Estrogen replacement therapy for the potential treatment or prevention of Alzheimer's disease.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in cognitive abilities. Although basic biological data suggest that estrogen may have neuroprotective and neuroenhancing functions, a number of studies have produced conflicting findings on the use of estrogen for maintaining cognitive function in older people. This review summarizes clinical studies that have examined the effects of estrogen in women with AD.

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Fisher symposium: strategies for the prevention of Alzheimer disease--overview of research planning meeting III.

Even though the prospect for preventing Alzheimer disease seems remote now, a plan must be developed to reach this goal in order to avoid a fiscal crisis in the health care system. The goals of delaying Alzheimer disease and eventually preventing it will become possible as more is learned about the brain mechanisms and risk factors involved. In response to a 1994 Congressional report, the National Institute on Aging in cooperation with the Zachary and Elizabeth M. Fisher Medical Foundation sponsored a workshop to address potential strategies for the prevention of Alzheimer disease. The workshop helped to identify the necessary resources and the types of technical problems involved in developing methods to prevent Alzheimer disease. This volume presents the position papers which served as the springboard for the discussions at the workshop, out of which developed a number of specific recommendations including new epidemiological studies for well defined population groups, identification of high risk populations for treatment and prevention studies, and coupling of new questions and add-on investigations to in-progress studies.

Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.

A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.

Ethanol does not affect serotonin receptor binding in rodent brain.

The effects of ethanol on serotonin (5-hydroxytryptamine, 5-HT) receptor binding in rat and mouse brain were determined under in vitro conditions and in mouse brain following seven days of ethanol ingestion. 5-HT1A receptor characteristics were measured utilizing the agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([ 3H]DPAT), and 5HT2 receptor-binding studies utilized the antagonist [3H]ketanserin. At the highest concentration of ethanol tested in vitro (680 mM), there was only 25% inhibition of [3H]DPAT binding in rat and mouse brain and 14% inhibition of [3H]ketanserin binding in rat brain. Effects of an anesthetic concentration of ethanol (100 mM) on agonist binding in the presence and absence of the guanine nucleotide GTP were also evaluated in vitro in mouse brain. In no case did ethanol (100 mM) significantly affect 5-HT1A or 5-HT2 receptor-binding characteristics. When 5-HT receptor characteristics were measured after mice consumed ethanol for seven days, there was no change in either 5-HT1A or 5-HT2 receptor-binding properties in any of the brain areas examined.

Lymphocyte beta-adrenergic receptor modification in bulimia.

beta-Adrenergic receptor binding on circulating lymphocytes was evaluated in young female bulimic patients (n = 12) and age- and sex-matched normal control volunteers (n = 10). Using iodine 125-labeled cyanopindolol, antagonist binding was evaluated (number of receptors [Bmax] and dissociation constant [KD]), and using isoproterenol competition of cyanopindolol binding, the concentration required to inhibit binding by 50% (IC50) for isoproterenol and the agonist affinity measure of KL/KH (ratio of dissociation constants for the low- and high-affinity states of the receptor) were determined. Plasma norepinephrine (NE) level was also measured. There was a trend toward lower plasma NE levels in the bulimic patients. The KL/KH ratio in bulimic patients was significantly greater than that for the normal volunteers, indicating increased receptor coupling. The KL/KH ratio was not significantly correlated with plasma NE level. Neither Bmax nor KD was different between the two groups. These findings suggest that beta-adrenergic receptors in bulimic patients may be more responsive than in normal subjects, without alteration of the traditional measures of receptor responses, a difference that cannot be explained on the basis of plasma NE. These findings provide another line of evidence for altered regulation of the noradrenergic system in bulimic patients during a controlled phase of their illness.

Serotonin2 agonist administration down-regulates rat brain serotonin2 receptors.

