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Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Memory retrieval is mediated by discharges of acetylcholine, glutamate, gammaaminobutyric acid, norepinephrine, and serotonin/5-hydroxytryptamine circuits. These projections and memory interact through engram circuits, neurobiological traces of memory. Increased excitability in engram circuits of the medial prefrontal cortex and hippocampus results in remote and recent memory retrievals, respectively. However, due to degenerated neurotransmitter projections, the excitability state of engram circuits is decreased in the patient with dementia; and thus, acquired- memory cannot be retrieved by natural cues. Here, we suggest that artificial neuropharmacological stimulations of the acquired-memory with an excitation potential higher than a natural cue can excite engram circuits in the medial prefrontal cortex, which results in the retrieval of lost memories in dementia. The neuropharmacological foundations of engram cell-mediated memory retrieval strategy in severe dementia, in line with this has also been explained. We particularly highlighted the close interactions between periaqueductal gray, locus coeruleus, raphe nuclei, and medial prefrontal cortex and basolateral amygdala as treatment targets for memory loss. Furthermore, the engram circuits projecting raphe nuclei, locus coeruleus, and pontomesencephalic tegmentum complex could be significant targets of memory editing and memory formation in the absence of experience, and a well-defined study of the neural events underlying the interaction of brain stem and memory will be relevant for such developments. We anticipate our perspective to be a starting point for more sophisticated in vivo models for neuropharmacological modulations of memory retrieval in Alzheimer's dementia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.

Neurotransmitters (NTs) play a central role in the efficient communication between neurons necessary for normal functioning of the nervous system. NTs can be divided into two groups: small molecule NTs and larger neuropeptide NTs. Inherited disorders of NTs result from a primary disturbance of NTs metabolism or transport. This group of disorders requires sophisticated diagnostic procedures. In this review we discuss disturbances in the metabolism of tetrahydrobiopterin, biogenic amines, γ-aminobutyric acid, foliate, pyridoxine-dependent enzymes, and also the glycine-dependent encephalopathy. We point to pathologic alterations of proteins involved in synaptic neurotransmission that may cause neurological and psychiatric symptoms. We postulate that synaptic receptors and transporter proteins for neurotransmitters should be investigated in unresolved cases. Patients with inherited neurotransmitters disorders present various clinical presentations such as mental retardation, refractory seizures, pyramidal and extrapyramidal syndromes, impaired locomotor patterns, and progressive encephalopathy. Every patient with suspected inherited neurotransmitter disorder should undergo a structured interview and a careful examination including neurological, biochemical, and imaging.

Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Arsenic (As) exposure has a toxic effect on the central nervous system, especially on learning and memory. Norepinephrine (NE), dopamine (DA), and serotonin (5-HT) play an important role in learning and memory function of the brain. In the present study, the protective effect of taurine on the disturbed biogenic amine neurotransmitter levels in the mouse brain induced by arsenic was examined. Sixty SPF mice were divided into three groups. The As exposure group was administered with 4 ppm As(2)O(3) through drinking water for 60 days. The protective group was treated with both 4 ppm As(2)O(3) and 150 mg/kg taurine. The control group was given drinking water alone. The levels of NE, DA, and 5-HT were determined by HPLC in the cerebrum and cerebellum of mice. Ultrastructure of synapses in brain tissue of mice was observed in these groups by transmission electron microscopy. The mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) as NE, DA, and 5-HT synzymes were also analyzed by real-time RT-PCR. The results showed that the concentrations of NE, DA, and 5-HT; the number of synaptic vesicles; and the expressions of TH, TPH, and DBH genes in the brains of mice exposed to As alone were significantly decreased. However, administration of taurine significantly alleviated the toxic effect on biochemicals detected in the experiment, compared with that in the brain of mice exposed to As alone. These results indicated that taurine was effective in counteracting the decreased biogenic amine neurotransmitter level and the mRNA expressions of their synzymes induced by arsenic.

Uptake1 and uptake2 transporters are involved in the extracellular clearance of biogenic amine neurotransmitters at synaptic clefts. We looked for them at the blood-brain barrier (BBB) and blood-retina barriers (BRB), where they could be involved in regulating the neurotransmitter concentration and modulate/terminate receptor-mediated effects within the neurovascular unit (NVU). Uptake2 (Oct1-3/Slc22a1-3, Pmat/Slc29a4) and Mate1/Slc47a1 transporters are also involved in the transport of xenobiotics. We used in situ carotid perfusion of prototypic substrates like [(3)H]-1-methyl-4-phenylpyridinium ([(3)H]-MPP(+)), [(3)H]-histamine, [(3)H]-serotonin, and [(3)H]-dopamine, changes in ionic composition and genetic deletion of Oct1-3 carriers to detect uptake1 and uptake2 at the BBB and BRB. We showed that uptake1 and uptake2 are involved in the transport of [(3)H]-dopamine and [(3)H]-MPP(+) at the blood luminal BRB, but not at the BBB. These functional studies, together with quantitative RT-PCR and confocal imaging, suggest that the mouse BBB lacks uptake1 (Net/Slc6a2, Dat/Slc6a3, Sert/Slc6a4), uptake2, and Mate1 on both the luminal and abluminal sides. However, we found evidence for functional Net and Oct1 transporters at the luminal BRB. These heterogeneous transport properties of the brain and retina NVUs suggest that the BBB helps protect the brain against biogenic amine neurotransmitters in the plasma while the BRB has more of a metabolic/endocrine role.

