Showing papers in "Annals of the New York Academy of Sciences in 1986"

Uterine receptivity for nidation.

Abstract: Receptivity is a notion that arose during the last two decades mainly from studies using the technique of egg transfer. It is by definition the unique and exclusive situation in which the uterus allows nidation to occur. In fact, since the initial observation of M. C. Chang' in the rabbit, the importance for implantation of a chronological relationship between the age of the embryo and the developmental stage of the endometrium has been shown in all species studied, although the time limits for a successful transfer appear to be extended to several days in some species. In more precise terms, a cooperation between the embryo and the uterus is necessary for egg implantation to occur. This can be achieved only if both partners have reached a certain degree of maturity. The embryo must have reached the blastocyst stage, thus being ready to participate in the nidation process. It also has to be present in the uterus at the proper time, that is, when the endometrium is undergoing the specific changes that are referred to as \"phase of receptivity.\"* In several species the blastocyst can, under certain conditions, wait for receptivity to occur. Thus, in species such as the rat3 and the mouse: the transfer of an egg to a developmentally younger uterus can even be more successful than when realized under a strict chronological synchronization. On the contrary, developmentally younger eggs when placed in advanced uteri can be forced to accelerate their development in order to be ready at the proper time, as in the case of sheep.' However, it can be considered a general rule that beyond the time at which nidation is normally expected to occur, that is, beyond the phase of receptivity, the intrauterine survival of transferred embryos of any stage becomes impossible. The uterus has entered into refractoriness, the state of nonreceptivity.2.6 A constant feature of the receptive endometrium is its high vascular reactivity towards the blastocyst stimulus or artificial This reactivity,

Quantum Theory of Measurement

Abstract: Quantum mechanics was discovered sixty-one years ago in 1925. It began with Heisenberg’s introduction of matrix mechanics, which was followed by Schrodinger finding his wave equation. Then Dirac gave a formulation of quantum mechanics that contained the two earlier theories as special cases and was much more general. The interpretation of the wave function as a probability amplitude was added by Born in 1926. The following discussion of the problem of measurement in quantum mechanics is limited to the nonrelativistic theory. Hence, there will be no mention of photons or spin. No doubt I will be taking other things for granted and I hope you will be able to infer them from the context. The Born probability interpretation was very well suited for discussing the blackening of a photographic plate exposed to a beam of electrons scattered by an atomic system. It was necessary to decide whether the wave function represented a beam of many electrons or only a single electron. One knows now that for the analysis of most such experiments, the theory is applied in a probabilistic way for a single electron, and the blackening of the plate by a beam of many electrons is worked out by plausible nonquantum mechanical considerations. The absolute square of the wave function at a point of the plate gives the probability for finding the electron there. If we had only to deal with that kind of problem in wave mechanics, there might not have been need for this conference. However, quantum mechanics lent itself very naturally to an enormous generalization of the theory of measurement. Dirac had introduced the two ideas of states and observables. The state was a generalization of the wave function, but without the emphasis on space coordinates associated with the SchrBdinger wave function. Observables were physical quantities that could be represented by Hermitian operators that were often, but not always, taken over from classical mechanics. Rules were given for calculation of real numbers (called expectation values) for any observable of a system in any of its states. The operator observables had eigenstates and eigenvalues. For the Hamiltonian observable, H(q,p), of a conservative dynamical system, the eigenstates were in close correspondence with the stationary states of the corresponding wave mechanical problem, and the eigenvalues were the stationary state energies known from the earlier quantum theory of Bohr. The structure of quantum mechanics makes it very natural to pretend that some (if not all) of the observables that characterize a dynamical system can be “measured” experimentally at least in principle. The following assumptions are made: If the state, 9, is one of the eigenstates, 9,, of the observable, R, a measurement of R should give the corresponding eigenvalue, R,. A measurement of observable Cl for a system in any state, 9, should give one of the eigenvalues, On, of 0. If this state, 9, is a linear combination of eigenstates of the form,

Free energy simulations.

Abstract: Monte Carlo or molecular dynamics simulations involve the numerical determinations of the statistical thermodynamics and related structural, energetic and (in the case of molecular dynamics) dynamic properties of an atomic or molecular assembly on a high-speed digital computer. Applications to molecular systems range from the study of the motions of atoms or groups of atoms of a molecule or macromolecule under the influence of intramolecular energy functions to the exploration of the structure and energetics of condensed fluid phases such as liquid water and aqueous solutions based on intermolecular potentials. The quantities determined in a typical Monte Carlo or molecular dynamics simulation include the average or mean configurational energy (thermodynamic excess internal energy), various spatial distribution functions for equilibrium systems, and time-correlation functions for dynamical systems, along with detailed structural and energetic analyses thereof. Diverse problems in structural and reaction chemistry of molecules in solution, such as solvation potentials, solvent effects on conformational stability and the effect of solvent on chemical reaction kinetics and mechanism via activated complex theory also require a particular knowledge of the configurational free energy, which in principle follows directly from the statistical thermodynamic partition function for the system. Considerations on free energy in molecular simulations take a distinctly different form for intramolecular and intermolecular degrees of freedom. For the intramolecular case, the problem involves vibrational and librational modes of motion on the intramolecular energy surface. We will discuss briefly a t the end of this paper the harmonic and quasiharmonic approximation used to compute vibrational contributions to the free energy, but we will restrict the focus herein to the intermolecular case, where the particles of the system undergo diffusional motion and a harmonic or quasiharmonic treatment breaks down. These considerations apply also in the case of a flexible molecule, where conformational transitions are effectively an intramolecular “diffusional mode.” Conventional Monte Carlo and molecular dynamics procedures for diffusional modes, although firmly grounded in Boltzmann statistical mechanics and dynamics, do not proceed via the direct determination of a partition function because of well-known

