Michael J. Forster

Enhancement of learning and memory in mice by a benzodiazepine antagonist.

Benzodiazepines, a class of drugs widely employed as anxiolytics and anticonvulsants, can induce impairments of learning and memory. The purpose of the present investigation was to determine if a benzodiazepine receptor antagonist, flumazenil (Ro 15‐1788), could enhance learning and memory. Pretraining injection of flumazenil (2.5 to 40.0 mg/kg) was found to enhance both learning and memory in a test requiring young mice to discriminate the correct arm of a T‐maze to escape mild electric shock. In a second test, which required mice to passively avoid a dark chamber after shock, flumazenil pretreatment prevented the occurrence of amnesia induced by the cholinergic receptor antagonist scopolamine. It is hypothesized that flumazenil may facilitate learning or memory processes by reversing a negative modulatory influence of endogenous diazepam‐like ligands for benzodiazepine receptors.— Lal, H.; Kumar, B.; Forster, M. J. Enhancement of learning and memory in mice by a benzodiazepine antagonist. FASEB J. 2: 2707‐2711; 1988.

Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats

Old F-344 rats were given endurance training over a 10-week period on a motorized treadmill. This treatment resulted in substantial heart-to-body weight ratio increases, indicative of effective training. To determine whether endurance training might alter some of the known immune system and cognitive changes observed during aging, exercised old rats were compared to nonexercised old and young controls on three variables: in vivo antigen-specific immune activity, brain-reactive antibody formation, and spatial memory. The exercise training did not influence any of these measures in the old rats. Both groups of old rats showed poorer antibody response to a specific antigen, more brain-reactive antibody formation, and poorer spatial memory than the young controls. There was, however, a significant relationship between brain-reactive antibody formation and spatial memory performance, regardless of training condition.

Age differences in acquisition and retention of one-way avoidance learning in C57BL/6NNia and autoimmune mice.

Acquisition and 48-h retention of a step-up active avoidance response were studied in separate age groups of C57BL/6NNia mice (aged 1.5, 3.5, 6, 12, or 26 months) and five strains of genetically autoimmune mice differing in life span. The C57BL/6NNia mice showed no change in ability to acquire the avoidance response between 1.5 and 3.5 months, but showed a steady decline in that ability thereafter. Mouse strains with early-onset autoimmune disorder (NZB/B1NJ, MRL/MpJ-lpr, and BXSB/MpJ) showed declines in acquisition capability between 1.5 and 3.5 months of age, whereas mouse strains with mild, late-onset autoimmune disorder (MRL/MpJ- + and NZBWF1/J) showed stable or improved acquisition during that period. Both the C57BL/6NNia and NZB/B1NJ mice showed age-dependent declines in 48-h retention performance by 12 months of age. These findings suggested that while 48-h retention performance deficits were most related to chronological age, avoidance acquisition deficits were related to development of autoimmunity.

Flumazenil improves active avoidance performance in aging NZB/B1NJ and C57BL/6NNia mice

C57BL/6NNia and autoimmune NZB/BlNJ mice aged 12-14 months were tested for acquisition and retention of an active avoidance response following vehicle or flumazenil (40 mg/kg), a benzodiazepine antagonist. Acquisition and retention performance was improved in flumazenil-treated mice when compared with vehicle-treated mice, although the degree of improvement varied with the level of performance in vehicle-treated mice of each strain. The NZB/BlNJ mice, which generally performed more poorly than the C57BL/6NNia mice, showed the greater improvements following flumazenil. These results suggest that antagonism of benzodiazepine receptors leads to improved learning and/or memory performance in mice with spontaneous age-associated deficits.

Autoimmunity and age-associated cognitive decline.

It is suggested that the immune system may play a role in the etiology of age-associated cognitive decline and/or Alzheimers disease. The relationship between brain-reactive antibodies (BRA) and age-associated cognitive dysfunction is reviewed and discussed. A parallel relationship between BRA increases with age and decline of avoidance learning capacity is described in mouse models. Transfer of immunity from old to young mice was found to accelerate both age-related formation of brain-reactive antibodies and age-related decline of avoidance learning capacity. Short-lived mouse genotypes with accelerated autoimmunity were found to show accelerated age-related declines in their ability to acquire an avoidance response when compared with nonautoimmune mice. Overall, these findings suggest that the immune system could be an important target for development of intervention strategies aimed at extending the intellectually competent period of life. Mice in which autoimmunity is accelerated may be useful as models for the development of such interventions.

