Small conductance potassium channels (SK) are activated by intracellular calcium and are voltage-independent channels. In the CNS, they are responsible for the neuronal hyperpolarisation after the action potential. Blockade of SK3 channels in the substantia nigra could lead to motor hyperactivity while blockade of SK2 channels in the hippocampus could improve memory formation and/or learning capabilities.

AG525E1 is a non-selective SK channel blocker with a K_i of 293 nM for the apamin sensitive sites. It is able to enter the central nervous system because of its physicochemical parameters. This preliminary study reports the effects of a peripheral injection of 10 mg/kg AG525E1 on motor activity in male Wistar rats.

In the first experiment, which was without habituation session, the distance travelled and the rearing time were significantly higher (student's t test, p = 0.03 and 0.017 respectively) for treated animals compared to the control group. In the second protocol, a habituation session has been carried out one day before the injection. Rats which received AG525E1 seemed to move less than those in the control group but this reduction was not statistically significant (Student's t test, p>0.05). Then, the animals were re-evaluated nine days after this experiment. Rats which received AG525E1 showed a lower motor activity but this effect did not reach a significant level.

Thus, we found that handling animals and habituation to the test environment might modify the response, possibly because of changes in stress levels.

These two facts might indicate that the increased motor activity in the first test might be related to a SK3 blockade in the dopaminergic neurons while the reduction in these parameters in the second protocol might be related to an interaction with SK2 sites mainly located in the hippocampus. However, further work is needed to confirm these hypotheses.