Daily administration of D-lysergic acid diethylamide (LSD) was previously shown to decrease serotonin2 (5-HT2) receptor binding in rat brain. Recently, 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropane, the substitution being with either iodine (DOI) or bromine (DOB), have been suggested to be relatively selective 5-HT2 agonists. These compounds share common behavioral and neurophysiological effects with LSD, suggested to be 5-HT2 receptor mediated, and the purpose of the present study was to determine whether they also affect 5-HT2 receptor binding after systemic administration in a similar way to LSD. Administration of DOI (1.0 mg/kg) or DOB (0.5 mg/kg) for 7 days resulted in a decrease in 5-HT2 binding, as evaluated with [3H]ketanserin, similar to the decrease after LSD. In a further evaluation of the parallelism of LSD and 5-HT2 agonists, it was found that 24 hr after one administration of a low dose of LSD (130 ug/kg) or DOI (1.0 mg/kg), there was no change in binding, but there was a decrease 24 hr after a high dose (LSD, 650 micrograms/kg; DOI, 7.0 mg/kg). Four hours after the high dose of LSD or DOI there was also a decrease in 5-HT2 binding. Thus, results have shown that 5-HT2 agonists are capable of down-regulating 5-HT2 receptors and that LSD acts in a parallel fashion. This study has also demonstrated that 5-HT2 receptors can be modified within hours after drug administration.

Effects of caffeine and L-phenylisopropyladenosine on locomotor activity of mice.

C57BL/6J and DBA/2J mice were used to determine if possible differences in the behavioral response to caffeine might be related to differences in A1 adenosine receptors. Caffeine stimulated locomotor activity of both strains, but the dose-response relationship and time course of drug action differed according to strain. Although their response to caffeine differed, the strains did not differ in response to the A1 adenosine agonist L-phenylisopropyladenosine (PIA) nor in the binding of the A1 agonist [3H]N6-cyclohexyladenosine (CHA) in various brain regions. Thus, the behavioral differences in response to caffeine could not be accounted for by differences in adenosine binding. Of alternative mechanisms, strain differences in A2 receptors appear to be the most promising.

Regulation and evolving science: neurobehavioral toxicology.

A number of policy and scientific issues are associated with the introduction of emerging or non-traditional scientific disciplines into the governmental regulatory apparatus. The present discussion derives from the issue of the extent of toxicological testing required for the evaluation of the health and safety aspects of pesticides and other compounds at the Environmental Protection Agency. The area of neurobehavioral toxicology is used as a case study for the introduction of a new biological endpoint into the regulatory arena. In that context, this paper addresses the following policy/regulatory issues: why expand the endpoints for toxicity testing from those currently in use; what is the current regulatory situation; what are the alternative means by which a new endpoint could be incorporated into the regulatory process; what would be the consequences of requiring examination of new endpoints? In the process of evaluating those issues, scientific issues involved with the selection of test systems are discussed. They include the selection of particular tests, the testing strategy, and the validity, reliability and sensitivity of the tests.

Combined inhibition of serotonin uptake and oxidative deamination attenuates audiogenic seizures in DBA/2J mice.

We previously reported that 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THBC) attenuated audiogenic seizures (AGS) in 21-day-old DBA/2J mice and also inhibited brain monoamine oxidase-A (MAO-A) and serotonin (5-hydroxytryptamine, 5-HT) uptake leading to increased brain 5-HT concentration. In this study, the sensitivity of AGS to 5-HT manipulation was evaluated by utilizing drug combinations which paralleled the actions of 6-MeO-THBC and which also have been associated with the production of a serotonergic motor syndrome in rats. Combination of a specific 5-HT uptake inhibitor (fluoxetine or citalopram) with the MAO-A inhibitor clorgyline inhibited AGS more effectively than the individual drugs but combination with the MAO-B inhibitor deprenyl did not. Combined administration of clorgyline plus deprenyl also suppressed AGS. Inhibition of AGS by tryptophan was potentiated by combination with either of the mixed MAO inhibitors nialamide or tranylcypromine. The effects of these drugs individually and in combination on brain MAO-A and MAO-B activity and 5-HT uptake were also determined ex vivo and were consistent with expected mechanisms of action. These results suggest, first of all, that the inhibition of AGS produced by 6-MeO-THBC is a consequence of its combined MAO-A and 5-HT uptake inhibition properties. Secondly, the similarity of results of pharmacological manipulations of the 5-HT system which produce the rat motor syndrome and which inhibit AGS in the mouse suggests that AGS in 21-day-old DBA/2J mice may be a useful system for assessing functional consequences of these serotonergic manipulations.

Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain.

The effect of ten daily injections of saline or d-lysergic acid diethylamide (LSD) (260 micrograms/kg i.p.) on serotonin1 (5-hydroxytryptamine1, 5-HT1) and 5-HT2 receptor binding was determined in brain membranes from rats killed 24 h after the last injection. [3H]LSD (3.0 nM) was used with either 30.0 nM 5-HT or 70.0 nM cinanserin to estimate 5-HT1 and 5-HT2 receptors, respectively. LSD administration decreased 5-HT2 binding in cortex, striatum, hippocampus, and diencephalon/midbrain without altering 5-HT1 or total specific binding.

The central actions of glycine and strychnine on prolactin and LH secretion.

Unanesthetized diestrous female rats were tested for the prolactin response following an intraventricular injection of several doses of the neuroinhibitory amino acid glycine, and the antagonist strychnine. Glycine in doses of 1.0 or 0.1 mumoles increased pituitary prolactin release, significantly elevating plasma hormone levels. Direct pituitary effects for glycine were not observed. Strychnine, a glycine antagonist, was effective in blocking the prolactin release caused by glycine in doses as low as 5 nmoles. Intraventricular glycine administration did not alter pituitary LH release significantly. These studies suggest a central stimulatory role for the neuroinhibitory amino acid glycine in provoking prolactin secretion, and that this effect is strychnine sensitive.

Monamine oxidase activity in bovine retina: subcellular distribution and drug sensitivities.

The activities of monoamine oxidase (MAO)-A and -B in subcellular fractions of bovine retina were determined using serotonin and beta-phenylethylamine, respectively, as substrates. The subcellular fractions were a P1 fraction containing photoreceptor cell synaptosomes and a P2 fraction enriched with small synaptosomes derived from the inner plexiform layer. MAO activities in the homogenate and P1 fraction were similar and lower than those in the P2 fraction for both MAO-A and -B. The activity of MAO-B was greater than that of MAO-A in all fractions, but the relative distribution of MAO-A and -B did not change in the different fractions. Studies using various MAO inhibitors showed effects which were generally similar to those seen in brain. These results provide further support for the localization of terminals of retinal monamine-containing neurons to the inner plexiform layer and suggest that pharmacological modification of MAO activity in the retina could play an important role in retinal function via changes in monoamine metabolism.

6-Methoxy-1,2,3,4-tetrahydro-beta-carboline: a specific monoamine oxidase-A inhibitor in CF-1 mouse brain.

The activities of monoamine oxidase (MAO)-A and MAO-B (using [3H]serotonin and [14C]beta-phenylethylamine, respectively, as substrates) were determined in homogenates of whole mouse brains using a solvent extraction procedure. 6-Methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-TH beta C) had an IC50 of 1.6 microM, in vitro, for MAO-A using whole brain homogenate. A time course of apparent in vivo MAO-A inhibition using 6-MeO-TH beta C (100 mg/kg i.p.) showed a maximal inhibition by 1 h (56%), a decline to 30% at 12 h, and no inhibition at 24 h. There was a maximal inhibition of MAO-B by 4 h (16%). A dose-effect study done at 1 h after injection showed 6-MeO-TH beta C to inhibit MAO-A by 23% at 25 mg/kg, 43% at 50 mg/kg, 58% at 100 mg/kg and 73% at 150 mg/kg; for MAO-B there was no inhibition at 25 and 50 mg/kg and 16% inhibition at 100 mg/kg. The data thus indicate that, at doses less than or equal to 50 mg/kg, 6-MeO-TH beta C is a specific MAO-A inhibitor in vivo.