Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain.

Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis.

Effects of chlordiazepoxide on runway behaviours of C57Bl/6 mice under continuous or partial reinforcement.

An earlier history of partial or continuous reinforcement produces differential behavioural effects during extinction in the runway, with an earlier partial reinforcement (PRF) leading to an increased resistance to extinction. This effect has been attributed to conditioned frustration or generalization-decrement processes. The actions of antianxiety drugs in this procedure are most easily interpreted as for reducing the emotional or aversive effects of nonreinforcement. In this study, C57Bl/6 mice were trained to asymptotic performance with food reinforcement on 50 or 100% of six trials in daily sessions. The anxiolytic benzodiazepine, chlordiazepoxide (15 mg/kg, intraperitoneally) or saline was administered before subsequent daily extinction sessions. Under saline, earlier PRF produced an increased resistance to extinction. Drug administration increased resistance to extinction, as measured by start, run and goal times, after either continuous or PRF. These findings are consistent with earlier findings of rats, but different from those obtained with chlordiazepoxide during extinction after operant training with either rats or mice. These findings can be interpreted in terms of frustration, anxiety or generalization-decrement theories of PRF.

Facilitation of extinction of operant behaviour in mice by D-cycloserine.

RATIONALE AND OBJECTIVE: The N-methyl-D-aspartate receptor agonist D-cycloserine (DCS) facilitates extinction following Pavlovian fear conditioning or conditioned place preference in rats, but its effects on extinction following operant conditioning are not previously established. We studied the effects of DCS on operant extinction with mice, previously shown to be facilitated by GABAergic potentiators including chlordiazepoxide. MATERIALS AND METHODS: Following training of lever pressing by C57Bl/6 male mice on a discrete-trial fixed-ratio food reinforcement schedule with six reinforcers per session, 48-trial extinction sessions were conducted at 3- (Experiment 1) or 4-day intervals (Experiment 2). Effects of DCS (15 or 30 mg/kg, i.p.) administered immediately after 48-trial extinction sessions were compared with those of saline injections. RESULTS: With 3-day intervals between extinction sessions, post-session administration of DCS facilitated extinction, and this effect was stronger with 4-day intervals between extinction sessions. Facilitation of extinction by post-session drug administration persisted over a number of extinction sessions. CONCLUSIONS: Operant extinction in mice can be facilitated by DCS, a glutamatergic agonist, as well as by GABAergic potentiators. The relationship between glutamatergic and GABAergic processes in operant extinction is yet to be established. These findings strengthen the basis for clinical uses of DCS.