Frequency-related, bidirectional limbic responses to cocaine: comparisons with amphetamine and lidocaine

Dual effects of cocaine on the electrical excitability of limbic structures were investigated by determining current thresholds for afterdischarges (AD) evoked by low and high frequency electrical stimulation. Cocaine, lidocaine and D-amphetamine treatments were compared in order to assess the extent to which cocaine's local anesthetic and monoaminergic actions contribute to its effects on limbic afterdischarges. Afterdischarge threshold, duration and propagation for both 3 and 50 Hz stimulation of the amygdala, hippocampus and septal area were tested following saline, cocaine (5 mg/kg), lidocaine (5 mg/kg) and D-amphetamine (2.5-5 mg/kg). Results provide clear evidence that cocaine has a bidirectional effect on hippocampal and amygdalar AD thresholds--significantly increasing sensitivity to low frequency stimulation while significantly decreasing sensitivity to high frequency stimulation at identical brain sites. A frequency-dependent threshold effect also occurred at the septal area. In addition, cocaine reduced limbic AD duration and propagation; these effects proved unrelated to the direction of AD threshold changes. Cocaine effects on afterdischarges differed significantly from those of amphetamine and lidocaine. Comparisons with amphetamine and lidocaine suggest that cocaine's local anesthetic action, but not its monoaminergic properties, may contribute to reductions in limbic afterdischarge duration and propagation. However, it is unlikely that either monoaminergic or local anesthetic actions are responsible for cocaine's pronounced dual effect on the electrical excitability of major limbic structures. This bidirectional drug effect has interesting neurobiological implications and, in addition, offers a potentially valuable tool for new research on frequency-related functions of the limbic system.