Hopelessness as a predictor of eventual suicide

Abstract: Clinicians are often faced with the awe-inspiring problem of assessing and predicting a person's suicide potential. The decision has important treatment implications as well as social and legal consequences. If the assessment is incorrect, its implications may be traumatic or even tragic. For these reasons, there is a pressing need for valid assessment techniques that enable early recognition of high-risk suicidal individuals. Recognition of variables associated with high suicidal risk is important for early intervention and appropriate treatment.

Conditioned fear-induced opiate analgesia: a competing motivational state theory of stress analgesia.

Abstract: Endogenous analgesic systems may play a critical role in modulating the behavioral responses that evolved as antipredator defense. Animals can innately recognize certain environmental danger signals and can learn to recognize others. To such danger stimuli they react with complex and coordinated innate defensive behavioral patterns.’ Bolles and I have pointed out that nociceptive stimulation delivered by the predator to the prey may disrupt these defensive behavioral patterns? For example, limping on an injured leg would compromise flight; the movements involved in licking a wound could attract a predator’s attention. If endogenous analgesic mechanisms were activated by the same stimuli that activate defensive behaviors, analgesia could function to prevent these disruptive influences of nociception on coordinated defensive activities. We incorporated such a role for endogenous analgesia into a more general model of aversively motivated behavior that we call the perceptual-defensive-recuperative m ~ d e l . ~ . ~

Three Coupled Relations for Relaxations in Complex Systemsa

Abstract: Some time ago, one of us'.' introduced a model of relaxation in complex systems in which the relaxation rate conventionally considered as time independent in simpler systems may become time dependent. Relaxations are manifested by the decay (or saturating growth) of some macroscopic variable such as polarization, stress, electric field, volume, or enthalpy, in appropriate complex systems such as glasses, amorphous polymers, polymer melts, viscous liquids, ionic conductors, and amorphous semicond u c t o r ~ . ~ The mechanism for the macroscopic relaxation can often be traced on the microscopic level, however, to a fundamental relaxation mode with simple relaxation rate W, = 7;' of the primitive species (PS) that is isolated except for its interaction with the heat bath. The PS can be a molecular moiety or a structural unit in structural relaxations; a dipolar group or a mobile charged entity (ionic or electronic) in dielectric relaxations; a polymer chain in polymer melt terminal viscoelastic relaxation; etc. In many complex systems, the fundamental relaxation mode often occurs within the domain of short-range order so that all PSs have essentially the same W,. For example, most glasses, metallic glasses, and viscous liquids have some short-range order. Even in a linear polymer melt, monodispersive samples can be prepared such that all chains have almost the same length (or molecular weight, M ) . Here the PS can be identified as the individual polymer chains. An example of a fundamental mode is the terminal ( p = 1) Rouse mode4 which describes the longest wavelength relaxation of the chain. The simple relaxation rate W, is the same for all chains. It is the nature of complex systems, however, that an individual PS cannot be considered to be completely isolated from other PSs or other neighboring species. Rather, a PS is coupled via molecular, ionic, electronic, or other interactions with its complex environment, an environment that may include other PSs. Relaxation of a PS then involves sequential cooperative adjustments by both its complex environment and the PS itself. For the example of entangled monodisperse linear polymer melts, the terminal Rouse mode of any chain cannot relax without coupling via entanglements with other chains. Such cooperative adjustments act to slow the simple relaxation rate W, at times longer than a time t , = w;' that is characteristic of the cooperative adjustments. The time t , is determined by the complex environment, which has a

