Paul E. Gold

Facilitation of time-dependent memory processes with posttrial epinephrine injections

This experiment examined the effect of posttraining epinephrine injections on memory-storage processes. Rats were trained with a weak footshock (0.7 mA, 0.35 sec) on a one-trial inhibitory avoidance task. The animals received epinephrine injections immediately, 10 min, 30 min, or 2 hr after training. On a retention test 24 hr after training, animals which received subcutaneous injections of epinephrine (0.01, 0.05, or 0.1 mg/kg) immediately after training had retention performance which was significantly better than that of saline control animals. A lower (0.001 mg/kg) or a higher (0.5 mg/kg) dose did not affect retention performance. Epinephrine injections (0.1 mg/kg) given 10 min after training also significantly facilitated retention, but injections given 30 min or 2 hr after training did not affect retention performance significantly. These findings suggest that the hormonal consequences of a training experience (e.g., epinephrine release) may normally modulate memory-storage processes in untreated animals.

Enhancement and impairment of memory processes with post-trial injections of adrenocorticotrophic hormone.

In these experiments, post-trial injections of adrenocorticotrophic hormone (ACTH) produced both enhancement and impairment of memory processes. Animals were trained in a one-trial inhibitory (passive) avoidance task and were tested for retention 24 hr later. In the first experiment, animals were trained in the avoidance task using a weak footshock. Immediate post-trial ACTH injections at two doses (0.03 or 0.3 IU/animal) enhanced later retention performance as compared to saline-injected control animals. If animals received a, higher ACTH dose (3.0 IU/rat), the treatment produced retrograde amnesia; i.e., there was an inverted-U dose-response curve for the effects of ACTH on memory. Both enhancement and impairment of memory processes were time-dependent; the effect on memory decreased as the time after training increased. The findings of a second experiment indicated that retention performance of control animals varied with time of day. Control animals trained and tested in the morning (9–10:00 AM) show retention performance significantly poorer than that of animals trained and tested in the afternoon (1–2:00 PM). Post-trial injections of ACTH enhanced later retention only in the afternoon conditions. A third experiment examined the interactions between the footshock parameters used in training and the effect, on memory, of ACTH. A single post-trial dose of ACTH (either 3 or 6 IU/rat) enhanced later retention of training with weak footshock and impaired later retention of training with a more intense footshock. These findings support the general view that ACTH may modulate memory storage processing of recent information. In addition, these results suggest the possibility that other post-trial treatments which facilitate or impair memory processes may act via hormonal mechanisms.

Posttraining brain norepinephrine concentrations: Correlation with retention performance of avoidance training and with peripheral epinephrine modulation of memory processing

Posttrial epinephrine injections can enhance or impair later retention performance of inhibitory (passive) avoidance training in rats. The findings reported here indicate that the effects on retention of epinephrine injections and of footshock level are closely related to transient posttraining decreases in whole brain norepinephrine concentrations. Posttraining norepinephrine levels, as measured 10 min after training and treatment, predict the later retention performance of groups of rats trained with high or low footshock and, in addition, predict the retroactive effects (enhancement or impairment) of posttrial epinephrine injections. These findings are consistent with the view that hormonal responses to training may modulate memory storage processing. In addition, the results suggest that memory modulation may involve neuroendocrine mechanisms that include the central noradrenergic system.

Effects of posttrial hormone injections on memory processes.

Abstract This experiment examined the effect on memory of posttrial injections of epinephrine, norepinephrine, ACTH, growth hormone, vasopressin and corticosterone. Rats were trained with a weak footshock (0.7 mA, 0.35 sec) in a one-trial inhibitory (passive) avoidance task. The animals received subcutaneous injections of one of the above hormones or saline immediately after training. On a retention test 24 hr after training, animals which received ACTH (0.03 or 0.3 IU/rat), epinephrine (0.1 mg/kg) or norepinephrine (0.1, 0.3 or 1.0 mg/kg) had retention performance which was significantly better than that of saline control animals. A higher posttrial ACTH dose (3.0 I.U./animal) impaired later retention performance. ACTH (0.3 I.U./animal) and norepinephrine (0.3 mg/kg) injections administered 2 hr after training had no significant effect on retention. Immediate posttrial injections of vasopressin (dose range 0.001–1.0 I.U./animal), growth hormone (0.5–1.0 mg/kg), or corticosterone (0.01–4 mg/kg) did not significantly enhance retention. These findings indicate that epinephrine, norepinephrine, and ACTH injections can enhance memory processes if the hormones are injected shortly after training. Such results are consistent with the view that hormonal consequences of an experience, particularly epinephrine, norepinephrine and ACTH release, may normally have a modulatory influence on memory processes in untreated animals. In addition, it is therefore possible that other posttrial treatments which enhance or impair later retention performance may act through hormonal mechanisms.

