John W. Haycock

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.

Enhancement of retention with centrally administered catecholamines.

Abstract These experiments examined the effects of intracerebroventricular norepinephrine and dopamine on retention performance of mice. The animals were trained in one of two inhibitory avoidance tasks and injected immedidiately post-training with various doses of norepinephrine or dopamine (0.01 to 100 μg). Retention was tested 24 hr later. In one training procedure, each mouse received a footshock as it stepped from one chamber to another in a “step-through” apparatus. In this task retention performance was enhanced by dopamine (0.1 μg) but not by norepinephrine. In the other training procedure, water-deprived mice were first well-trained to step from the first chamber into the second chamber and lick from a water spout. They were then given a footshock while licking. Norepinephrine (1 μg) but not dopamine enhanced retention of the lick avoidance training. These findings provide direct evidence that central catecholamines can modulate memory storage processes.

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.

Effects of catecholaminergic drugs upon memory storage processes in mice

These experiments examined the effects of drugs that interfere with catecholamine metabolism upon retention performance by Ha/ICR mice in an inhibitory avoidance task. When administered shortly before training, most of the drugs impaired subsequent retention performance. However, of the drugs studied, only diethyldithiocarbamate (DDC) produced retention deficits when administered posttraining. A series of experiments examined in detail the effects of DDC upon (1) retention performance of inhibitory avoidance learning, (2) whole brain norepinephrine and dopamine levels, (3) brain seizure activity recorded from cortical electrodes, and (4) Timms staining in the hippocampal mossy fiber system. DDC influenced all measures, and the degree of effect varied directly with dose. But, the amnestic effect of DDC did not depend in any simple manner upon reduction of brain catecholamine levels or upon induction of brain seizure activity.

Enhanced stimulus-secretion coupling from brains of aged mice

Fractional calcium-dependent release of accumulated [3H]dopamine and γ-[14C]aminobutyric acid (GABA), but not [3H]norepinephrine or [14C]choline-acteylcholine, from isolated mouse forebrain synaptosomes was enhanced in 12- as compared to 2-month-old mice. In the case of [3H]-dopamine, differences in the storage of accumulated dopamine may have been responsible for these differences. No differences were observed in GABA accumulation or storage. The enhanced release of accumulated GABA in synaptosomes from 12- vs. 2-month-old mice is discussed in terms of age-related changes in secretion processes.

Noncontingent footshock attenuation of retrograde amnesia: A generalization effect

Abstract Mice were either well trained and rendered amnesic with transcorneal electroconvulsive shock (ECS) or poorly trained on a one-trial inhibitory avoidance task and given a retention test 24 and 48 hr later. Noncontingent footshock administered either 1 hr after the training or 1 hr after the 24 hr test significantly increased retention latencies of groups which had received training and ECS, as well as those of groups which were poorly trained. These findings suggest that animals which are partially amnesic or poorly trained are able to generalize the effects of a subsequent NCFS experience to the inhibitory avoidance training task.

Stimulation-dependent depression of readily releasable neurotransmitter pools in brain.

Previously accumulated GABA was released from isolated forebrain synaptosomes with repeated calcium stimulation in elevated-potassium medium. Fractional release (calcium-dependent) in response to a second calcium pulse (90-120 sec later) was depressed to approximately 60% of initial release. Neither initial GABA release nor the subsequent depression of release was affected by variations in the labelling duration. Stimulation-dependent depression of labelled GABA and norepinephrine release was demonstrated from both cerebral cortex and cerebellum synaptosomal preparations. In addition, depression resulted from prior stimulation in the presence of veratridine, A23187 or elevated-potassium. Although release of previously accumulated GABA was depressed by calcium stimulation, the release of GABA accumulated between stimulations was not. Release of this recently accumulated GABA was indistinguishable from the initial release of previously accumulated GABA and larger than the subsequently depressed release from the previously accumulated pools. These data imply (1) that the depressed release resulted from a decrease of available transmitter in pools that support secretion processes, (2) that depressed release did not result from a depression of stimulus-secretion coupling processes, and (3) that transmitter accumulated subsequent to release events is released preferentially to transmitter accumulated prior to the intervening stimulation.

Facilitation of retention performance in mice by posttraining diethyldithiocarbamate.

These experiments examined the effects in mice of posttraining injections of diethyldithiocarbamate (DDC) upon retention (7 days after training) of active avoidance learning and upon whole brain catecholamine levels. When administered immediately following training, DDC enhanced retention performance. The degree of enhancement varied directly with dose. DDC did not significantly affect retention performance if the injections were delayed 1 or 4 hours after training. Also, DDC administered 30 min prior to training did not affect retention performance. DDC (900 mg/kg) produced a large but transient increase in whole brain dopamine (DA) levels while norepinephrine (NE) levels were lowered.

ON THE FUNCTIONAL COUPLING OF NEUROTRANSMITTER UPTAKE AND RELEASE IN BRAIN

1 Isolated synaptosomal fractions from mouse forebrains were incubated with [14C]‐γ‐aminobutyric acid ([14C]‐GABA). Release of the accumulated label in high potassium solution was measured. 2 The fractional release dependent upon calcium was decreased by raising the concentration of [14C]‐GABA during labelling but was not affected by altering the time allowed for labelling or the time between labelling and stimulation. 3 These data suggest that extracellular GABA gains rapid access to available intraterminal pools. The relative distribution of the accumulated GABA in different pools can be influenced by the concentration of GABA in the incubation medium but, once ‘stored’, there is no net redistribution of accumulated GABA in the absence of stimulation.