Effects of Stimulus Parameters on Cognitive Side Effects

Abstract: This symposium has already focused on recent experimental data directed toward an understanding of the differential effects of electrode placement upon both therapeutic response and adverse cognitive effects with electrmnvulsive therapy (ECT). In addition, we have yet to hear a number of further expositions on this subject. The available data, presented both here and elsewhere, suggest that unilateral nondominant (UL) ECT is roughly as effective as bilateral (BL) ECT in producing a remission in severely depressed patients.’” At the same time, it must be pointed out that technical factors such as sufficient interelectrode distance and the assurance of suprathreshold stimuli also appear to play a role in the efficacy of UL treatments. In addition, there is also a possibility that some patients might respond better to the combination of more intense seizures and denser organic interictal changes produced by bilateral stimulation. The situation with regard to adverse effects, however, is considerably clearer: unilateral nondominant ECT offers a distinct advantage to bilateral treatments with regard to the presence and extent of cognitive disruption, a t least with respect to those functions that depend on the dominant herni~phere.~ Still, the extent of data indicating that such amnestic differences exist longer than a few weeks has been largely limited to reports of self-ratings.Another form of ECT modification, discussed both within this volume as well as elsewhere in the literature, though to a lesser degree than electrode placement, is the

Differential localization of MAP-2 and tau in mammalian neurons in situ.

Abstract: Microtubules are one of the major constituents of the neuronal cytoskeleton. Although it is generally accepted that these linear polymers play an important role in regulating cell morphology and intracellular transport processes, the mechanisms that dictate their assembly, their interactions with each other, as well as their interactions with other cytoplasmic structures are poorly understood. In addition to their dimeric tubulin subunits, microtubules contain numerous accessory proteins known collectively as microtubule-associated proteins (MAPs).' It is thought that the MAPs control the dimer-polymer equilibrium' and mediate the interaction of microtubules with other cytoskeletal elements and cytoplasmic organelle^.^^ Therefore, it is likely that the MAP composition of microtubules will affect not only microtubule stability but also the structure and stability of the surrounding cytoplasmic elements with which these microtubules interact. Most of what is currently understood regarding microtubule stability stems from studies performed on microtubules isolated by repetitive cycles of in vitro assembly' from soluble adult brain extracts. Initial homogenization of adult whole brain results in the simultaneous mixing of many regions, cell types (neurons and glia), and cell compartments (dendrites and axons) that in turn, results, upon purification by assembly-disassembly procedures, in a composite microtubule polymer containing as many as 21 tubulin isoforms' and numerous MAPS.'~'' In vitro analyses of brain microtubule assembly have definitively demonstrated that two MAPs, MAP-2 (MI > 300,000)\" and tau (MI 55-62,000)L2 stimulate assembly stoichiometrically and can displace each other from binding sites on microtubules (Kim et al., this volume). Results such as these lead one to speculate whether or not these two proteins are present on the same microtubule in situ and raise the possibility that they may be differentially compartmentalized in brain tissue. In this regard, MAP-2 is known to be a predominantly dendritic protein,\"-\" whereas the distribution of tau in brain tissue has not been previously reported. Because different neuronal cell compartments perform different tasks, an understanding of microtubule function requires the precise localization of MAP-2 and tau to specific cell compartments and subclasses of microtubules. To this end, the present monograph outlines our initial immunohistochemical and biochemical localization experiments using monoclonal antibodies to MAP-2 and tau in both adult and developing brain.

Thrombin-cellular interactions.

Abstract: It is clear that there are a number of different types of reactions between thrombin and the cell surface (TABLE 6). In one type, thrombin binds to cell-surface receptors resulting in cellular activation. In other types of reactions, there are at least two components to the thrombin-specific pathway of cellular activation: a classical receptor to which thrombin binds, and a protein that is cleaved. In both types of reactions, thrombin binding and/or proteolysis is linked to changes in GTP-binding proteins, protein kinase C, or other pathways. In most cases, the receptor and membrane substrates involved in cellular activation are not well characterized. In another type of reaction, the interaction between thrombin and proteins in the extracellular fluid is regulated by cell-surface receptors. Binding of thrombin to these receptors can result in acceleration or inhibition of the reactions with the soluble proteins. In the fourth type of reaction, thrombin cleaves a cell-membrane protein that is involved in reactions with plasma proteins. Recognition of the different types of interactions between thrombin and the cell surface is necessary for the correct interpretation of experimental observations. Although the term receptor has classically referred to a cell-surface component to which an agonist binds, it is now clear that there are additional membrane components that specifically bind potential agonists not leading to cellular activation.

Preferential stimulation of dopamine release in the nucleus accumbens by opiates, alcohol, and barbiturates: studies with transcerebral dialysis in freely moving rats.