Biogenic amines are small cationic monoamines that function broadly as neurotransmitters and/or neuromodulators in every animal phylum. They include such ubiquitous substances as serotonin, dopamine and invertebrate-specific phenolamines (tyramine, octopamine), among others. Biogenic amines are important neuroactive agents in all the flatworms, including blood flukes of the genus Schistosoma, the etiological agents of human schistosomiasis. A large body of evidence spanning nearly five decades identifies biogenic amines as major modulators of neuromuscular function in schistosomes, controlling movement, attachment to the host and other fundamental behaviors. Recent advances in schistosome genomics have made it possible to dissect the molecular mechanisms responsible for these effects and to identify the proteins involved. These efforts have already provided important new information about the mode of action of amine transmitters in the parasite. Moreover, these advances are continuing, as the field moves into a post-genomics era, and new molecular tools for gene and protein analysis are becoming available. Here, we review the current status of this research and discuss future prospects. In particular, we focus our attention on the receptors that mediate biogenic amine activity, their structural characteristics, functional properties and "druggability" potential. One of the themes that will emerge from this discussion is that schistosomes have a rich diversity of aminergic receptors, many of which share little sequence homology with those of the human host, making them ideally suited for selective drug targeting. Strategies for the characterization of these important parasite proteins will be discussed.

The β-phenylethylamines are known to act as ligands for the trace amine receptors, a novel family of G-protein-coupled receptors. The trace amines are stored and released along with various neurotransmitter agents such as norepinephrine, serotonin, and dopamine and thus work as neuromodulator or neurotransmitter agents. Trace amines are known to play an important role in the pathophysiology of major depression. In our earlier study, we have demonstrated the synthesis of various β-substituted phenylethylamine molecules hypothesized to be effective in various central nervous system disorders. The present study is an attempt to evaluate one of such molecules, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, in animal models of depression. Various behavioral paradigms of despair such as forced swim and tail-suspension tests were used to assess the antidepressant-like activity. Further, an alteration in the levels of various neurotransmitters (norepinephrine, serotonin, and dopamine) in the mouse brain following 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol administration was evaluated. The molecule (4-16 mg/kg., i.p.) dose-dependently inhibited the immobility period in mouse forced swim test, the effect comparable to venlafaxine. The ED50 values of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol and venlafaxine in mouse forced swim test were found to be 5.27 [4.38-6.35] mg/kg., i.p and 4.66 [3.48-6.25] mg/kg., i.p., respectively. Further, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol at 4-16 mg/kg., i.p. reversed the immobility period in mouse tail-suspension test. Additionally, the molecule at 8 mg/kg., i.p. reversed reserpine-induced behavioral despair in mouse forced swim test. When administered simultaneously, it (4 and 8 mg/kg., i.p) enhanced the antidepressant activity of sub-effective doses of imipramine (2mg/kg., i.p.) or fluoxetine (2mg/kg., i.p.) in the mouse forced swim test. Neurochemical analysis revealed that the molecule at 8 mg/kg., i.p. increased the levels of norepinephrine (21% increase) without affecting serotonin in the mouse brain. However, at higher dose (16 mg/kg., i.p.), it increased the levels of norepinephrine (13% increase), serotonin (37% increase), and dopamine (42% increase). The molecule enhanced the locomotor activity in mice only at higher doses. The molecule, unlike venlafaxine, which potentiated barbiturate-induced hypnosis, was devoid of any sedative activity. In conclusion, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, possess antidepressant-like activity in animal models of depression by modulating the neurotransmitter levels in the brain. Such an activity might be due to the modulating action of this novel molecule on trace amine receptors. Such a molecule may be the future drugs of choice for the treatment of major depression., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

The amount of biogenic amines (dopamine and serotonin) and their metabolites (DOPAC, HVA, 5-HIAA, and 5-HTOL) in five regions of the brain (frontal cortex, hypothalamus, hippocampus, striatum, and brainstem) was studied in the male and female offspring of control and perinatally (48 h before birth or 48 h after birth) food and water deprived dams, when they were three months old, by using HPLC-EC determination. The increase of amine or metabolite level was dominant (19 values increased and 10 decreased related to control). Before-birth stress caused increase in 9 case and only 2 decreased, while in the case of after-birth stress 10 increased and 8 decreased. However, though there is no possibility to decide an exact tendency of direction, the after-birth stress (transmitted by milk) has more expressed effect. Striatum and brainstem were the most touched regions. There was a gender dependence with the dominance of males, except striatum. Blood plasma nociceptin level was also studied and there was a significant elevation in males after pre- and postnatal deprivation, while in females only after postnatal deprivation. The importance of the results in correlation with other stress effects is discussed., (Copyright © 2010 ISDN. Published by Elsevier Ltd. All rights reserved.)

Neurotransmitter systems have been long recognized as important targets of the developmental actions of alcohol (i.e., ethanol). Short- and long-term effects of ethanol on amino acid (e.g., γ-aminobutyric acid and glutamate) and biogenic amine (e.g., serotonin and dopamine) neurotransmitters have been demonstrated in animal models of fetal alcohol spectrum disorders (FASD). Researchers have detected ethanol effects after exposure during developmental periods equivalent to the first, second, and third trimesters of human pregnancy. Results support the recommendation that pregnant women should abstain from drinking-even small quantities-as effects of ethanol on neurotransmitter systems have been detected at low levels of exposure. Recent studies have elucidated new mechanisms and/or consequences of the actions of ethanol on amino acid and biogenic amine neuro-transmitter systems. Alterations in these neurotransmitter systems could, in part, be responsible for many of the conditions associated with FASD, including (1) learning, memory, and attention deficits; (2) motor coordination impairments; (3) abnormal responsiveness to stress; and (4) increased susceptibility to neuropsychiatric disorders, such as substance abuse and depression, and also neurological disorders, such as epilepsy and sudden infant death syndrome. However, future research is needed to conclusively establish a causal relationship between these conditions and developmental dysfunctions in neurotransmitter systems.

