Anxiolytic-like effect of the selective neuropeptide Y Y2 receptor antagonist BIIE0246 in the elevated plus-maze.

The involvement of Neuropeptide Y (NPY) in the pathophysiology of mood disorders has been suggested by clinical and preclinical evidence. NPY Y1 and Y2 receptors have been proposed to mediate the NPY modulation of stress responses and anxiety related behaviors. To further investigate the role of Y2 receptors in anxiety we studied the effect of BIIE0246, a selective Y2 receptor antagonist, in the elevated plus-maze test. Rats treated with 1.0 nmol BIIE0246 showed an increase in the time spent on the open arm of the maze. In addition, to study the effects of the Y2 antagonism on NPY protein level, NPY-like immunoreactivity was measured in different brain regions following treatment with BIIE0246, but no statistically significant effects were observed. These results suggest that BIIE0246 has an anxiolytic-like profile in the elevated plus-maze.

Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity.

The 5-HT1B receptor has attracted significant interest as a potential target for the development of therapeutics for the treatment of affective disorders such as anxiety and depression. Here we present the in vivo characterisation of a novel, selective and orally bioavailable 5-HT1B receptor antagonist, SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride). SB-616234-A reversed the 5-HT1/7 receptor agonist, SKF-99101H-induced hypothermia in guinea pigs in a dose related manner with an ED50 of 2.4 mg/kg p.o. Using in vivo microdialysis in freely moving guinea pigs, SB-616234-A (3-30 mg/kg p.o.) caused a dose-related increase in extracellular 5-HT in the dentate gyrus. Evaluation of antidepressant- and anxiolytic-like effects of this 5-HT1B receptor antagonist was performed in a variety of models and species. SB-616234-A produced a decrease in immobility time in the mouse forced swim test; an effect suggestive of antidepressant activity. Furthermore, SB-616234-A produced dose-related anxiolytic effects in both rat and guinea pig maternal separation-induced vocalisation models with an ED50 of 1.0 and 3.3 mg/kg i.p., respectively (vs fluoxetine treatment ED50 = 2.2 mg/kg i.p. in both species). Also a significant reduction in posturing behaviours was observed in the human threat test in marmosets; an effect indicative of anxiolytic activity. In summary, SB-616234-A is a novel, potent and orally bioavailable 5-HT1B receptor antagonist which exhibits a neurochemical and behavioural profile that is consistent with both anxiolytic- and antidepressant-like activity in a variety of species. Taken together these data suggest that SB-616234-A may have therapeutic efficacy in the treatment of affective disorders.

Conditioning properties of social subordination in rats: behavioral and biochemical correlates of anxiety.

To develop a socially based model of anxiety, the contextual fear conditioning properties of social defeat were examined in rats. Social threat consisted of exposing intruders to aggressive residents in resident home cage, separated by a partition. During 3 daily encounters, intruders were either defeated or threatened by residents, providing the defeated-threatened (DT) and threatened-threatened (TT) groups respectively. On Day 4, both DT and TT animals were subjected to a social threat only. Additional animals received a 4-day exposure to a novel empty cage (EC group). Further DT, TT, and EC rats were confronted to a different context on Day 4. DT rats exhibited a robust and context-specific anxiety-like response, characterized by significant behavioral and biochemical alterations. DT rats showed increased risk assessment and decreased exploration compared to TT and EC rats that in turn were not different towards each other. DT and TT rats exhibited increased ACTH levels, while only DT rats showed enhanced corticosterone and decreased testosterone levels compared to EC. These differences were context-specific since they were absent confronting animals to a different context and since they were not long lasting. Overall, these data demonstrate the induction of an anxiety-like state in rats through a context conditioning process based upon social factors. The social basis of this paradigm offers good face validity with anxiety disorders, which in humans are mainly related to social factors and associated with HPA axis deregulations. The present procedure may provide a useful experimental model to further investigate the neurobiological mechanisms underlying anxiety-related disorders.