Alteration of blood-brain barrier function by methamphetamine and cocaine

The integrity of the blood-brain barrier (BBB) plays an important role in maintaining a safe neural microenvironment in the brain. Loss of BBB integrity has been recognized as a major cause of profound brain alterations. Psychoactive drugs such as methamphetamine (METH) or cocaine are well-known drugs of abuse that can alter the permeability of the BBB via various mechanisms. In addition, the neurotoxicity of METH is well documented, and alterations in BBB function can contribute to this toxicity. A great deal of effort has been devoted to understanding the cellular and molecular mechanisms of the action of these drugs in the central nervous system. However, only a few investigations have focused on the effects of METH and cocaine on BBB function. The aim of this short review is to summarize our present knowledge of this subject.     

Evidence for a widely distributed peripheral dopaminergic system

The hypothesis presented in this paper is that dopamine (DA) is a widely distributed neurotransmitter and/or cotransmitter in the autonomic nervous system. This hypothesis is based on the following evidence. Morphologically, DA-containing neurons have been demonstrated in autonomic ganglia, and dopaminergic axons have been identified in kidney and canine paw pad. On the basis of pharmacological experiments, the existence of dopaminergic nerves was suggested in vas deferens, stomach, and mesenteric artery. Biochemically, we found intensive catabolism of DA in different peripheral tissues of the rat and human. Furthermore, dopaminergic receptors have a widespread distribution in the body, and a high concentration of DA occurs in plasma with only some originating from the adrenal gland. The concentration of plasma DA closely reflects the activity of the autonomic nervous system. These observations together with our finding of relatively high concentrations of DA and its metabolites in several peripheral nerves suggest the possibility of a widely distributed peripheral dopaminergic system.     

gamma-Aminobutyric acid in peripheral tissues

Significant amounts of gamma-aminobutyric acid (GABA), an endogenous amino acid, are present in mammalian peripheral tissues. This finding led to the suggestion that GABA may act as a neurotransmitter in the peripheral nervous system as it does in the central nervous system. This review deals with recent identification of GABA in the autonomic nervous system and the possible functional role of GABA in neuronal and non-neuronal tissues. The identification of GABA in the autonomic nervous system has paved the way for new approaches in pharmacological investigations.     

Neurotensin analogs indications for use as potential antipsychotic compounds

This review will be an update, focusing on the central nervous system (CNS) roles of the neurotransmitter, neurotensin. We will provide a summary of current knowledge about neurotensin, why it is an important peptide to study, and where the field is heading. Special emphasis is placed on the development of neurotensin analogs, which has been a major effort of our group, the potential role of neurotensin in Parkinson's disease, and the interaction of neurotensin with other neurotransmitters as evidenced by microdialysis studies.     

Protein kinase C-dependent remodeling of glutamate transporter function

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and is critical for essentially all physiological processes ranging from control of motor and somatosensory function to information processing and storage. Like many other small molecule neurotransmitters, transporters localized to the plasma membrane control the extracellular concentrations of glutamate. These transporters are both acutely and chronically regulated by several different mechanisms that presumably contribute to the protection of the nervous system from hypo- or hyper-glutamatergic function. In this review, we will describe our emerging understanding of one aspect of glutamate transporter regulation that is dependent on protein kinase C. More than a decade of extensive research on glutamate receptor-specific therapeutics has been driven by the hypothesis that these agents might be useful for pain management, treatment of schizophrenia or other psychiatric disorders, and prevention of neurodegenerative diseases. We assume that, in this modern era of drug discovery, understanding the endogenous regulatory mechanisms that are activated under physiological and pathological conditions will be required before one can target transporters for a ubiquitous neurotransmitter like glutamate.     

The placebo effect and the autonomic nervous system: evidence for an intimate relationship

For many subjectively experienced outcomes, such as pain and depression, rather large placebo effects have been reported. However, there is increasing evidence that placebo interventions also affect end-organ functions regulated by the autonomic nervous system (ANS). After discussing three psychological models for autonomic placebo effects, this article provides an anatomical framework of the autonomic system and then critically reviews the relevant placebo studies in the field, thereby focusing on gastrointestinal, cardiovascular and pulmonary functions. The findings indicate that several autonomic organ functions can indeed be altered by verbal suggestions delivered during placebo and nocebo interventions. In addition, three experimental studies provide evidence for organ-specific effects, in agreement with the current knowledge on the central control of the ANS. It is suggested that the placebo effects on autonomic organ functions are best explained by the model of 'implicit affordance', which assumes that placebo effects are dependent on 'lived experience' rather than on the conscious representation of expected outcomes. Nevertheless, more studies will be needed to further elucidate psychological and neurobiological pathways involved in autonomic placebo effects.     

