Central administration of a caspase inhibitor impairs shuttle-box performance in rats

• Published in: Neuroscience 2005, Vol.136 (2), p.579-591
• Main Authors: Stepanichev, M. Yu, Kudryashova, I.V., Yakovlev, A.A., Onufriev, M.V., Khaspekov, L.G., Lyzhin, A.A., Lazareva, N.A., Gulyaeva, N.V.
• Format: Article
• Language: English
• Subjects: active avoidance; Animals; Avoidance Learning - drug effects; caspase; Caspase 3; Caspase Inhibitors; Cells, Cultured; Cerebellum - cytology; Cerebellum - enzymology; Conditioning, Operant - drug effects; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Injections, Intraventricular; learning; Learning - drug effects; Male; memory; Memory - drug effects; Oligopeptides - pharmacology; Peptide Hydrolases - chemistry; Peptide Hydrolases - metabolism; plasticity; Protease Inhibitors - pharmacology; Rats; Rats, Wistar
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2005.08.010

Recent studies suggest that caspase-3-mediated mechanisms are essential for neuronal plasticity. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val- Asp(OMe)-fluoromethyl ketone (z-DEVD-fmk), a caspase inhibitor with predominant specificity toward caspase-3, has been shown to block long-term potentiation in hippocampal slices. Intrahippocampal infusion of a caspase-3 inhibitor to rats has been shown to significantly impair spatial memory in the water maze. The present work was designed to study whether i.c.v. administration of a caspase-3 inhibitor z-DEVD-fmk impairs learning in other tasks related to specific forms of memory in rats. The rats received bilateral injections of z-DEVD-fmk or N-benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (z-FA-fmk) (“control” peptide) at a dose of 3nmol. Administration of z-DEVD-fmk significantly decreased the number of avoidance reactions in some blocks of trials in the active avoidance (shuttle box) learning, while z-FA-fmk had no effect as compared with intact rats. However, only a slight effect of the caspase inhibitor across the session was found. z-DEVD-fmk impaired development of some essential components of the two-way active avoidance performance, such as escape reaction, conditioned fear reaction, and inter-trial crossings. Measurement of caspase-3 activity in rat brain regions involved in active avoidance learning revealed most expressed z-DEVD-fmk-related inhibition of the enzyme activity (about 30%) in the fronto-parietal cortex. A similar effect was close to significant in the hippocampus, but not in the other cerebral structures studied. In primary cultures of cerebellar neurons z-DEVD-fmk (2–50μM) inhibited caspase-3 activity by 60–87%. We suggest that moderate inhibition of caspase-3 resulting from the central administration of z-DEVD-fmk to rats may impair active avoidance learning. Taking into account previous data on the involvement of neuronal caspase-3 in neuroplasticity phenomena we assume that the enzyme may be important for selected forms of learning.