Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat

Synchronous hippocampal electroencephalographic activity occurring in a fre quency range of 3 to 12 Hz (i.e., hippocampal theta rhythm) has been associ ated with mnemonic processes in vivo. However, this link is tenuous and the ta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition- enhancing drugs should enhance theta rhythm regardless of their primary bio logical target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral mode ls and that vary with respect to their primary biological target: 1) the no otropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-act ivated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the ace tylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognitio n-enhancing drugs produced dose-dependent increases in hippocampal theta rh ythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthet ized rat. These increases were reversed by the muscarinic receptor antagoni st scopolamine, suggesting a common final cholinergic action of these compo unds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleat e and scopolamine reduced theta amplitude (both) and frequency (dizocilipin e maleate only). These data demonstrate that hippocampal theta rhythm is se nsitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.