Abstract: Opiates, alcohol, and barbiturates are widely abused drug classes, These drugs are known to possess behavior-stimulating and reinforcing properties in animals-’ Indeed opiates, alcohol, and barbiturates produce a complex behavioral syndrome characterized by motor stimulation and depression depending on the animal species, the dose, and the time of observation after administration.e’ Brain dopamine has been related both to the reinforcing*-” and the motor ~timulating’~-” properties of opiates, alcohol, and barbiturates. This evidence, however, is essentially indirect since it is based on the interaction of opiates, alcohol, and barbiturates with drugs interfering with DA tran~rnission’~~’~ or on indirect indices of DA function like DA metabolism and synthesis,” recording of dopaminergic neuronal firing a~tivity,2’-~’ or measurement of DA release in vitro or in anesthetized animals?”6 We have recently introduced the technique of brain dialysis in awake, freely moving rats as a means to correlate behavioral activity to changes in release and metabolism of brain DA.*’*** Using this method we have studied the effect of opiates, alcohol, and barbiturates on the release and metabolism of DA in two terminal dopaminergic areas, the nucleus accumbens and the striatum and its relation to behavior. We report that low doses of opiates, alcohol, and barbiturates stimulate DA release specifically in the nucleus accumbens and this effect is related to the behavioral stimulating effects of these drugs both on a time and on a dose basis. The results suggest that specific activation of dopaminergic transmission in the limbic system is a common mechanism for the stimulant and reinforcing properties of drugs of abuse.

Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin.

Abstract: The most important goal of our laboratory is to understand how several hormones, each of which presumably has a unique mechanism of action, provide an integrated biological response. We have concentrated our efforts on the regulation of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) (EC 4.1.1.32) in cultured H4IIE cells, a clone of Reuber H35 rat hepatoma cells. PEPCK catalyzes the conversion of oxalacetate to phosphoenolpyruvate and is a rate-limiting gluconeogenic enzyme. Cyclic AMP, which mediates the action of glucagon, and glucocorticoids increase the rate of synthesis of this protein and enhance gluconeogenesis.'*2 Insulin decreases the rate of synthesis of PEPCK and correspondingly decreases glucone~genesis.'~~ By coupling measurements of PEPCK synthesis with assays capable of quantitating the activity and the amount of mRNA coding for PEPCK (mRNApepcK), we were able to exclude the following possibilities as means of hormonal control: alterations of mRNAPEPCK translational efficiency, alterations in the rate of mRNAPEPCK egress from the nucleus, and changes in the rate of degradation of mRNAPEPCK in the nucleus or cytoplasm.2-M Our interpretation of these studies was that CAMP, glucocorticoids, and insulin affect mRNAPEPCK production. The purpose of the studies described in this paper was to determine whether each of these molecules regulated PEPCK synthesis at the level of PEPCK gene transcription and then to explore how they acted in concert. Steroid hormones are thought to regulate metabolic processes by affecting the rate of transcription of specific genes. The first step in this action involves the binding of the ligand to intracellular receptors. The hormone-receptor complex binds in a sitespecific manner to DNA, and thereby regulates the transcription of specific genes.

Multiple endogenous opiate and non-opiate analgesia systems: evidence of their existence and clinical implications.

Abstract: The observation that various environmental stimuli can profoundly modulate the response of animals to noxious stimuli' has stimulated widespread interest in this topic. This work is intimately related to the discovery of endogenous opiates;* and that discovery, in turn, stimulated further examination of analgesia systems. This chapter briefly reviews the development of these concepts, summarizes evidence that such systems can be activated by environmental stimuli, and reviews recent evidence for the existence of non-opiate analgesia systems. A simple invariant relationship between stimulus intensity and the magnitude of pain perception is often not present. Earlier theories of pain perception recognized this fact, despite the lack of direct evidence to support it3A Interest in the detailed study of pain modulatory circuitry was spurred by the observation that electrical stimulation of specific brain areas could powerfully suppress the perception of pain.s Further investigation of stimulation-produced analgesia provided considerable detail about the neural circuitry inv0lved.69~ Importantly, several similarities were recognized between these observations and information emerging from a concomitant resurgence of interest in the mechanisms of opiate analgesia.6 The most important parallel facts revealed by these studies were (1) effective loci for both opiate and stimulation-produced analgesia6 lie within the periaqueductal and periventricular gray matter of the brain stem; (2) opiate analgesia'O,ll and stimulation-produced analgesia'* are both mediated, at

Suicidal people. One population or two

Abstract: A continuing controversy in the field of suicidology has been how to characterize and label the subject under study. The generic term suicidal behavior variously includes completed suicide, nonfatal deliberate self-harm (e.g., suicide attempts, suicide gestures, parasuicide, self-injury, self-poisoning, self-harm) with or without suicidal intent, suicide communications, including suicide threats, and suicide ideation. It is not unusual to find studies where subjects are mixed together from each of these categories with little attention to differences that might exist between the groups. Less common but still too frequent is the practice of studying one group, e.g., individuals who deliberately harm themselves but do not die, and drawing conclusions about another group, e.g., suicide. This terminological and methodological confusion reflects a similar confusion about the nature of the population under study. In an influential 1958 monograph, Stengel, Cook, and Kreeger made a controversial argument that individuals who suicide and those who deliberately but nonfatally harm themselves (suicide attempters) represent two separate populations.’ Their primary rationale was that the two groups could be distinguished both epidemiologically and in terms of the observed and functional characteristics of the suicidal acts. More recently, Kreitman and his colleagues have made a similar argument, contending that parasuicides (a term they introduced) form a population distinct from suicides? The basis of their argument is that many nonfatal parasuicidal acts do not appear motivated by an intent to die, and thus are improperly viewed as unsuccessful attempts to suicide. Furthermore, they contend that intent at the time of a suicidal act is difficult to measure and is often based on questionable clinical inferences. Intent to die, therefore, should not be part of the criteria for defining suicidal behavior. This point of view is in marked contrast to the previous assumption that individuals who contemplate suicide, threaten suicide, attempt suicide, or otherwise harm themselves, and those who in fact kill themselves, are drawn from a single population. Suicidal behavior is seen as on a continuum of intensity with suicide ideation at one end and completed suicide at the other. Lester and Beck’,4 and Lester et aLs have argued that individuals who deliberately harm themselves are members of a single suicide population. Weiss has taken a similar position, labeling those who are characterized by high medical risk and high intent to die as “aborted successful suicides.””