In this work, focal cerebral ischemia/reperfusion was induced by the model of middle cerebral artery occlusion. The dialysates of extracellular fluid in hypothalamus were obtained by using brain microdialysis technique. An efficient and sensitive chiral capillary electrophoresis with laser-induced fluorescence detection procedure was developed for the simultaneous determination of multiple amino acids neurotransmitter including Arg, Lys, Trp, GABA, l-Ser, Ala, Tau, Gly, Glu and Asp; catcholamine (dopamine) and neuromodulator (d-Ser and O-phosphoethanolamine) in microdialysate. Different parameters that influenced CE separation were optimized. The optimal method was used to investigate the dynamic changes of neurotransmitters and neuromodulators during cerebral ischemia/reperfusion. The results indicated that extracellular levels of multiple neurotransmitters and neuromodulators were elevated during cerebral ischemia/reperfusion. The dynamic changes and functional status of releasable neurotransmitters and neuromodulators during ischemia/reperfusion were discussed., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Orexin/hypocretin neurones in the posterior hypothalamus are mutually connected with noradrenergic, serotonergic, dopaminergic, histaminergic, and cholinergic neurone systems. They activate these targets by direct post-synaptic and indirect pre-synaptic mechanisms and in turn receive inhibitory feedback and excitatory feed forward control. With respect to behavioural state control, orexin/hypocretin neurones are conducting the orchestra of biogenic amines. This review highlights the role of these players in the control of energy administration, sleep-wake architecture, cortical activation, plasticity, and memory functions in health and disease.

The review describes the initial experiments suggesting a fast intra-axonal transport of transmitter related substances, in addition to the "classic" slow flow. Early experiments were mainly conducted in the peripheral adrenergic system, focusing on transport of amine storage granules, the extent of the vast sympathetic adrenergic system and the importance of axonal transport of amine granules for the adrenergic system. Further, it describes important advances obtained from studies of other neuron systems regarding local axonal protein synthesis, motor proteins and new insights regarding relation between faults in the transport machinery and some neuropathological conditions., (Copyright 2009 Elsevier Ltd. All rights reserved.)

We described the production and characterization of antibodies against three important groups of neuro-active haptens, e.g., neurotransmitters and biogenic amines. First, from the tryptophane metabolic pathway: tryptamine, serotonin, 5-hydroxy-indole acetic acid, and melatonin. Secondly, the tyrosine metabolic pathway: tyramine, dopamine, dihydroxyphenyl acetic acid, and norepinephrine. Thirdly, antibodies against excitatory and inhibitory neurotransmitters: glycine, glutamate, glutamine, and GABA. Immunogenic conjugates were prepared after linking haptens to carrier proteins. Most antibodies displayed high specificity against corresponding neuro-active haptens conjugated in vitro and in situ in biological specimens, but not to closely related conjugated metabolites, precursors, pharmaceuticals, agonists, antagonists, or free neuro-active haptens. Conjugated norepinephrine was highly tolerant in different animal species and produced incidentally a short specific antibody response.

Serotoninergic neurons in the central nervous system impinge on many other neurons and modulate their neurotransmitter release. This review focuses on 1) the function of presynaptic 5-hydroxytryptamine (5-HT) heteroreceptors on axon terminals of central cholinergic, dopaminergic, noradrenergic, or GABAergic neurons and 2) the role of GABAergic interneurons expressing 5-HT heteroreceptors in the regulation of acetylcholine, dopamine, or noradrenaline release. In vitro studies on slices or synaptosomes and in vivo microdialysis experiments have shown that 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3), and/or 5-HT(4) heteroreceptors mediate this modulation. 5-HT(1B) receptors on neocortical cholinergic, striatal dopaminergic, or hippocampal GABAergic axon terminals are examples for release-inhibiting 5-HT heteroreceptors; 5-HT(3) receptors on hippocampal GABAergic or 5-HT(4) receptors on hippocampal cholinergic axon terminals are examples for release-facilitating 5-HT heteroreceptors. GABA released from GABAergic interneurons upon activation of facilitatory 5-HT receptors, e.g., 5-HT(2A) or 5-HT(3) receptors, mediates inhibition of the release of other neurotransmitters such as prefrontal neocortical dopamine or neocortical acetylcholine release, respectively. Conversely, attenuated GABA release in response to activation of inhibitory 5-HT heteroreceptors, e.g., 5-HT(1A) or 5-HT(1B) receptors on GABAergic interneurons is involved in paradoxical facilitation of hippocampal acetylcholine and striatal dopamine release, respectively. Such 5-HT heteroreceptors are considered potential targets for appropriate 5-HT receptor ligands which, by enhancing the release of a relevant neurotransmitter, can compensate for its hypothesized deficiency in distinct brain areas. Examples for such deficiencies are the impaired release of hippocampal or neocortical acetylcholine, striatal dopamine, and hippocampal or neocortical noradrenaline in disorders such as Alzheimer's disease, Parkinson's disease, and major depression, respectively.

