It has been proposed that activation of metabotropic glutamate receptor subtype 2/3 (mGluR2/3) may induce both antipsychotic and anxiolytic effects. The aim of this study was to evaluate further the effect of the mGluR2/3 agonist, LY354740 [(+)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylate monohydrate] in animal models relevant to both psychotic and cognitive impairment in schizophrenia. The elevated plus maze was used to select the doses for further experiments, LY354740 induced anxiolytic-like effects at doses of 3 and 10 mg/kg but not 1 mg/kg. At a dose of 10 mg/kg. LY354740 attenuated phencyclidine (PCP)-induced locomotor activity. Administered alone, it had no effect on horizontal activity, but at doses of 3 and 10 mg/kg, slightly decreased vertical activity (rearings). LY354740 (1-10 mg/kg intraperitoneally) affected neither prepulse inhibition in normal rats nor reversed the disruption of prepulse inhibition produced by PCP (2 mg/kg subcutaneously). Moreover, LY354740 (3-10 mg/kg) did not modify PCP-induced working memory deficits assessed in a spontaneous alternation task and had no effect on PCP-evoked amnesia in the passive avoidance test. LY354740 alone (3 and 10 mg/kg) induced working memory deficits, but had no effect on acquisition of passive avoidance. In conclusion, LY354740 was effective in models for anxiety and positive symptoms of schizophrenia but not in models for sensorimotor gating and cognitive impairment.

Our preclinical pilot study suggests that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans.

No abstract

No abstract

One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.