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A unique form of pharmacodynamic tolerance develops when effective anticonvulsants are given as pre-treatment before once-daily amygdala-kindled seizures in animals.1,2 This loss of efficacy (i.e., tolerance) is contingent upon the drug’s administration before, but not immediately after, the kindling stimulation.3, 4, 5, 6 This form of tolerance can be reversed after a period of seizures off anticonvulsants, or even continuing to give anticonvulsants on a once-daily basis but after a fully developed kindled seizure has already occurred.

Electrical kindling, first described by Goddard and associates (14), was elicited by repeated intermittent electrical stimulation of a variety of brain areas culminating in the production of major motor seizures to a previously subconvulsant stimulation. This process is accompanied by growth and spread of afterdischarges and a succession of behavioral seizure stages progressing to the onset of major motor seizures (14,38). With sufficient repetition of the kindled seizures, a stage of spontaneity occurs in which exogenous electrophysiological stimulation is no longer required in order for the animal to experience a seizure (20–22,43).

Psychomotor stimulant-induced behavioral sensitization and electrophysiological kindling are not animal models of stress with obvious face validity; however, we discuss them here as they may guide us to new principles concerning changes in long-term responsivity in behavior that may be relevant to some stress situations. Moreover, there is an extensive literature indicating that there are important interactions between psychomotor stimulant-induced behavioral sensitization and stress-induced behavioral alterations. Stimulants such as amphetamine and cocaine are thought to exert many of their actions by potentiating noradrenergic and dopaminergic neurotransmission. Stresses, in many instances, are also capable of acting on these catecholamine and related neurochemical substrates. Thus, it is not surprising that under some conditions, stresses may facilitate subsequent reactivity to psychomotor stimulants and, vice-versa, that psychomotor stimulant pretreatment may enhance stress responsivity. Seymour Antelman and colleagues have reviewed elsewhere (1,2) evidence for cross-sensitization between stress and stimulants. It is not the point of this paper to argue that this is a universal principle; we and others have observed in some instances that stresses may decrease subsequent stimulant-induced behavior. What we are suggesting is that, in many instances, stimulant-induced effects on short- and long-term alterations in behavior may be mediated by the same neurochemical systems that are relevant to the consideration of stress-induced changes in behavior.