bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of endogenous dopamine on measures of [18F]N‐methylspiroperidol binding in the basal ganglia: Comparison of simulations and experimental results from PET studies in baboons
Authors: Logan Jean , Dewey Stephen L. , Wolf Alfred P. , Fowler Joanna S. , Brodie Jonathan D. , Angrist Burton , Volkow Nora D. , Gatley S. John 
Published: December 2004

AbstractThe effect of endogenous dopamine on PET measures of radioligand binding is important to the measurement of receptor density (or availability) and neurotransmitter interactions in vivo. We recently reported that pretreatment with amphetamine, a drug which stimulates dopamine release, significantly reduced NMS binding in the baboon brain as determined by the product λk3 dervied from the graphical analysis method for irreversible systems (lambda; is the ratio of the forward to reverse plasma to tissue transport constants and k3 is proportional to receptor density) (Dewey et al.: Synapse 7:324–327, 1991). The purpose of this work is twofold: to evaluate the sensitivity and stability of the analysis method used for the NMS data and from simulation studies which include the competitive effects of dopamine on NMS binding to predict the effect of dopamine on the in vivo PET experiment. Using a measured plasma [18F]‐NMS input function from a control study in a baboon, simulation data was numerically generated explicitly allowing competition between NMS and dopamine in the calculation. This data was analyzed using the same techniques as used for the experimental data and the results were compared to in vitro calculations. The following conclusions were reached: (1) The effect of dopamine on specific binding was found to be greater in vivo than in vitro because the in vitro equilibrium experiment is controlled only by the relative Kd's of tracer and dopamine while the in vivo experiment also depends upon the halftime of tracer in tissue which is controlled by the tissue‐to‐plasma transport constant; (2) Experimental evidence from rodent studies (Seeman et al.: Synapse 3:96–97, 1989) and the agreement between PET studies (Wong et al.: Science 225:728–731, 1984) in schizophrenics suggest that NMS is not likely to be affected by normal levels of endogenous dopamine. From the calculations reported here the effective in vivo Kd of dopamine for the NMS binding site would have to be on the order of or greater than 100 nM, assuming a synaptic dopamine concentration of 20 nM, in order that this concentration of dopamine have little effect on NMS binding.
Excitatory responses to serotonin (5‐HT) in neurons of the rat piriform cortex: Evidence for mediation by 5‐HT1C receptors in pyramidal cells and 5‐HT2 receptors in interneurons
Authors: Sheldon Priscilla W. , Aghajanian George K. 
Published: December 2004

AbstractAs a prerequisite to pharmacological analysis of the excitatory effects of serotoinin (5‐HT) on piriform pyramidal cells and interneurons, this study first examined the physiological characteristics of these two cell types. Intracellular recordings confirmed that the subpopulation of 5‐HT‐activated cells located at the border of layers II and III and indeed interneurons. Voltage clamp recordings in pyramidal cells showed that the increase in excitability produced by 5‐HT in these cells was the result of voltage‐ and Ca2+‐dependent outward currents with the characteristics of IM and IAHP.Pharmacological studies were designed to discriminate 5‐HT2 from 5‐HT1C responses in interneurons and pyramidal cells of piriform cortex. The 5‐HT antagonist spiperone, which has a much higher affinity for 5‐HT2 receptors than for 5‐HT1C receptors, blocked the excitatory effect of 5‐HT at lower concentrations in interneurons (IC50 = 31 nM) than in pyramidal cells (IC50 = 2.1 μM). Similarly, ritanserin, a drug which also has a higher affinity for 5‐HT2 than 5‐HT1C receptors, blocked the effect of 5‐HT at lower concentrations in interneurons (IC50 = 400 nM) than in pyramidal cells (IC50 = 8.1 μM). In contrast, LY 53857, an antagonist with higher affinity for 5‐HT1C than for 5‐HT2 receptors, blocked the effect of 5‐HT at lower concentrations in pyramidal cells (IC50 = 26 nM) than in interneurons (IC50 = 364 nM). The 5‐HT1C partial agonist/5‐HT2 antagonist mCPP produced agonist‐like effects in only 66% of pyramidal cells tested indicating that not all pyramidal cells may express 5‐HT1C receptors.In that both spiperone and ritanserin have higher affinity for 5‐HT2 receptors than for 5‐HT1C receptors and LY 53857 has a higher affinity for 5‐HT1C receptors than for 5‐HT2 receptors, these data suggest that in piriform cortex excitatory effects of 5‐HT are mediated by 5‐HT1C receptors in pyramidal cells and by 5‐HT2 receptors in interneurons.
Compartmentation and glycoprotein substrates of calpain in the developing rat brain
Authors: Sheppard Allan , Wu Justina , Bahr Ben A. , Lynch Gary 
Published: December 2004