Simulations of Proteins in Water

Abstract: Molecular dynamics simulations of hydrated protein crystals have been carried out in only three cases: two simulations of pancreatic trypsin inhibitor (PTI) and one of avian pancreatic polypeptide (aPP). The purpose of such simulations is to evaluate the accuracy and reliability of molecular dynamics simulations of hydrated proteins. A 40-psec simulation on crystalline PTI, involving 4 protein molecules (of 58 amino acids each), 552 water molecules, and 24 Cl- ions is described. Considerations are energetic and structural stability, division of interaction energy among water and protein, and precision of average structure and structural fluctuations compared to X-ray data from a new 0.94-A resolution study of Wlodawer et al. Water and ion dynamics are considered by analysis of diffusional motions and of residence times of water molecules in specific sites.

Personality and suicide

Abstract: Individuals with psychiatric disorders are at greatly increased risk for suicide: Robins et al. found that 94% of suicides had a psychiatric disorder,' Barraclough found similar rates in Britain: and Martin et al. found suicide rates to be 15 times higher in psychiatric outpatients than in matched nonpsychiatric controls? Most suicide studies have focused on Axis I disorders: increased risk has been identified for primary affective disorders;\" ~chizophrenia;~-\" and Although the relationship between Axis I1 disorders and suicide is less well established, several reports suggest that personality disorder patients represent a significant proportion of completed suicides and even more at tempter^:^^^^^.^^^^ moreover, the presence of a concurrent personality disorder may increase suicide risk in patients with Axis I di~orders.2~~' This paper summarizes the literature on the two personality disorders (borderline and antisocial) and on the personality traits most associated with suicide behavior, outlines some of the methodological problems involved in this type of research, and discusses the clinical and research implications of available findings.

Smoking and interstitial lung disease. The effect of cigarette smoking on the incidence of pulmonary histiocytosis X and sarcoidosis.

Abstract: Cigarette smoking produces marked alterations in the lung parenchyma and in the population of immune and inflammatory cells present in the lower respiratory tract. These cigarette-induced changes appear to influence the incidence of two different interstitial lung diseases, histiocytosis X and sarcoidosis. Smoking is a strong risk factor for the development of pulmonary histiocytosis X, since the incidence of smoking is very high among patients with histiocytosis X: 90% of the patients with histiocytosis X were smokers; 46% of the controls were smokers (p less than .001). In contrast, smoking appears to reduce the incidence of sarcoidosis: 31% of the patients with sarcoidosis were smokers (p less than .05 compared to controls). In an effort to understand how cigarette smoking influences the incidence of these two disorders, we compared the numbers and types of immune and inflammatory cells recovered by bronchoalveolar lavage from nonsmoking and smoking controls and patients with histiocytosis X and sarcoidosis. Although nonsmoking patients with histiocytosis X did not have a significant increase in the number of alveolar macrophages recovered by lavage (p greater than .2 compared to normals), smoking patients had an increase in the number of alveolar macrophages similar to that observed in the control population. In contrast, the number of macrophages recovered from patients with sarcoidosis who smoked was considerably less than that observed in normal smokers (p less than .05 comparing patients with sarcoidosis and controls who smoked 1-20 cigarettes/day). This difference in the intensity of the cigarette-induced macrophage alveolitis observed in the two patient groups may be important in explaining the opposite effects of cigarette smoking on the incidence of histiocytosis X and sarcoidosis.

The relationship between cardiovascular and pain regulatory systems.