Neuropeptide Y: a putative neurotransmitter

Since its isolation in 1982, neuropeptide Y (NPY) has received considerable interest. This 36 amino acid peptide has been identified widely throughout the central and peripheral nervous systems, and within the autonomic system it appears in close association but not exclusively within catecholamine containing nerves. NPY begins to meet some of the criteria required to be established as a neurotransmitter. Thus, the peptide has been localised exclusively within nerves, and electron microscopy has shown NPY within nerve terminals. High affinity, saturable binding sites for NPY have been demonstrated in rat brain membranes, and the peptide has been reported to be released into the circulation during sympathetic nerve stimulation. The peptide is pharmacologically active both within the central nervous system by altering blood pressure, feeding and anterior pituitary function and in the periphery where NPY acts as a vasoconstrictor.     

The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance

An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids.     

Development and sensitivity to serotonin of Drosophila serotonergic varicosities in the central nervous system

Serotonin is a classical small-molecule neurotransmitter with known effects on developmental processes. Previous studies have shown a developmental role for serotonin in the fly peripheral nervous system. In this study, we show that serotonin can modulate the development of serotonergic varicosities within the fly central nervous system. We have developed a system to examine the development of serotonergic varicosities in the larval CNS. We use this method to describe the normal serotonergic development in the A7 abdominal ganglion. From first to third instar larvae, the volume of the neuropil and number of serotonergic varicosities increase substantially while the varicosity density remains relatively constant. We hypothesize that serotonin is an autoregulator for serotonergic varicosity density. We tested the sensitivity of serotonergic varicosities to serotonin by adding neurotransmitter at various stages to isolated larval ventral nerve cords. Addition of excess exogenous serotonin decreases native varicosity density in older larvae, and these acute effects are reversible. The effects of serotonin appear to be selective for serotonergic varicosities, as dopaminergic and corazonergic varicosities remain qualitatively intact following serotonin application.     

Central nervous system involvement in the autonomic responses to psychological distress

Psychological distress can trigger acute coronary syndromes and sudden cardiac death in vulnerable patients. The primary pathophysiological mechanism that plays a role in stress-induced cardiac events involves the autonomic nervous system, particularly disproportional sympathetic activation and parasympathetic withdrawal. This article describes the relation between psychological distress and autonomic nervous system function, with a focus on subsequent adverse cardiovascular outcomes. The role of the central nervous system in these associations is addressed, and a systematic review is presented of studies examining the association between stress-induced central nervous system responses measured by neuroimaging techniques and autonomic nervous system activation. Results of the systematic review indicate that the primary brain areas involved in the autonomic component of the brain-heart association are the insula, medial prefrontal cortex, and cerebellum (based on 121 participants across three studies that fitted the inclusion criteria). Other areas involved in stress-induced autonomic modulation are the (anterior) cingulate cortex, parietal cortex, somatomotor cortex/precentral gyrus, and temporal cortex. The interaction between central and autonomic nervous system responses may have implications for further investigations of the brain-heart associations and mechanisms by which acute and chronic psychological distress increase the risk of myocardial infarction, cardiac arrhythmias, and sudden cardiac death.     

Extrahypothalamic thyrotropin releasing hormone (TRH) -- its distribution and its functions.

Thyrotropin releasing hormone (TRH) is distributed throughout the extrahypothalamic nervous system and spinal cord, in the retina, in the pancreas and gastrointestinal tract, in the placenta, in amniotic fluid, in the adrenals and in frog skin. TRH has been shown to have a variety of effects in the central nervous system, both on isolated neurones and in a number of in vivo situations. TRH interacts with endogenous and exogenous opiates and it has been suggested that endogenous TRH may mediate part of the opiate withdrawal syndrome. The presence of TRH in the retina suggests the possibility that TRH plays a role in the visual process. TRH appears to be integrally related to central thermoregulatory mechanisms. The role of TRH in psychiatric disorders is at present controversial. Recent studies suggest a role for TRH as a modulator of gastrointestinal and pancreatic function. The gastrointestinal actions of TRH include inhibition of gastric acid secretion and alterations in gastic motility. The high concentrations of TRH in the neonatal pancreas suggest a role for TRH in the early development of the pancreas. One of the metabolites of TRH histidyl-proline diketopiperazone, appears to have a number of extrahypothalamic actions and this suggests the need for further exploration of the affects of this compound both on the central nervous system and the gastrointestinal tract. The multiple extrahypothalamic actions of TRH have led to the concept that it is an ubiquitous neurotransmitter that has been co-opted by the pituitary as a releasing factor.     