AbstractAn activated form of calpain I associates with telencephalic membranes in a developmentally regulated fashion during early postnatal ontogeny. During this period, the cytoskeletal component spectrin is available and appears to be differentially susceptible to calpain‐mediated cleavage. Lectin blotting techniques demonstrated that the leupeptin‐sensitive action of calpain is primarily directed toward large proteins which are glycoconjugate in nature; neuronal cell adhesion molecules are among the glycoproteins whose associations with the telencephalic membranes decrease due to calpain activity. These data suggest that cytoplasmic calpain is translocated to the membrane during early brain development in order to act on the cytoskeletal and adhesive structures responsible in part for neuronal shape and function.
200 kD neurofilament protein and synapse elimination in the rat soleus muscle
Authors: Roden R. L. , Donahue S. P. , Schwartz G. A. , Wood J. G. , English A. W. 
Published: December 2004

AbstractWe studied the distribution and appearance of the phosphorylated form of the 200 kD neurofilament protein in the rat soleus muscle during the period of postnatal synapse elimination. Unlike many muscles, the appearance of singly innervated muscle cells in soleus occurs well after myogenesis has been completed, so that synapses are eliminated from a stable population of muscle cells. Immunoreactivity to the 200 kD neurofilament protein is present in the terminals of neuromuscular synapses of animals at all postnatal ages from 0 to 21 days. Before postnatal day 10, when physiological studies indicate that all soleus muscle cells receive more than one synaptic input, as many as 30% of soleus muscle cells contain phosphorylated 200 kD neurofilament protein immunoreactivity in only one synaptic terminal. At older ages the number of polyneuronally innervated muscle cells observed using immunostaining is similar to that observed physiologically. These findings suggest that not all developing neuromuscular synapses contain phosphorylated 200 kD neurofilament protein, and that those terminals lacking it comprise most of those eliminated early in the postnatal period. We conclude that the presence of phosphorylated 200 kD neurofilament protein might be highly correlated with the survival of motor nerve terminals during postnatal neuromuscular synapse elimination.
Arylamine spider toxins antagonize NMDA receptor‐mediated synaptic transmission in rat hippocampal slices
Authors: Mueller Alan L. , Albensi Benedict C. , Ganong Alan H. , Reynolds Linda S. , Jackson Hunter 
Published: December 2004

AbstractThe effects of arylamine spider toxins on synaptic transmission in rat hippocampal slices were investigated. Two different responses were monitored: the AMPA receptor‐mediated population spike recorded in control buffer (selectively antagonized by DNQX) and the NMDA receptor‐mediated EPSP recorded in nominally magnesium‐free buffer containing 20 μM DNQX (selectively antagonized by AP5, AP7, and dizocilpine (MK‐801)). The synthetic arylamine spider toxins JSTX‐3, argiotoxin‐636, and argiotoxin‐659 were 26 to 73 times more potent at antagonizing the NMDA receptor‐mediated EPSP (IC50 values ranging from 12 to 24 μM) than the AMPA receptor‐mediated population spike (IC50 values ranging from 612 to 878 μM). These results indicate that arylamine spider toxins are selective antagonists of NMDA receptors in the mammalian CNS.
Action of serotonin in the medial prefrontal cortex: Mediation by serotonin3‐like receptors
Authors: Ashby Charles R. , Edwards Emmeline , Wang Rex Y. 
Published: December 2004