Influence of taurine on the pool of central neuroactive compounds during alcohol withdrawal syndrome has been investigated. Alcohol withdrawal syndrome was accompanied by a pronounced dysbalance in the formation of the pool of neuroactive compounds. The most remarkable changes were found in the levels of markers related to the central serotoninergic system, as well as dopaminergic system. Taurine administration in a dose of 650 mg/kg (i.g.) one hour before decapitation during ethanol withdrawal syndrome alleviates disturbances in the functioning of serotoninergic and (to a lesser extent) dopaminergic systems and improves the ratio of inhibitory and excitatory mediator amino acids.

Neurotoxic effects of methoxychlor (MTX) are poorly understood at present. This study was undertaken to evaluate the possible effects of MTX in norepinephrine, dopamine and amino acid contents and serotonin turnover in rat striatum. For this purpose, adult male Sprague-Dawley rats were administered 25 mg/kg/day of MTX in sesame oil or vehicle only for 30 days. The neurotransmitters of interest were measured in the striatum by HPLC. MTX decreased norepinephrine and 5-hydroxyindole acetic acid (5-HIAA) content and serotonin turnover (measured as 5-HIAA/serotonin ratio), and increased glutamate and GABA concentrations. However, the content of serotonin, aspartate, glutamine and taurine was not modified by MTX exposure. These data suggest that MTX exposure inhibits norepinephrine synthesis and serotonin metabolism. The inhibitory effect on norepinephrine could be explained, at least in part, by the increase of both GABA and glutamate contents. Further studies are needed to understand the effects of MTX on serotonin. Also a disruptive effect of MTX on the metabolisms of glutamate, aspartate, glutamine and GABA emerges.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

The flatworm nervous system employs a wide repertoire of neuroactive substances, including small chemical messengers, the so called classical transmitters, and several types of neuropeptides. A large body of research accumulated over four decades has provided a wealth of information on the tissue localization and effects of these substances, their biochemistry and, recently, their molecular modes of action in all major classes of flatworms. This evidence will be reviewed, with particular emphasis on the small (classical) transmitters and the receptors that mediate their effects. One of the themes that will emerge from this discussion is that classical transmitters regulate core activities such as movement, metabolism and transport, and thus are essential for survival of the organism. In addition, the evidence shows that flatworms have multiple neurotransmitter receptors, many with unusual pharmacological features, which make them particularly attractive as drug targets. Understanding the molecular basis of these distinctive properties, and developing new, more specific receptor agonists and antagonists will undoubtedly become a major challenge in future research.

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

Although a number of neuromodulators influence the cerebellar circuitry, their functions remain largely unknown. By reviewing and combining results from data-driven and theory-driven studies, we attempt to provide an integrated systems view of cerebellar neuromodulation. First, we review the short- and long-term effects of neuromodulators on the cerebellar circuitry. Second, we review recent theories of the cerebellum and show that a number of modulatory signals are needed for powerful cerebellar learning and control. Finally, we attempt to match each theoretically derived modulatory signal with a specific neuromodulator. In particular, we propose that serotonin controls the 'responsibility' of each cerebellar unit (or microcomplex) in cerebellar learning and control; norepinephrine gates unsupervised learning in the cerebellar cortex; dopamine enhances goal-oriented cerebellar learning; and, finally, acetylcholine controls the speed of supervised learning in Purkinje cells.

An evolutionarily conserved feature of neural systems is that they can be modified by neuromodulators. These modulatory chemical signals include the biogenic amines, octopamine (OA), serotonin (5-HT) and dopamine (DA). Such modulation effectively broadens the operational range in which specific neural circuits can function adaptively. This report discusses how these amines are themselves modulated; for example, by the steroid hormone 20-hydroxyecdysone (20-E) or by the addition of a second biogenic amine. Such second-order neuromodulation, termed metamodulation, is discussed in the context of two well-studied invertebrate systems: the tobacco hornworm moth Manduca sexta, a model of neurodevelopment and plasticity, and the medicinal leech Hirudo medicinalis, a long-favored preparation used to study neural circuits at the level of identified neurons. A portion of this article reviews our previous research of M. sexta that shows that the 'preadult' rise in 20-E is both necessary and sufficient for the increased levels of octopamine observed in the adult. Such elevated levels likely play an important role in the production and modulation of adult behaviors. The somatic growth of median octopaminergic neurons and the late expression of OA-immunoreactivity by novel lateral neurons are also demonstrated to be dependent on 20-E. New immunocytochemical results of stained dopaminergic neurons in the larval and adult moth brain are provided as well, and the potential influence of 20-E on the developmental expression of this neuromodulator is presented. Turning attention to the leech, data indicate that the actions of OA are dramatically altered when 5-HT is combined with OA in the bath surrounding the isolated nervous system. Although either OA or 5-HT alone induces fictive swimming behavior, a cocktail of these two amines strongly inhibits the generation of swimming. Subsequent removal of such a mixture induces nearly continuous swimming and constitutes the best swim-inducing stimulus encountered to date. To understand better how these nonadditive effects are achieved, new results are discussed that indicate that the leech brain is the target of metamodulation by the two amines. Both the arthropod and annelid systems presented here highlight the multiple levels of metamodulation that can exist in nervous systems, and the diverse ways that a modulator's actions can become altered over short or long time periods., (Copyright 2003 S. Karger AG, Basel)

There is now substantial evidence that GM1 ganglioside is effective in partially correcting the consequences of neuroinjury in a number of in vivo and in vitro model systems. Although the molecular mechanism(s) and the substrates for the neurotrophic activity of the gangliosides are not fully understood, the published experimental work suggests that GM1 has antineurotoxic, neuroprotective, and neurorestorative effects on various central neurotransmitter systems. This review focuses attention on studies reporting that GM1 restores neuronal integrity and function in the brain of lesioned young as well as aged animals. Critical analysis of these studies can provide guidance for future ganglioside research and may point to novel approaches for treating neuroinjury and a variety of degenerative conditions, including aging.