Abstract: An increasing amount of anatomical, physiological, and pharmacological evidence suggest that pain inhibitory circuitry is linked with cardiovascular regulatory systems in man and laboratory animals. Induction of hypertension in rats by different methods (mineralocorticoid treatment, stenosis of renal artery, or social deprivation) is associated with reduced responsiveness to noxious thermal stimuli (hot-plate) or to noxious mechanical stimuli (paw pressure). Genetically hypertension-prone rats derived from the SABRA strain and spontaneously hypertensive rats derived from Wistar/Kyoto strain also display a similar hypoalgesia. Acute increases in blood pressure are associated with reduced sensitivity to painful stimuli. Additionally, the interaction between blood pressure and pain perception has also been supported by the demonstration that various experimental interventions that diminish the magnitude of hypertension also attenuate the hypoalgesia. Recent clinical findings are also in agreement with the laboratory animal findings since sensory and pain thresholds have been shown to be significantly higher in unmedicated essential hypertensive subjects compared to normotensive controls. Thus, the human data corroborate animal data and suggest that a relation between blood pressure and pain sensitivity is likely to be a general phenomenon. It is unlikely that damage to peripheral pain fibers caused by a change in blood pressure contributes to the observed hypoalgesia. Naloxone, which has no effect on blood pressure, returns the pain sensitivity to normal levels. Behavioral tests (open field and motor activity cage) of normotensive and of renal and genetically (SBH and SHR) hypertensive rats exclude the possibility of a general motor deficit in hypertensive rats. Endogenous opioid peptides in central and peripheral nervous systems as well as in endocrine organs are implicated, although non-opioid mechanisms are also evident. Activation of baroreceptor afferents by acute or chronic increases in arterial or venous blood pressure may play an important role in the somatosensory responses associated with the increase in blood pressure. Coordinated cardiovascular-pain regulatory responses may be part of an adaptive mechanism that helps the body to face stressful events.

Cerebral blood flow and metabolic rate during seizures. Relationship to epileptic brain damage.

Abstract: UNLABELLED After long periods of status epilepticus, selective neuronal necrosis is incurred in the neocortex (layer III-IV), in the hippocampus (CA1 and CA4), and in the thalamus (VPL-VPM). In these areas the cerebral metabolic rate for glucose is increased to between 200-300% of control, indicating a correlation between neuronal damage and enhanced neuronal activity. Measurements of local cerebral blood flow indicate that the damage is not due to insufficient supply of oxygen. In most rats with status epilepticus lasting longer than 30 minutes, an infarction develops in the substantia nigra pars reticulata. In this region the metabolic rate is first increased but later during the seizure activity falls to very low values indicating cell necrosis. CONCLUSION prolonged neuronal hyperactivity with a concomitant increase in the metabolic rate for glucose is a prerequisite for the development of neuronal damage. However, the necrosis of the SNPR demonstrates that other factors determine the vulnerability of neurons to hyperexcitation, e.g., the type of agonist acting on the neuron.

The migration of substances in the neuronal microenvironment.

Abstract: An inescapable characteristic of the neuronal microenvironment is the diffusion of substances, whether from capillary to cell or from preto postsynaptic site. Since the reticular theory of the nervous system was laid to rest by Ramon y Cajal’ and the subsequent use of the electron microscope, it has been established that the cellular entities of the nervous system are distinct entities. Some modification of this view has taken place with the demonstration of gap junctions between specific cells, but overall, cellular isolation appears to be a necessity, presumably to ensure selective molecular information transfer. Given this fact, diffusion is, to borrow a phrase from Sherrington: the “final common path” for all substances to reach cells in the nervous system. This path is constrained by the geometry of the neuronal microenvironment. A fundamental characteristic of all physiological systems is the movement of substances. We may broadly divide this process into two categories: energetic and informational. By the former we signify the movement of metabolic substrates, products, and by-products responsible for maintenance of the living organism. Such migrations are usually characterized by the relatively large fluxes involved. In contrast, informational flows are not destined to provide fuel, but rather to change the state or behavior of the recipient, that is, to signal or communicate. Only small amounts of an “informational substance” (see Schmitt’ for the origin of this term and a review of the concept) are required, but the information content is large. In addition to the quantity of substance involved, informational substances are distinguished from energetic by the presence of specific receptors that enable signal transduction. All parts of physiological systems feature both energetic and informational flows, but the balance is usually in favor of the energetic. The brain differs radically in this respect; here information flows have achieved extraordinary prominence, and the energetic flows have become subservient to the task of providing energy for the processing of information and for maintaining the environment in a state where communication can take place.

Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier.

Abstract: Osmotic opening of the blood-brain barrier (BBB) most likely is mediated by modification of interendothelial tight junctions, subsequent to shrinkage of cerebrovascular endothelial cells, and not by stimulation of transendothelial vesicular transport or by channel formation. This paper summarizes evidence for this conclusion: osmotic BBB opening is mediated by endothelial cell shrinkage, electron microscopy, with single or serial thin sections, demonstrates penetration of intravascular tracer into brain via tight junctional complexes, the BBB remains open after the brain is fixed, osmotic BBB opening is rapidly reversible, and is insensitive to phenothiazines, and BBB closure following osmotic treatment is size-dependent, indicative of a sieve (pore) mechanism with bulk flow. The entire mechanism of vesicular transport in normal tissue is, furthermore, in doubt, because vesicles that are found in tissue layers connected by tight junctions (e.g., frog nerve perineurium and capillary endoneurium) do not support macromolecular transport.