Effects of α- and β-adrenergic receptor antagonists on post-trial epinephrine modulation of memory: Relationship to post-training brain norepinephrine concentrations

Rats were trained in a one-trial inhibitory (passive) avoidance task. Each animal received a 30-min pretrial injection of saline, phenoxybenzamine, or propranolol and an immediate post-trial injection of saline or epinephrine. Animals were tested for retention 24 hr later. In the absence of pretreatment with either adrenergic blocking agent, epinephrine enhanced retention of training with low footshock and impaired retention of training with high footshock. Pretrial injections of propranolol, but not phenoxybenzamine, attenuated epinephrine-produced enhancement of retention performance. Conversely, pretrial treatment with phenoxybenzamine, but not propranolol, attenuated epinephrine-produced retention impairment. Post-training brain norepinephrine concentrations were sensitive to the training-treatment conditions; the extent of a transient decrease (maximal 10 min after training) predicted, in most cases, the retention performance observed in comparably trained and treated animals. These findings thus extend and corroborate our previous evidence suggesting that hormonally mediated central noradrenergic activity may underlie retrograde amnesia and enhancement of memory processes. In addition, these findings suggest that memory storage processing may be modulated by normal post-training hormonal and central aminergic responses to training.

Epinephrine facilitation of appetitive learning: attenuation with adrenergic receptor antagonists

Previous studies using aversive training tasks have reported that retention is enhanced by post-training administration of epinephrine. This study investigated the effects of post-training administration of epinephrine on retention of an appetitive task. The results indicate that epinephrine can enhance retention performance in an appetitive task of both rats and mice. Pretraining injections of propranolol and phenoxybenzamine, alpha- and beta-adrenergic receptor antagonists, attenuate the memory-enhancing effects of epinephrine. These results are consistent with the view that release of peripheral epinephrine may regulate storage of new information and may mediate memory modulation produced by a variety of treatments.

Retrograde amnesia produced by subseizure amygdala stimulation

Rats received low-level bilateral electrical stimulation of the amygdala after training on a one-trial inhibitory (passive) avoidance task. The stimulation did not produce brain seizures. Animals which received the stimulation 5 sec or 1 hr, but not 6 hr, after training had retrograde amnesia as measured on a retention test 24 hr later. The amnesia was permanent over an 8 day period. Following extinction and retraining, amygdala stimulation produced retrograde amnesia only in animals which had complete amnesia (i.e., animals which performed at the naive level) for the first training experience.

Modulating influences of hormones and catecholamines on memory storage processes.

Publisher Summary This chapter discusses the modulating influences of hormones and catecholamines on memory storage processes. Most of the studies of memory storage modulation have used treatments, such as electrical stimulation of the brain, convulsant drugs, or antibiotics, which have non-specific, widespread, and poorly understood influences on brain function. Such findings suggest that memory storage is influenced perhaps by any alteration in brain function. However, there is extensive recent evidence indicating that some treatments that have profound influences on neural activity have no modulating influences on memory storage. On the other hand, memory storage can be modulated by treatments that produce no gross alterations in brain functioning. The findings of recent studies from several laboratories suggest that it resembles like coming closer to achieving an understanding of the modulating influences of posttraining treatments on memory storage processes. Also investigation of the influences of alterations in central catecholamines and hormones should continue to provide important clues to the processes involved in memory storage.

Effects of posttraining epinephrine injections on retention of avoidance training in mice

These experiments examined the effects, on retention, of posttraining epinephrine injections in mice. Mice were trained in a one-trial inhibitory (passive) avoidance task and retention performance was measured 24 hr after training. In the first experiment, animals received an immediate posttraining injection of saline or epinephrine (3–1000 μ g/kg). An intermediate epinephrine dose (30 μ g/kg) enhanced later retention performance and the high dose (1000 μ g/kg) impaired later retention performance. In a second experiment, an intermediate epinephrine dose (50 μ g/kg) again enhanced later retention if the treatment was administered immediately after training but not if delayed by 10 or 30 min after training. A higher epinephrine dose (500 μ g/kg) had no effect on retention performance if the drug was administered immediately after training or 30 min after training. However, this dose did enhance retention if administered 10 min after training. Thus, the dose—response characteristics of epinephrine enhancement of retention vary with time after training. These findings are consistent with the general view that hormonal consequences of training may modulate the storage of recent information and, furthermore, that posttraining treatments may affect memory through mechanisms which interact with the hormonal responses to training.

Effects on retention of posttraining amphetamine injections in mice: Interaction with pretraining experience

These experiments examined the effects of d-amphetamine on retention of one-trial inhibitory (passive) avoidance training in mice. Water-deprived mice were pretrained to lick from a water spout at the end of a darkened compartment. Footschock was administered during licking after 4, 6, or 7 days of pretraining. Retention performance (latency to lick) was measured 24 h after training. The effects on memory of posttraining amphetamine varied not only with amphetamine dose but also with the amount of pretraining. In animals pretraining for 7 days, 0.3 and 1.0 mg/kg but not 0.03, 0.1, or 3.0 mg/kg posttraining amphetamine significantly enhanced later retention performance. In mice pretrained for 6 days, 1 mg/kg amphetamine also enhanced retention performance. However, in mice pretrained for only 4 days, 1 mg/kg amphetamine impaired later retention performance. These results are consistent with the view that posttraining treatments may affect memory storage processes by interacting with training-related arousal levels.