CGS 8216, a benzodiazepine receptor antagonist, enhances learning and memory in mice ☆

Mice pretreated with the benzodiazepine antagonist, CGS 8216 (2.5, 10, or 40 mg/kg, i.p.) learned a T-maze discrimination to a fixed performance criterion more rapidly than vehicle-treated mice. In retention tests conducted one week later, the drug-treated groups had better first-trial recall and greater difficulty reversing the previously trained maze habit when compared with controls, suggesting improved memory for the previously trained maze habit. The enhanced acquisition and retention following CGS 8216 was similar to that observed previously with another benzodiazepine antagonist, flumazenil (Ro 15-1788). It is postulated that CGS 8216 and flumazenil could act at benzodiazepine receptors to antagonize a tonic inhibitory influence of endogenous, diazepam-like, benzodiazepine receptor ligands on memory processes.

Learning and memory-enhancing effects of Ro 15-4513: A comparison with flumazenil

Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous benzodiazepine-like endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-dependent enhancement of diazepam sensitivity is accelerated in New Zealand black mice

Separate age groups of C57BL/6 and autoimmune New Zealand Black (NZB) mice were compared for diazepam-induced ataxia and barbiturate-induced loss of righting reflex. Between 1 and 3 months of age, both strains showed a similar age-related decrease in ED50 for diazepam-induced ataxia. However, between 3 and 12 months the decrease in ED50 was markedly greater in NZB mice. In contrast, age-related increases in the durations of loss of righting reflex following hexobarbital or barbital were similar in both strains. The results suggest that NZB mice show relatively accelerated age-related increases in sensitivity to benzodiazepine, but not to barbiturates.

Differences in behavioral responses to oxotremorine and physostigmine in New Zealand black (NZB/B1NJ) and C57BL/6 mice

The NZB/BlNJ (NZB) mice are an autoimmune-prone strain, known to develop brain-reactive antibodies in serum at much earlier chronological ages than normal mice. Measurement of locomotor activity in 8-10 month old C57BL/6 (C57) mice following the administration of either oxotremorine or physostigmine, revealed a biphasic response consisting of inhibition at small doses, but increased motor activity at large doses. In contrast, age-matched NZB mice exhibited little inhibition at the smaller doses, but had much greater increases in activity after the larger doses. Similarly, when compared to C57 mice, NZB mice were less sensitive to oxotremorine-induced salivation, diarrhea and visible tremors. Moreover, oxotremorine-induced hypothermia occurred at smaller doses in C57 mice than in NZB mice and was of a greater magnitude. Thus, at an age when NZB mice possess high levels of brain-reactive antibodies, and exhibit impairment in tests of learning/memory, these mice also show diminished responses in several tests of cholinomimetic-induced behavior and physiological alterations.

Autoimmunity and Cognitive Decline in Aging and Alzheimer's Disease

This chapter focuses on the presence of important psychoneuroimmunological factors in the etiology of neurobehavioral pathology associated with aging and Alzheimers disease. The neuroimmunopathological effector mechanisms that could be involved have been identified and characterized in studies of other neurological diseases, and various sites and mechanisms for interactions between the central nervous system and peripheral immune system have also been revealed. Brain-reactive antibodies are found in the sera and cerebrospinal fluid of patients with Alzheimers disease, and some of the antibody populations have specificities matching the neurological targets known to undergo deterioration in Alzheimers disease. The identification of brain-reactive antibodies in association with Alzheimers disease has suggested both novel diagnostics and potentially successful therapeutic approaches. Aging mice show formation of both diverse and specific brain-reactive antibodies, and immune transfer studies have implicated age-related changes in immune function as important factors in the appearance of these antibodies. The same immune factors may be involved in age-related changes in brain functions related to capacity for avoidance acquisition of the age-related acquisition deficits following transfer of immunity from aged to young mice.