Behavioral and Neurochemical Consequences Associated with Stressors

Abstract: A series of neurochemical changes occur in response to stressors that may permit the organism to contend with environmental demands. When the organism is exposed to a stressor the utilization and synthesis of brain NE and DA increases. Under conditions where utilization exceeds synthesis, owing either to the nature of the stressor (uncontrollability), experiential factors (e.g., prior exposure to acute stressors), or organismic variables (e.g., strain, age), reductions of the amine may be incurred. It is suggested that the reduced amine concentrations leave the organism less well prepared to deal with the demands placed upon it, and ultimately increase vulnerability to psychological disturbances. It follows that the more persistent the amine reduction, the greater the probability of pathology being engendered. In effect, in our analyses of stressor effects it is not sufficient merely to determine whether amine reductions occur, but also to assess the ability of the system to re-establish adequate levels and turnover. Additionally, since stressors may result in the conditioning or sensitization of neurochemical processes, it is essential not only to assess the immediate impact of the stressor, but also the neurochemical variations that occur upon re-exposure to stressors or cues associated with the stressor. In considering the consequences of stressors and the potential implications for human pathology, it is important to consider the impact of chronic stressors. After all, many stressors encountered by humans are chronic in nature, particularly if one considers ruminations associated with the aversive event. It seems that with repeated stressor application a further series of adaptive neurochemical changes occur. The activity of tyrosine hydroxylase is increased, and concentrations of NE and DA approach those of nonstressed animals. Indeed, it appears that after stressor termination the increased amine synthesis may persist for some time leading to a further increase of amine concentrations, which may enable the organism to deal with environmental demands. In addition, receptor variations may occur, including down-regulation of beta-NE receptors, and possibly alterations of alpha-1 and alpha-2 receptors as well. It is believed that the receptor variations may be the essential element in maintaining the integrity of the organism. It is our contention that where such adaptive changes do not occur or are slow in occurring, pharmacological intervention may be necessary to engender such neuronal variations.

Significant determinants of susceptibility to alcohol teratogenicity.

Abstract: Typically, the rate of abusive drinking during pregnancy considerably exceeds the rates of fetal alcohol syndrome (FAS) and alcohol-related birth defects, suggesting that other factors may modify the impact of alcohol on the developing organism. Data in the literature supporting this susceptibility hypothesis are sparse. In this paper, two studies in different samples, using different analytic strategies to examine susceptibility to different adverse outcomes are presented. Among 176 pregnancies in which lowered birth weight for gestational age was detected as an effect attributable to frequent beer drinking, 27 infants weighted less than 2,700 grams and 149 weighed more. Using discriminant analysis to contrast these groups, lowered birth weight for gestational age was associated with black race and lower maternal weight and weight gain. The effects of these factors were additive with that of persistent alcohol exposure; no interactions were detected, but pregnancies with risks in addition to alcohol were more likely to yield growth-retarded infants. In a second study, pregnancies resulting in 25 FAS cases were contrasted with 50 controls. A four-factor model accounted for nearly two-thirds of the explainable variance in the occurrence of FAS. Adjusted for frequency of maternal drinking, chronic alcohol problems and parity, there was a sevenfold increase in risk for FAS among black infants. The findings from both studies are consistent with the susceptibility hypothesis and have potentially important implications for public health and clinical approaches to prevention, as well as for future research.

Enzymatic Control of Estrogen Production in Human Breast Cancer: Relative Significance of Aromatase versus Sulfatase Pathways

Abstract: One-third of the cases of breast cancer in postmenopausal women are hormone-dependent and the lesions regress upon treatment with antiestrogens or inhibition of estrogen biosynthesis. In these patients, estrogens are synthesized in extraglandular tissues from adrenal precursors and re-enter plasma to produce estrone levels of 52 +/- 6.5 pg/ml (mean +/- SEM) and estradiol concentrations of 13.1 +/- 0.7 pg/ml. However, the fact that the levels of estrogen in breast tumor tissue are an order of magnitude higher than plasma levels suggested the possibility of in situ estrogen production. To address this possibility, we measured several enzymes involved in estradiol biosynthesis in human tumors. Forty-eight of 61 tumors contained aromatase (estrogen synthetase) activity ranging from 5-80 pg/gm protein per hour. By comparison, the levels of estrone sulfatase were 10(6) higher, ranging from 0.8-125 micrograms/gm protein per hour. Because the sulfatase enzyme was of lower affinity (i.e., Km = 27 microM) than that of aromatase (i.e., 0.027 microM), the amount of estrogen formed under conditions of similar substrate concentrations was compared and found to be 10-fold higher via the sulfatase enzyme. In 41 additional tumors, the 17 beta-hydroxysteroid dehydrogenase enzyme, catalyzing the conversion of estrone to estradiol, was uniformly present. To test the biologic relevance of the estrone sulfate to estrone to estradiol pathway, estrogen-dependent nitrosomethylurea rat mammary tumors were grown in soft agar in the presence of estrone sulfate. Concentrations of estrone sulfate of 10(-6) microM significantly (p less than 0.01) stimulated colony formation in this system in which 75.5-98.6% of estrone sulfate was converted to estrone and 0.2 to 6% to estradiol. These data support the hypothesis that mammary carcinomas can synthesize estradiol in situ from circulating estrogen precursor and that local conversion is biologically important. On the basis of comparative data, the estrone sulfate to estrone to estradiol pathway is quantitatively more important than that involving androstenedione to estrone to estradiol.