AbstractIn the present study, we investigated the effects of various serotonin (5‐HT) antagonists on 5‐HT's action on medial prefrontal cortical cells (mPFc) using the techniques of single cell recording and microintophoretic The microiontophoretic application of 5‐HT (10–80 nA) produced a current‐dependent suppression of mPFc cell firing and this effect was blocked by the selective 5‐HT3 receptor antagonists (±)‐zacopride, ICS 205930 and granisetron at currents of 5–20 nA. Furthermore, the intravenous (i.v.) administration of (±)‐zacopride (5–50 μg/kg) markedly attenuates the suppressive action of 5‐HT on mPFc cell firing. In contrast, the microinotophoresis of 5‐HT1 and 5‐HT2 receptor antgonists such as (±)‐pindolol, spiperone, metergoline, and ritanserin (10–20 nA) failed to block 5‐HT's effect. In fact, in some cells, spiperone and ritanserin potentiated 5‐HT's action and prolonged neuronal recovery. In addition, the intravenous administration of either ritanserin (5–2,000 μg/kg) or metergoline (4–2,400 μg/kg) failed to alter 5‐HT's action. The electrical stimulation of the caudal linear raphe nucleus (CLi) suppressed the spontaneous activity of 83% of the mPFc cells tested by 45 ± 2%. This suppression was significantly attenuated by the iontophoresis of granisetron (2.5–5 nA) but not by the 5‐HT2 and 5‐HT1C receptor antagonist ritanserin or the relatively selective 5‐HT2 receptor antagonist (+)‐MDL 11,939 (10–40 nA). However, the i.v. administration of ritanserin (0.5–1.5 mg/kg) or S‐zacopride (0.1 mg/kg) significantly blocked the suppression of mPFc cell firing produced by CLi stimulation. Overall, our results suggest that 5‐HT's physiological effect in the mPFc may be primarily mediated by its interaction with 5‐HT3‐like receptors and that ritanserin's blockade of CLi‐induced suppression of mPFc cell firing may be indirect.
Compartmental distribution of cytochrome oxidase in the striatum of the rat
Authors: Augood Sarah J. , Emson Piers C. 
Published: December 2004

AbstractEndogenous cytochrome oxidase activity was investigated in the adult rat striatum at the light microscope level to see if it was distributed in accordance with the established striatal patch/matrix compartmentalisation. Striatal sections stained to visualise cytochrome oxidase activity were compared with serial sections stained to visualise tyrosine hydroxylase and calbindinD28k‐like immunoreactivity, established markers of the matrix compartment. The distribution of endogenous cytochrome oxidase activity was found to coincide with the immunocytochemical staining pattern seen for tyrosine hydroxylase and calbindinD28k whereby areas of intense tyrosine hydroxylase and calbindinD28k‐like immunoreactivity (termed the matrix) corresponded to areas of intense cytochrome oxidase activity. Conversely, areas of less intense tyrosine hydroxylase and calbindinD28k‐like immunoreactivity (termed patches) corresponded to areas of low cytochrome oxidase activity. In addition, the distribution of two other oxidative enzymes involved in the regulation of mitochondrial respiration, succinic dehydrogenase and NADH‐diaphorase, was examined in the striatum and substantia nigra by using histochemical techniques. Both NADH‐diaphorase and succinic dehydrogenase histochemistry showed an uneven pattern of neuropil staining in the striatum. In the substantia nigra a few intensely stained cell bodies were seen in the dorsal‐lateral tip of the pars reticulata with both histochemical techniques. By using an anti‐cytochrome oxidase antibody an abundance of immunoreactive cell bodies and processes were seen in the substantia nigra, particularly in the dorso‐medial rim and dorsal tip of the pars reticulata. The substantia nigra pars lateralis contained many intensely stained cytochrome oxidase‐like immunoreactive cell bodies and processes. Our results demonstrate that the neurochemically distinct compartments of the adult rat striatum contain differential amounts of endogenous cytochrome oxidase activity suggesting that the matrix compartment is more metabolically active than the patch compartment. This difference in metabolic activity may reflect a difference in synaptic activity between the two striatal compartments.
Cholinergic and GABAergic mediations of the effects of apomorphine on serotonin neurons
Authors: Chen H. Y. , Lin Y. P. , Lee E. H. Y. 
Published: December 2004