Cocaine and central monoaminergic neurotransmission: a review of electrophysiological studies and comparison to amphetamine and antidepressants

Psychomotor stimulants (e.g. cocaine and amphetamine) and many antidepressants are believed to elicit their psychotropic actions by interacting primarily with central monoaminergic neurons. The acute central neuronal effects of amphetamine and antidepressants have been extensively investigated in rats utilizing extracellular single unit electrophysiological and microiontophoretic techniques in vivo. In recent years the chronic effects of these compounds on the above neuronal systems have also been reported. Such investigations have proliferated because of the realization that the mechanisms underlying the psychotomimetic effects (e.g. amphetamine and cocaine) and mood elevation (i.e. antidepressants) observed with the administration of these drugs are more accurately reflected in chronic studies. For many years it has been assumed that cocaine and amphetamine produce very similar if not identical psychotropic effects through their actions on central monoaminergic neurotransmission. In terms of effects on single monoaminergic neurons, this assumption had gone by untested until two years ago, when the first report of the electrophysiological effects of cocaine on central monoaminergic (locus ceruleus) neurons appeared in the literature (61). This review discusses recent electrophysiological studies with cocaine at the level of single identified monoaminergic neurons and compares such data with that previously reported for amphetamine and antidepressants. In addition to identifying some of the similarities and differences between these compounds, this review also highlights some of the gaps in our knowledge regarding the effects of these drugs on central monoaminergic neurotransmission.     

Docosahexaenoic acid and cognitive function: Is the link mediated by the autonomic nervous system?

Docosahexaenoic acid is a long-chain polyunsaturated fatty acid that is found in large quantity in the brain and which has repeatedly been observed to be related in positive ways to both cognitive function and cardiovascular health. The mechanisms through which docosahexaenoic acid affects cognition are not well understood, but in this article, we propose a hypothesis that integrates the positive effects of docosahexaenoic acid in the cognitive and cardiovascular realms through the autonomic nervous system. The autonomic nervous system is known to regulate vital functions such as heart rate and respiration, and has also been linked to basic cognitive components related to arousal and attention. We review the literature from this perspective, and delineate the predictions generated by the hypothesis. In addition, we provide new data showing a link between docosahexaenoic acid and fetal heart rate that is consistent with the hypothesis.     

Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease

The kinesin, dynein, and myosin superfamily molecular motors have fundamental roles in neuronal function, plasticity, morphogenesis, and survival by transporting cargos such as synaptic vesicle precursors, neurotransmitter and neurotrophic factor receptors, and mRNAs within axons, dendrites, and synapses. Recent studies have begun to clarify the mechanisms of cargo selection and directional transport in subcellular compartments. Furthermore, molecular genetics has revealed unexpected roles for molecular motors in brain wiring, neuronal survival, neuronal plasticity, higher brain function, and control of central nervous system and peripheral nervous system development. Finally, it is also evident that molecular motors are critically involved in neuronal disease pathogenesis. Thus, molecular motor research is becoming an exciting frontier of neuroscience.     

Glial cells more than support cells?

Glial cells are the most abundant cells in the human brain and have long been considered as passive supporting cells for neurons. In contrast to the extensive studies on various neuronal functions in the nervous system, we still have limited knowledge about glial cells. Recently a number of pioneering studies have provided convincing evidence that glia play active roles in development and function of the central nervous system. This review discusses recent advances in our understanding of the molecular mechanisms underlying glial cell differentiation. We then highlight some of the novel findings about glial function, i.e. the role of glia in synaptogenesis and the intricate relationship between astrocytes and adult neural stem cells. Finally, we summarize the emerging studies that implicate abnormalities in the formation or maintenance of glia leading to severe brain diseases, such as Alexander disease, glioblastoma and multiple sclerosis, and potential therapeutic strategies to tackle these diseases.