Groups of adult male Sprague Dawley rats (64 rats each) were exposed for 8 months to electromagnetic fields (EMF) of two different field strength combinations: 5microT - 1kV/m and 100microT - 5kV/m. A third group was sham exposed. Field exposure was 8 hrs/day for 5 days/week. Blood samples were collected for hematology determinations before the onset of exposure and at 12 week intervals. At sacrifice, liver, heart, mesenteric lymph nodes, bone marrow, and testes were collected for morphology and histology assessments, while the pineal gland and brain were collected for biochemical determinations. At both field strength combinations, no pathological changes were observed in animal growth rate, in morphology and histology of the collected tissue specimens (liver, heart, mesenteric lymph nodes, testes, bone marrow), and in serum chemistry. An increase in norepinephrine levels occurred in the pineal gland of rats exposed to the higher field strength. The major changes in the brain involved the opioid system in frontal cortex, parietal cortex, and hippocampus. From the present findings it may be hypothesized that EMF may cause alteration of some brain functions.

Vesicular monoamine transporters are known to transport monoamines from the cytoplasm into secretory vesicles. We have used homologous recombination to generate mutant mice lacking the vesicular monoamine transporter 2 (VMAT2), the predominant form expressed in the brain. Newborn homozygotes die within a few days after birth, manifesting severely impaired monoamine storage and vesicular release. In heterozygous adult mice, extracellular striatal dopamine levels, as well as K+- and amphetamine-evoked dopamine release, are diminished. The observed changes in presynaptic homeostasis are accompanied by a pronounced supersensitivity of the mice to the locomotor effects of the dopamine agonist apomorphine, the psychostimulants cocaine and amphetamine, and ethanol. Importantly, VMAT2 heterozygous mice do not develop further sensitization to repeated cocaine administration. These observations stress the importance of VMAT2 in the maintenance of presynaptic function and suggest that these mice may provide an animal model for delineating the mechanisms of vesicular release, monoamine function, and postsynaptic sensitization associated with drug abuse.

The paper deals with the consequences of exogenous taurine (Tau) administration (650 mg/kg, i.p., singly, for 30 min) and possible mechanisms of this compound participation in the formation of the structure of the neuroactive amino acid pool, biogenic amines and their metabolites in the hypothalamus (H), basal ganglia (BG) and cerebellum (C) of the brain of male rats weighing 160-280 g. The concentrations of amino acids as OPA derivatives were determined by reverse-phase HPLC and the content of biogenic amines and their metabolites--by ion-pair HPLC-ECD. The Tau load was followed by an elevation of the concentrations of glutamate, aspartate and their amides, GABA and tyrosine concentrations in cerebellum whereas in basal ganglia that of tyrosine and dopamine. The tryptophan, beta-alanine, dioxyphenylacetic acid, dopamine and norepinephrine levels were diminished in hypothalamus. The metabolic and functional relationships governing the imbalance of the neuroactive amino acid and biogenic amine pool in the neuroactive amino acid and biogenic amine pool in the CNS occurring after the Tau administration in vivo are interpreted using statistical analysis.

Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.

Transcription factors are known to act as gene expression regulators, possibly linking extracellular stimuli to long-term modifications at the neuronal level. Such modifications may potentially underlie chronic psychostimulant- and stress-induced behavioral alterations. This study illustrates how a 2 week, twice daily 7.5 mg/kg d-amphetamine or saline regimen alters rat brain regional expression of transcription factor genes, including c-fos, fos-B, jun-B, c-jun, and zif 268, and seeks potential correlations between those changes and alterations in neurotransmitter levels and behavioral novelty responses. Amphetamine withdrawal-induced decreases in transcription factor mRNA levels, assessed using Northern blot analysis, appear most prominent in prefrontal cortex, begin approximately 12 h after the last injection, and largely recover to control levels by 54 h. Prefrontal cortical and striatal dopamine content, assessed using HPLC, decrease and recover over a similar time course. Behavioral "stereotypy time" manifest by animals exposed to a novel environment, a measure sensitive to psychostimulant withdrawal, also decreases beginning 12 h after the last injection, is still significantly reduced at 54 h, and recovers at 72 h. Chronic saline injections are followed by a consistent decrease in transcription factor gene expression, observed 6 h after the last injection, followed by a "rebound" increase at 12 h. These changes are accompanied by dramatic, mostly biphasic alterations in prefrontal cortical biogenic amines and by a short-lived increase in striatal dopamine turnover. At the same time, rats display much longer-lasting decreases in locomotor responses when exposed to a novel environment, with recovery occurring only 54 h after the last injection. The delayed recovery of behavioral responses to novelty is consistent with potential involvement of changes in transcription factor-mediated gene expression in neurochemical mechanisms underlying psychostimulant withdrawal and chronic injection stress-induced behavioral alterations.

Recently, the central roles of interleukin-1 (IL-1) in physical stress responses have been attracting attention. Stress responses have been characterized as central neurohormonal changes, as well as behavioral and physiological changes. Administration of IL-1 has been shown to induce effects comparable to stress-induced changes. IL-1 acts on the brain, especially the hypothalamus, to enhance release of monoamines, such as norepinephrine, dopamine, and serotonin, as well as secretion of corticotropin-releasing hormone (CRH). IL-1-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in vivo depends on secretion of CRH, an intact pituitary, and the ventral noradrenergic bundle that innervates the CRH-containing neurons in the paraventricular nucleus of the hypothalamus. Recent studies have shown that IL-1 is present within neurons in the brain, suggesting that IL-1 functions in neuronal transmission. We showed that IL-1 in the brain is involved in the stress response, and that stress-induced activation of monoamine release and the HPA axis were inhibited by IL-1 receptor antagonist (IL-1Ra) administration directly into the rat hypothalamus. IL-1Ra has been known to exert a blocking effect on IL-1 by competitively inhibiting the binding of IL-1 to IL-1 receptors. In the latter part of this review, we will attempt to describe the relationship between central nervous system diseases, including psychological disorders, and the functions of IL-1 as a putative neurotransmitter.

Biogenic amine transport systems in the presynaptic plasma membrane and the synaptic vesicle provide a mechanism for rapidly terminating the action of released transmitters and for recycling neurotransmitters. Alterations in the activity of these transporters, either by endogenous regulatory mechanisms or by drugs, affect the regulation of synaptic transmitter levels. For drugs such as antidepressants and stimulants that interact with these transport systems, the therapeutic and behavioral consequences are profound. Now that the cDNAs encoding the transporters have been isolated, we can expect rapid progress in understanding how the individual proteins work at the molecular level to couple ion gradients to the reuptake and storage of biogenic amine neurotransmitters.

The turnover rate of dopamine and serotonin and the level of glutamate in superior colliculus are increased in adult, neonatally enucleated rats compared with normal control adult animals. Moreover, immunocytochemical data showed that the stratum zonale and the stratum griseum superficiale of the superior colliculus, specifically of bienucleated rats, display a dense network of serotonin-immunoreactive fibres, suggesting an increase in serotoninergic innervation. At the electron microscope level, serotonin-immunoreactive fibres and large postsynaptic serotonin-immunoreactive profiles exhibiting microtubules could be observed in the stratum zonale and the stratum griseum superficiale of the bienucleated rat. These results suggest that neonatal enucleation produces reorganization of serotoninergic and glutamatergic inputs. It is possible that serotonin may exert a profound influence upon collicular function.

There is evidence of abnormalities in the brain-stem monoamine-containing neurons in infants with sudden infant death syndrome (SIDS). By taking advantage of the rich innervation of the human basal ganglia by monoaminergic afferents from cell bodies in the brainstem, we studied the synaptic chemistry of catecholamine and associated neurons of the putamen obtained postmortem from 14 SIDS infants, eight age-matched control infants, and older control subjects of various ages. We found significantly lower concentrations of dopamine and higher homovanillic acid/DA ratios in samples from SIDS infants compared with age-matched control infants. Noradrenaline and 5-hydroxytryptamine were lower in SIDS compared with control subjects, but the difference did not reach statistical significance. There was no clear evidence that dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid were altered. Immunoblot analysis of striatal tissue showed that samples from infants with SIDS, which exhibited lower DA, also had lower tyrosine hydroxylase protein. Other transmitter-specific neuronal markers were also assessed, including enzymes associated with cholinergic and GABA-containing neurons. We found significantly decreased choline acetyltransferase activities. However, GABA, glutamate, or somatostatin concentrations or monoamine oxidase activities were unchanged in SIDS. We also noted age-dependent changes in brain weights and some synaptic markers by comparing the age-matched infants with older control subjects. Analysis of variance revealed that homovanillic acid, dihydroxyphenylacetic acid, and monoamine oxidase B activities were increased with age. DA and choline acetyltransferase were also found to be positively correlated in putamen. Our findings suggest developmental changes in some transmitter-specific neurons in SIDS that may result from apneic episodes or chronic hypoxia induced before death.

Monoaminergic nerves are characterized by the presence of a population of small synaptic vesicles (40-60 nm in diameter) containing a few large vesicles (80-90 nm in diameter). Thus, although both types of vesicles contain monoamines, the small vesicles must be considered as the organoid responsible for the storage and release of the neurotransmitter, whereas the large ones possibly are involved in the modulation of the process. The small vesicles are electron-lucent or have an osmiophilic electron-dense core that is always linked to the vesicle membrane. Considering morphological and histochemical evidence under different experimental conditions, we proposed the existence of two compartments in the small vesicles: the core and the matrix, corresponding respectively to the electron-dense core and the electron-lucent space between the core and the vesicle membrane in osmium tetroxide fixations. The sizes of both compartments are inversely related, i.e., the smaller the core, the larger the matrix and vice versa. The core even disappears, giving way to a small electron-lucent vesicle made exclusively by the matrix. Thus, the matrix is a constant component of the vesicle, whereas the core is a transient one. Each compartment has a different pool of amine: a loosely bound, easily releasable pool in the matrix and a tightly bound, more resistant pool in the core. These two pools subserve, respectively, a tonic or phasic release of the neurotransmitter, correlated with a tonic or phasic stimulation of the receptor. The core may be considered as a storage or reserve pool. Experimental evidence from our laboratory supports the concept that different mechanisms are operative in both compartments in the release of the neurotransmitter. For instance, a Ca2(+)-independent release would be primarily concerned with the neurotransmitter contained in the matrix, and a Ca2(+)-dependent efflux would be primarily related with the neurotransmitter stored in the core. However, it still must be established that a simple relationship exists between each kind of stimulus and each vesicle compartment, rather than both compartments being integrated in a dynamic functional unit.