The role of ultrasonic vocalizations in the regulation of reproduction in rats.

Abstract: To the casual observer, many rodents appear to vocalize only rarely. Usually, as with rats, one hears squeaks or cries only in response to painful or stressful stimulation. There is little audible spontaneous vocalization or vocalization directed to conspecifics. Yet, there is ample evidence that many small rodents vocalize in the ultrasonic range and that they can hear these sounds as well.’ Perhaps it is because we cannot hear these calls that we tend to minimize the importance of acoustical communication in animals such as rats, mice, and other small rodents. For small rodents, olfaction provides a major channel for social communication, especially in reproduction.2 Tactile stimulation, too, is of major importance in the regulation of reproductive behavior and physiology? Do ultrasonic vocalizations produced during mating activity also contribute to the coordination of reproduction in rodents? We have been investigating this question in rats and some of our findings will be presented in this review. Adult rats emit ultrasonic calls during mating and aggressive activity, and also while investigating strange areas. Infant rats, like many other rodents, also vocalize ultra~onically.~ In addition, lactating rats may also produce ultrasonic calls? The discussion that follows will focus primarily on those calls occurring during sexual activity and their possible roles in the coordination of reproduction.

Stressor Controllability and Stress-Induced Analgesia

Abstract: The existence of multiple forms of stress-induced analgesia (SIA) focuses attention on factors that determine which form occurs. Experimental work has tended to focus on the physical characteristics of the putative stressor. Thus some investigators have compared the type of analgesia that follow exposure to different types of stressors (such as electric shock, cold water swim, rotation, etc.),’ while others have studied the differential effects of the same type of stressor (e.g., electric shock) administered with different parameters,” or to different parts of the body.3 Instead, we have explored the importance of a psychological dimension of the stress situation, the degree to which the organism can exert behavioral control over the stressor (alter by its behavior the onset, termination, intensity, or temporal pattern of the stressor), as a factor in determining the type of analgesia produced by the stressor. In a typical study in our laboratory one group of rats is given a series of electric shocks each of which can be terminated by a behavioral response (turning a small wheel in the front of the chamber), while each member of a second group is yoked to a member of the first and is given the identical shocks as determined by the behavior of its partner. Thus both groups receive physically identical shocks, but one group has control over the termination of each shock (escapable shock) while the other does not (inescapable shock). A third group does not receive shock. Thus, the effects of exposure to shock per se and the impact of control versus lack of control can be isolated. This experimental design has revealed that controllability exerts important modulatory effects on both behavioral and physiological changes produced by exposure to a stressor. Rats exposed to a series of 80 moderate intensity uncontrollable shocks later (1) fail to learn to escape or avoid shock or other stressors in different situations in which escape and avoidance is p~ss ib le ;~ (2) are inactive in the presence of aversive events;5 (3) show reduced aggression and social d~minance;~.’ and (4) show impairments in their ability to attend to relationships between their own behavior and shock termination? None of these behavioral changes follow exposure to physically identical but escapable shock and so depend on the uncontrollability of the stressor rather than on mere exposure to the stressor. Behavioral outcomes such as these, which depend on the controllability/uncontrollability of the stressor, have been called “learned helplessness” effects? Similarly, a variety of neurochemical changes produced by stressors depend on the controllability of the stressor.’O,*’

Cerebrospinal fluid studies in suicide. An overview.

Abstract: In the chain of events that terminates in a suicide, biological factors may be more important than previously thought. Recent research has identified two clusters of biological factors that tend to correlate with suicidal behavior, namely, variables associated with monoaminergic neurotransmission and variables associated with certain neuroendocrine functions. The most convincing evidence for an involvement of monoamines in suicide stems from measurements of serotonin and its main metabolite, 5-hydroxyindoleacetic acid (SHIAA), in brains from suicide victims and in cerebrospinal fluid (CSF) from patients who have attempted suicide.' Initially, such investigations were performed in order to study the biological correlates of depressive disorders, but more recently, interest has focused on the possible biological background of suicidal behavior as such. The present article will review CSF studies of monoamine metabolites in suicidal individuals, published until 1984, and also discuss some possible mechanisms for the relationship between suicide and serotonin.