Effects of single and simultaneous lesions of serotonergic and noradrenergic pathways on open-space and bright-space anxiety-like behavior in two animal models.

The objective of the present study is to investigate the effects of single and simultaneous lesions of the noradrenergic and serotonergic pathways (NA-X, 5-HT-X and XX, respectively) by intracerebroventricular administration of selective neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-HCl (DSP-4) and 5,7-dihydroxytryptamine (5,7-DHT) on anxiety-like behavior in rats. To evaluate the effects of the various lesions, animals were tested in elevated plus-maze (EPM) and light-dark (LD) paradigms. In EPM, single lesions produced strong, statistically significant increase (p<0.001) of both time spent in the open arms (OT) and number of entries into the open arms (OE) compared to sham-lesioned animals. Simultaneous lesion further strengthened this anxiolytic effect causing an approximate 500% elevation of OT compared to sham-lesioned animals. In LD, 5-HT lesion caused a significant (p<0.05) increase in both light movement time and light horizontal activity parameters compared to intact, sham, and NA-lesioned groups. Neither of the lesions caused any change in the spontaneous locomotor activity of the animals up to 15min as measured in activity meter. These findings suggest that single and simultaneous lesions of 5-HT- and NA-pathways modify anxiety-related state of experimental animals to different extents and these modifications alter the behavior of animals differently in the two models used: NA-X and 5-HT-X reduce open space anxiety-like behavior and XX further strengthens this effect in the EPM, while only 5-HT-X is resulting in reduced bright-space anxiety-like behavior leaving the performance of NA-X and XX animals unchanged.

A mouse model of anxiety molecularly characterized by altered protein networks in the brain proteome.

Recently, several attempts have been made to describe changes related to certain anxiety states in the proteome of experimental animal models. However, these studies are restricted by limitations regarding the number and correct identification of separated proteins. Moreover, the application of a systems biology approach to discover the molecular mechanisms of anxiety requires genetically homogenous inbred animal models. Therefore, we developed a novel mouse model of anxiety using a combination of crossbreeding (inbred for 35 generations) and behavioral selection. We found significant changes in 82 proteins in the total brain proteome compared to the control proteome. Thirty-four of these proteins had been previously identified in other anxiety, depression or repeated psychosocial stress studies. The identified proteins are associated with different cellular functions, including synaptic transmission, metabolism, proteolysis, protein biosynthesis and folding, cytoskeletal proteins, brain development and neurogenesis, oxidative stress, signal transduction. Our proteomics data suggest that alterations in serotonin receptor-associated proteins, in the carbohydrate metabolism, in the cellular redox system and in synaptic docking are all involved in anxiety.

Chronic mild stress generates clear depressive but ambiguous anxiety-like behaviour in rats.

A 3-week chronic mild stress (CMS) protocol decreased sucrose preference of rats and increased immobility in the forced swim test. It also induced social avoidance and increased grooming, but acted as if reducing anxiety in the plus-maze. Sucrose preference and social avoidance, but not other measures of the behaviour, showed significant correlation. We conclude that CMS-induced depression-like behaviour is associated with social avoidance, a seemingly anxiety-related measure, but not with other anxiety-like traits in rats.

Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: effects of GYKI 52466 and its novel analogues.

RATIONALE: Although emerging number of data supports the role of glutamate receptors and the potential of their antagonists in anxiety disorders, the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in anxiety is less well characterized. OBJECTIVE: To evaluate the anxiolytic potential of 2,3-benzodiazepine (2,3BDZ) type AMPA receptor antagonists in various models of anxiety. MATERIALS AND METHODS: Whole-cell currents, hippocampal field potentials, elevated plus maze (EPM), meta-chlorophenylpiperazine (mCPP)-induced anxiety model, Vogel test in rats and light-dark test (LD) in mice were used to determine AMPA/kainite receptor properties and anxiolytic-like activity of a series of 2,3BDZ-type compounds. RESULTS: The reference compound GYKI 52466 was proved active in two anxiety models in non-sedative doses: minimal effective dose (MED) was especially low in EPM (0.01 mg/kg) GYKI 53405 and GYKI 53655 showed anxiolytic-like activity in two tests (EPM and mCPP). EGIS-8332 was active in EPM and LD while EGIS-9637 showed anxiolytic-like potency in EPM, mCPP and Vogel model. EGIS-10608 was the most effective compound among 2,3BDZs tested in EPM and Vogel models (MEDs are 0.01 and 2.5 mg/kg, respectively). 2,3BDZs were active in anxiety models at doses lower than those produced sedative effects. NBQX showed anxiolytic-like activity in EPM only (3 mg/kg). CONCLUSIONS: The results show that non-competitive AMPA receptor antagonists can profoundly block anxiety-like behavior in rodents independently from their motor depressant activity. However, the sedative properties at higher doses might limit their therapeutic utility as new anxiolytic drugs.

(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists.

A series of potent 5-hydroxytryptamine 7 (5-HT 7) ligands has been synthesized that contain a 1,3-dihydro-2 H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT 7 and 5-HT 1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT 7 receptor. According to the structure-activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT 7 receptor-ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2 H-indol-2-one ( 9e') exhibited selective 5-HT 7 antagonist activity ( K i = 0.79 nM). The in vivo pharmacological potencies of these 5-HT 7 receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests.