposed to the test following administration of drugs known to induce panic and anxiety in panic disorder and post-traumatic stress disorder patients, namely m-chlorophenylpiperazine (mCPP), caffeine and yohimbine. The sensitivity of the UEEPM to two further putative anxiogenic agents, the benzodiazepine partial inverse agonist FG 7142 and pentylenetetrazole (PTZ), was also assessed. METHODS: Male Hooded Lister rats received a single dose of mCPP (0.5-2.0 mg/kg; ip), caffeine (3.0-30.0 mg/kg; ip), yohimbine (1.25-5.0 mg/kg; ip), FG 7142 (3.0-30.0 mg/kg; ip) or PTZ (3.0-30.0 mg/kg; ip) before being exposed to the UEEPM for a period of 5 min. Subjects' behaviour was analysed to determine the effects of each compound on unconditioned escape. RESULTS: mCPP (1.0 and 2.0 mg/kg), caffeine (30 mg/kg), FG 7142 (3.0 and 30.0 mg/kg) and PTZ (30.0 mg/kg) significantly increased animals' propensity to escape from the UEEPM, i.e. they had a clear anxiogenic effect, whilst yohimbine had no effect on escape. CONCLUSIONS: The UEEPM is sensitive to the behavioural effects of anxiogenic agents. Furthermore, pharmacological similarities exist between symptoms of panic and anxiety in patients and escape from the UEEPM in rats. The UEEPM may therefore represent a paradigm to facilitate investigation into the neurochemical basis of extreme anxiety disorders.