We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.

Effect of diethyl carbamazine (DEC) on the levels of neurotransmitter amino acids and on the activities of related enzymes of S. digitata have been studied. When the worms were incubated in DEC, substances known to have neurotransmitter effect were found increased except glycine. Among the amines the level of serotonin, dihydroxy phenyl alanine and epinephrine were increased and that of histamine remained the same. DEC inhibited activities of monoamine oxidase, aspartate amino transferase and alanine amino transferase and enhanced those of cathepsin and glutamate dehydrogenase. The effect of DEC on the activities of the enzymes appear to account for the increased level of amino acids and amines. Results indicate that the reversible paralysis caused by DEC is due to the accumulation of neurostimulants and associated decrease in the concentration of inhibitors.

After a relatively mild course of uncontrollable shocks, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stressor. Response-deficient (RD) rats do not learn to terminate the controllable stressor, whereas nondeficient (ND) rats learn this response as readily as do untreated control rats. The current studies were designed to determine the neurochemical correlates of the behavioral differences between these groups of rats. The major findings concerned postsynaptic beta-adrenergic effects in the hippocampus of RD rats. These included an up-regulation of beta-adrenergic receptors and, in parallel experiments, an increase in the sensitivity of adenylyl cyclase to stimulation by norepinephrine. There was no difference in brain levels of catecholamines between the three groups of rats. A statistically significant increase in levels of 5-hydroxytryptamine was noted in the hippocampus and hypothalamus of RD rats as compared to levels in ND rats, but no significant differences were measured between groups of rats in terms of S1 or S2 serotonergic receptor binding. These results implicate both beta-adrenergic and serotonergic mechanisms in the behavioral deficit caused by uncontrollable shock.

Peripheral administration of monosodium-L-glutamate (MSG) has been found to be neurotoxic in neonatal rats. When administered in an acute, subconvulsive dose (500 mg/kg i.p.), MSG altered neurotransmitter content in discrete brain regions of adult (6 month old) and aged (24 month old) male Fischer-344 rats. Norepinephrine (NE) content was reduced in both the hypothalamus (16%) and cerebellum (11%) of adult rats, but was increased in both the hypothalamus (7%) and cerebellum (14%) of aged rats after MSG treatment. MSG also altered the dopamine content in adult rats in both the posterior cortex and the striatum, causing a reduction (23%) and an increase (12%), respectively. Glycine content in the midbrain of aged rats increased (21%) after MSG injection. Of particular interest is the widespread monoamine and amino acid deficits found in the aged rats in many of the brain regions examined. NE content was decreased (11%) in the cerebellum of aged rats. Dopamine content was reduced in both the posterior cortex (35%) and striatum (10%) of aged rats compared to adult animals. Cortical serotonergic deficits were present in aged rats with reductions in both the frontal (13%) and posterior cortex (21%). Aged rats also displayed deficits in amino acids, particularly the excitatory amino acids. There were glutamate deficits (9-18% reductions) in the cortical regions (posterior and frontal) as well as midbrain and brain stem. Aspartate, the other excitatory amino acid transmitter, was reduced 10% in the brainstem of aged rats. These data indicate that an acute, subconvulsive, dose of MSG may elicit neurochemical changes in both adult and aged male Fisher-344 rats, and that there are inherent age-related deficits in particular neurotransmitters in aged male Fisher-344 rats as indicated by the reductions in both monoamines and amino acids.

The object of the present study was to examine the effects of temperature, oxidation, and pH on in vitro relative recovery of catecholamine and indoleamine neurotransmitters and their metabolites using microdialysis probes. Relative recovery of norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), homovanillic acid (HVA), and 5-hydroxytryptamine (5HT) increased with temperature from 0 to 46 degrees C. For each compound, the increase in the amount recovered with increasing temperature was different. The stability of norepinephrine and dopamine was not affected at any temperature using deoxygenated calibration standard solutions containing ascorbic acid but was greatly reduced when exposed to ambient air without antioxidant treatment; catecholamine metabolites and the indole compounds were less affected. No change for in vitro relative recovery was observed by varying the pH of the perfusing solution from 6 to 8. Thus, temperature control in probe calibration as well as analyte stability using antioxidant treatment are important in reducing the error when estimating extracellular concentrations of neurotransmitter and metabolites.

Concentrations of dopamine (DA), its metabolites 3-methoxytyramine and homovanillic acid (HVA), noradrenaline (NA), its metabolites normetanephrine (NM) and 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT, serotonin), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in 14 brain regions and in CSF from the third ventricle of 27 human autopsy cases. In addition, in six cases, lumbar CSF was obtained. Monoamine concentrations were determined by reversed-phase liquid chromatography with electrochemical detection. Ventricular/lumbar CSF ratios indicated persistence of rostrocaudal gradients for HVA and 5-HIAA post mortem. Ventricular CSF concentrations of DA and HVA correlated positively with striatal DA and HVA. CSF NA correlated positively with NA in hypothalamus, and CSF MHPG with levels of MHPG in hypothalamus, temporal cortex, and pons, whereas CSF NM concentration showed positive correlations with NM in striatum, pons, cingulate cortex, and olfactory tubercle. CSF 5-HT concentrations correlated positively with 5-HT in caudate nucleus, whereas the concentration of CSF 5-HIAA correlated to 5-HIAA levels in thalamus, hypothalamus, and the cortical areas. These data suggest a specific topographic origin for monoamine neurotransmitters and their metabolites in human ventricular CSF and support the contention that CSF measurements are useful indices of central monoaminergic activity in man.

