Effect of methscopolamine, physostigmine, and neostigmine on neuron activity in the midbrain, the hippocampus, and the hypothalamus in the behaving rat

The effect of systemic injection of physostigmine (0.1 mg/kg) on spontaneous and evoked neuronal activity and on behavior has been examined in the freely moving rat. There was a decrease in the frequency of firing of hippocampal neurons in a large majority of cases. There was a smaller but significant decrease in the frequency of firing of midbrain neurons, although in a few cases increases were observed. There were either no changes or small increases in the frequency of discharge of hypothalamic neurons. Parkinsonian-type tremors recorded as increases in movements were observed in all animals after methscopolamine, physostigmine, and neostigmine. Decreases in the rate of neuronal discharges in the hippocampus and the midbrain occurred after methscopolamine; increases were observed in the hypothalamus. Neostigmine caused large increases in behavior, but no increases in the frequency of discharge of neurons. The results show that the hippocampus contains a large number of neurons whose rate of firing was modified by cholinergic agents which cross the blood-brain barrier; the midbrain contains a smaller number of such neurons, whereas the hypothalamus contains neurons responsive to cholinergic agents acting at the periphery.     

Pearls,perils, and pitfalls in the use of the electroencephalogram

Despite advances in neuroimaging techniques over the past three decades that have helped in identifying structural lesions of the central nervous system, electroencephalography (EEG) continues to provide valuable insight into brain function by demonstrating focal or diffuse background abnormalities and epileptiform abnormalities. It is an extremely valuable test in patients suspected of epilepsy and in patients with altered mental status and coma. Patterns in the EEG make it possible to clarify the seizure type; it is indispensable for the diagnosis of nonconvulsive status epilepticus and for separating epileptic from other paroxysmal (nonepileptic) episodes. There are EEG patterns predictive of the cause of the encephalopathy (i.e., triphasic waves in metabolic encephalopathy) or the location of the lesion (i.e., focal polymorphic delta activity in lesions of the subcortical white matter). The various EEG characteristics of infantile, childhood, and adult epilepsies are described as well as the EEG patterns that are morphologically similar to interictal/ictal epileptiform discharges but unrelated to epilepsy. An EEG is most helpful in determining the severity and, hence, the prognosis of cerebral dysfunction. Lastly, EEG is extremely helpful in assessing normal or abnormal brain functioning in a newborn because of the serious limitation in performing an adequate neurologic examination on the neonate who is intubated or paralyzed for ventilatory control. Under such circumstances, the EEG may be the only available tool to detect an encephalopathic process or the occurrence of epileptic seizures.     

Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons

Maintenance of adequate intracellular glutathione (GSH) levels is vital for intracellular defense against oxidative damage. The toxic effects of methylmercury (MeHg) are attributable, at least in part, to elevated levels of reactive oxygen species, and thus decreases in GSH synthesis may increase methylmercury toxicity. Astrocytes have recently been proposed to play an essential role in providing GSH precursors to neurons. Therefore, cystine transport, a prerequisite to GSH production, was characterized in cultured astrocytes and neurons, and the effects of methylmercury on this transport were assessed. Astrocytes and neurons both possessed temperature dependent transport systems for cystine. Astrocytes accumulated cystine by Na+-independent (X(C)-) and -dependent (X(AG)-) systems while neurons used exclusively Na+-independent systems. Inhibition of the X(AG)- transport system decreased cystine transport in astrocytes to levels equivalent to those in sodium-depleted conditions, suggesting that cystine is carried by a glutamate/aspartate transporter in astrocytes. Inhibition of the multifunction ectoenzyme/amino acid transporter gamma-glutamyltranspeptidase (GGT) decreased cystine transport in both neurons and astrocytes. Inhibition of System X(C)- with quisqualate also decreased cystine uptake in both astrocytes and neurons. These data demonstrate that cultured astrocytes accumulate cystine via three independent mechanisms, System X(AG)-, System X(C)-, and GGT, while cultured hippocampal neurons use System X(C)- and GGT exclusively. Inhibition of cystine uptake in astrocytes by methylmercury appears to be due to actions on the System X(AG)- transporter.     

Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression

Five hundred four outpatients suffering from a major depressive episode were randomly assigned to receive either amitriptyline, doxepin, alprazolam, or placebo. The study was conducted in three treatment centers during a six-week period. All three active medications produced significantly more clinical improvement than did placebo, irrespective of the patient's initial anxiety, depression, and psychomotor retardation and irrespective of the patient's assignment to various subtypes of depression, including the DSM-III melancholia subtype. Compared with placebo, sedation was reported more frequently with all three medications, whereas anticholinergic effects were reported more frequently only for the two tricyclic antidepressants, but not for alprazolam.     

Immunohistochemical localization of the pro-opiomelanocortin-gene product, glycylglutamine, in the intermediate pituitary

Glycylglutamine, the car☐yterminal sequence of β-endorphin_1–31, is produced as a free dipeptide during the posttranslational synthesis of β-endorphin_1–27. Antisera which recognize glycylglutamine were raised in rabbits and used for immunohistochemistry. With these antisera, glycylglutamine immunoreactivity was demonstrated in cells of the rat intermediate pituitary. In contrast, anterior pituitary cells, which exhibited β-endorphin immunoreactivity, did not react with the anti-glycylglutamine sera. The conclusion that the antisera distinguished glycylglutamine immunoreactivity from β-endorphin_1–31 immunoreactivity is based upon cellular specificity, fixation requirements and blocking studies. The antisera demonstrated the differential expression of this dipeptide product of the proopiomelanocortin prohormone. The efficacy of carbodiimide as an immunohistochemical fixative for small molecules is also known.     

Distribution of the protein IMPACT, an inhibitor of GCN2, in the mouse, rat, and marmoset brain

IMPACT is an inhibitor of GCN2, a kinase that phosphorylates the alpha subunit of the translation initiation factor 2 (eIF2 alpha). GCN2 has been implicated in regulating feeding behavior and learning and memory in mice. IMPACT is highly abundant in the brain, suggesting its relevance in the control of GCN2 activation in the central nervous system. We describe here the distribution of IMPACT in the brain of rodents (mice and rats) and of a primate (marmoset) using highly specific antibodies raised against the mouse IMPACT protein. Neurons expressing high levels of IMPACT were found in most areas of the brain. In the hippocampal formation the lack of IMPACT in the dentate gyrus granule cells was striking. The hypothalamus is exceptionally rich in neurons expressing high levels of IMPACT, particularly in the suprachiasmatic nucleus. The only exception to this pattern was the ventromedial nucleus. The thalamic neurons are mostly devoid of IMPACT, with the exception of the paraventricular, reuniens and reticular nuclei, and intergeniculate leaf. The brainstem displayed high levels of IMPACT. For the marmoset, IMPACT expression in the brain is not as prominent when compared to other organs. In the marmoset brain the pattern of IMPACT expression was similar to rodents in most areas, except for the very strong labeling of the Purkinje cells, the lack of IMPACT-positive neurons in the nucleus reuniens, and weak labeling of interneurons in the hippocampus. GCN1, the activator of GCN2 to which IMPACT binds, is widely distributed in all neuronal populations, and all IMPACT-positive cells were also GCN1-positive. The data presented herein suggest that IMPACT may be involved in biochemical homeostatic mechanisms that would prevent GCN2 activation and therefore ATF4 (CREB-2) synthesis in neurons.     

Ethics in the practice of psychiatry--origins, functions, models, and enforcement

The author points out that psychiatric ethics are coming under increasing critical scrutiny by psychiatrists and by those outside of the profession. On the basis of an examination of APA Ethics Committee records, he concludes that criticism of psychiatry's inability to police itself might have some merit but cautions that the critics might be expecting too much from a code of ethics, which has the job of sensitizing psychiatrists to an ethical way of professional life and helping sort out ethical conflicts. After outlining a number of the problems in the self-policing aspect of ethics, the author makes suggestions for their resolution.     

Misunderstandings,misperceptions, and mistakes in the management of the inflammatory myopathies

Many misconceptions persist concerning fundamental issues related to the idiopathic inflammatory myopathies. Such misconceptions can lead to frank mistakes in the diagnosis and management of these disorders. In some cases, these misperceptions have resulted from overreliance on out-of-date information and "classic" articles that are no longer classic! In other instances, misperceptions persist because of the many voids in our understanding of these diseases. This review uses case presentations to highlight important caveats in diagnosing and managing the common idiopathic inflammatory myopathies.     

Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain

The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.     

Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat

Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.     

Neuroprotective effects of Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the hippocampus in vitro

Insulin-like growth factor 1 (IGF-1) plays a critical role in CNS development. IGF-1 can block neuronal apoptosis in vitro and in vivo. IGF-1 is thought to be cleaved into des-N-(1-3)-IGF-1 and an amino terminal glycine-proline-glutamate (GPE tripeptide). Here we report a neuroprotective role for GPE tripeptide, with enhanced survival of the CA1-2 hippocampal neurons following an excitotoxic insult in vitro. Binding and displacement studies suggest uniquely distributed sites of action within the rat including the hippocampal CA1-2, pyriform cortex, amygdala, choroid plexus, blood vessels and to a lesser extent in the cortical regions. A similar pattern of binding was seen in the human. This finding could lead to new strategies to reduce neuronal death after injury and in disease.     

Ethics in Neuroscience Curricula: A Survey of Australia, Canada, Germany, the UK, and the US

This paper analyses ethical training in neuroscience curricula at universities in Australia, Canada, Germany, the United States and the United Kingdom. The main findings are that 52 % of all courses have ethical training available, while in 82 % of those cases, the training is mandatory. In terms of specific contents of the teaching, ethical issues about ‘animal subjects and human participation in research’, ‘scientific misconduct’, and ‘treatment of data’ were the most prominent. A special emphasis during the research was placed on the prevalence of dual-use bioethics. In total, only 3 % of all courses mention it in any of their modules. One of the major findings of the survey was the trend towards ‘mainstreaming’ ethics education particularly in the UK, which is to disperse ethics among the various modules within the education instead of relying on a single ethics module. The paper discusses the utility of this approach for science education as well as describes the overall difficulties that course coordinators face when trying to teach ethics based on the responses to the qualitative part to the survey.     

Colocalization of somatostatin,neuropeptide Y,and NADPH-diaphorase in the caudate-putamen of the rat

Somatostatin, neuropeptide Y, and nicotinamide adenine dinucleotide phosphatediaphorase are colocalized within a small population of medium aspiny neurons in the caudate-putamen of the rat. The extent of colocalization, however, appears to be in dispute. In order to examine the question of colocalization between these three neuroactive substances, a series of double-labelling experiments was performed. This was accomplished by combining immunocytochemistry for somatostatin or neuropeptide Y or enzyme histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase with in situ hybridization for somatostatin and/or neuropeptide Y mRNA. The results of such analysis indicate that nicotinamide adenine dinucleotide phosphate-diaphorase and somatostatin mRNA are 100% colocalized throughout the caudate-putamen, except for the area bordering the globus pallidus. All neurons that contain neuropeptide Y contain somatostatin message. Only 84% of the neurons that contain somatostatin mRNA, however, also contain neuropeptide Y. Neurons that contain somatostatin 28 but not neuropeptide Y are found throughout the caudate-putamen. These results indicate that the somatostatin neuron population in the rat caudate-putamen is not homogeneous. Instead, the medium aspiny neuron population is actually composed of several subpopulations based on the content of neuroactive substances. © 1995 Willy-Liss, Inc.     

The use of the opiate antagonist, naloxone, in the treatment of intractable pain

Thirteen adult patients with established thalamic syndrome, resistant to prior analgesic and other therapy, were treated with intravenous infusions of the opiate antagonist, naloxone. A total of twenty treatments were administered with doses of naloxone varying from 4.0-8.0 mgs. Seven patients exhibited beneficial effects with the duration of the resultant pain relief ranging from four days to two and a half years. In these patients, pain and hyperpathia were completely obtunded in six out of seven and partially in one. Side effects of therapy were minimal and of short duration being mainly confined to the cardiovascular system. During therapy all patients had continuous E.C.G. monitoring. In certain ischaemic conditions of the central nervous system, endogenous opioids possibly reduce cerebral blood flow via. inhibition of the locus coeruleus and subsequent release of noradrenaline: hence naloxone by inhibiting the opioids could increase cerebral perfusion pressure. This study has shown the benefit of treating patients with cerebral ischaemic lesions with an opioid antagonist. The rapidity of onset of pain relief in these patients would appear to indicate a mode of action by increasing cerebral perfusion.