The effects of the organophosphate acetylcholinesterase (AChE) inhibitor soman (31.2 micrograms/kg s.c.) on guinea-pig brain AChE, transmitter, and metabolite levels were investigated. Concentrations of acetylcholine (ACh) and choline (Ch), noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites, and six putative amino acid transmitters were determined concurrently in six brain regions. The brain AChE activity was maximally inhibited by 90%. The ACh content was elevated in most brain areas by 15 min, remaining at this level throughout the study. This increase reached statistical significance in the cortex, hippocampus, and striatum. The Ch level was significantly elevated in most areas by 60-120 min. In all regions, levels of NA were reduced, and levels of DA were maintained, but those of its metabolites increased. 5-HT levels were unchanged, but those of its metabolites showed a small increase. Changes in levels of amino acids were restricted to those areas where ACh levels were significantly raised: Aspartate levels fell, whereas gamma-aminobutyric acid levels rose. These findings are consistent with an initial increase in ACh content, resulting in secondary changes in DA and 5-HT turnover and release of NA and excitatory and inhibitory amino acid transmitters. This study can be used as a basis to investigate the effect of toxic agents and their treatments on the different transmitter systems.

At 1, 2, and 4 weeks after unilateral premotor and motor cortex ablation in rats, a significant and lasting decrease in glutamate levels in the ipsilateral versus contralateral striatum was observed. A significant corresponding fall in aspartate was seen only after 1 week. In contrast, there was a large increase in the striatal concentrations of lysine, threonine, alanine, and glutamine 1 week after the cortical ablation. This correlates with the extensive glial proliferation in the deafferented ipsilateral striatum. Four weeks after cortical ablation the GABA concentration was significantly increased. There was no decrease in other putative transmitters (dopamine, serotonin, acetylcholine, glycine and taurine), nor was a glutamate decrease observed in the hippocampus or in the hypothalamus, which do not receive direct premotor and motor cortical inputs. Both biochemical and morphological evidence for a minor contralateral cortico-striatal projection was obtained. Correlating with the fall in glutamate, ultrastructural observations indicated the degeneration of two types of striatal synapses, i.e., those of the axo-spinous type III and of the axo-dendritic type VII. Frontal cortex ablation clearly affects, in opposite directions, the metabolism of various striatal amino acids but not that of acetylcholine and the monoamine transmitters. The results strongly support the view that glutamate is the transmitter of the cortico-striatal fibers.

The tuberculum olfactorium of the adult rat was investigated by means of neurohistological, fluorescence histochemical and enzyme histochemical methods. Using the rapid Golgi impregnation technique, seven neuron types could be demonstrated which can clearly be differentiated according to morphological criteria. Using the glyoxylic acid techniques, strongly fluorescent dopamine fibers are, in different densities, visible within the various laminae. Kainic acid application into the ventral tegmental area is followed by a strikingly reduced, no more structurally associated dopamine fiber fluorescence. After DFP intoxication, only a small proportion of the neuron population of the tuberculum olfactorium does exhibit an AChE activity; the AChE containing neurons are different as to their size and shape. The findings presented here are discussed with respect to the attributability of histochemical findings to cytoarchitectural features of this brain area.

Aminergic neurotransmitters and their main metabolites concentrations are measured in four areas (posterior cortex, striatum, hippocampus, hypothalamus) of the rat brain, 24 hours after an acute ischemic injury (created by the occlusion of the four cephalic vessels). Simultaneously, spontaneous motility and neurological status are evaluated. The main results are the increase of 5 HIAA in striatum, hippocampus and cortex, associated with an increase of HVA in striatum. Motility as well as neurological scores are significantly decreased in ischemic animals when compared with controls. The conclusion is that this model of cerebral ischemia is may be useful for pharmacological assessment of drugs liable to antagonize cerebrovascular disorders.

The organization of the interpeduncular nucleus (IPN) in the adult rat was analyzed using cytoarchitectonic, histochemical and immunohistochemical methods. Four paired and four unpaired subnuclei can be distinguished in the IPN on the basis of neuronal size, morphology, staining characteristics and packing density. The rostral portion of the IPN contains a rostral dorsal, a rostral ventral and paired rostral lateral and dorsal lateral nuclei. The dorsal lateral nuclei continue into the caudal IPN, which also contains a caudal dorsal, a caudal ventral and paired caudal lateral nuclei. The distribution of extrinsic afferents and of chemically identified intrinsic neuronal and fiber populations within subdivisions of the IPN was examined using immunohistochemistry, acetylcholinesterase histochemistry, catecholamine histofluorescence and the autoradiographic tracing method. Six immunohistochemically distinct neuronal groups are identified in the IPN. Perikarya and axons showing substance P-, leu-enkephalin-, somatostatin-, avian pancreatic polypeptide-, serotonin- and glutamic acid decarboxylase-like immunoreactivity are localized to specific IPN subnuclei. Acetylcholinesterase-positive staining, extrinsic norepinephrine-containing fibers and afferents from the dorsal tegmental nuclei are also distributed specifically to IPN subnuclei. These findings demonstrate a cytoarchitectonic and cytochemical complexity in the rat IPN that implies an important functional role for this poorly understood nuclear complex.