AbstractApomorphine (APO) has been shown to elevate tryptophan, serotonin (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations in the dorsal raphe (DR) and its corresponding projection site, the striatum, but not in the median raphe (MR) and its terminal area, the hippocampus. We have previously demonstrated that these effects are indirectly mediated through dopamine (DA) autoreceptors in the substantia nigra and possibly γ‐aminobutyric acid (GABA) neurons in or near the DR. In the present study, we have further found that the effects of APO on 5‐HT neurons are also mediated through both nicotinic and M1 muscarinic cholinergic receptors as well as GABAA receptors in the DR. This suggestion is based on the findings that both atropine and mecamylamine antagonized the effects of APO, while carbachol at a high dose exerted an effect opposite to that of APO. Besides, pirenzepine and bicuculline at low doses also antagonized, whereas saclofen did not alter the influence of APO on 5‐HT in the striatum. Bicuculline at a higher dose enhanced tryptophan and 5‐HT measures by itself. None of the drugs studied had a significant effect on tryptophan, 5‐HT, or 5‐HIAA in the hippocampus. These results together suggest that DA, ACh, and GABA neurons are all involved in the actions of APO on 5‐HT, while the direct synaptic relationships among these neurotransmitters and the precise anatomical locus for these interactions to occur are still unknown. It is possible that APO, by inhibiting DA neuron firing in the substantia nigra and through the GABA disinhibition mechanism, therefore indirectly activates 5‐HT neurons in the DR and the striatum. While the above neuronal firing model well explains the elevation of 5‐HIAA, the simultaneous increases of tryptophan and 5‐HT, especially tryptophan, may be more readily explained by a mechanism of tryptophan uptake upon APO administration. Further anatomical, biochemical, and electrophysiological studies are ongoing to test this hypothesis and to clarify the circuit and the anatomical locus (loci) for these interactions to occur.
Multiple heteroreceptors on limbic thalamic axons: M2 acetylcholine, serotonn1B, β2‐adrenoceptors, μ‐opioid, and neurotensin
Authors: Vogt Brent A. , Crino Peter B. , Jensen Eugene L. 
Published: December 2004

AbstractLigand binding to many transmitter receptors is much higher in layer Ia of rat posterior cingulate cortex than it is in other layer, and this is where most axons from the anterior thalamus terminate. The present study explores the possibility that a number of receptors may be expressed on axons from limbic thalamic nuclei that terminate in layer Ia. Unilateral thalamic lesions were placed in rats and, 2 weeks later, five ligand binding protocols, coverslip autoradiography, and single grain counting techniques were used to qunatify binding in control and ablated hemispheres. Binding to the following receptor subtypes was analyzed: M2 acetylcholine, 3H‐oxotremorine‐M, or 3H‐AF‐DX 116 with 50 nM pirenzepine; serotonin1B, 125I‐(−)‐cyanopindolol with 30 μM isoproterenol; β2‐adrenoceptors, 125I‐(−)‐cyanopindolol with 1 μM serotonin and 10 μM atenolol; μ‐opioid, 3H‐Tyr‐D‐Ala‐Gly‐MePhe‐Gly‐ol; neurotensin, 3H‐neurotensin. Thalamic lesions reduced binding in two laminar patterns. In one pattern, there was a major reduction in binding in most superficial layers with that in layer Ia ranging from 50 to 70% for binding to M2 muscarinic and serotonin1B receptors. Binding to β2‐adrenoceptors was also reduced in most superficial layers but to a lesser extent. In the second pattern, reductions were limited to layer I with losses in layer Ia of 20–30% for μ‐opioid and neurotensin receptors. In no instance was layer Ia binding completely abolished (i.e., postlesion peaks remained).Since the transmitters for each of the five receptors analyzed in this study are not synthesized by anterior or laterodorsal thalamic neurons, these receptors are heteroreceptors. The greatest postlesion reduction in M2 binding was for AF‐DX 116 and so most M2 heteroreceptors are of the “cardiac” subtype. Finally, the diverse population of heteroreceptors on limbic thalamic axons provides for presynaptic modulation by a wide range of transmitter systems and suggests that thalamocortical transmission may not be a simple, unmodulated event.
Local application of bicuculline potentiates NMDA‐receptor‐mediated sensory responses of brain noradrenergic neurons
Authors: Shiekhattar Ramin , Aston‐Jones Gary 
Published: December 2004

AbstractDirect application of bicuculline methiodide (BIC) to noradrenergic locus coeruleus (LC) neurons potently enhanced their sensory responsiveness. This increased responsiveness was due to the long‐lasting expression of a new, N‐methyl‐D‐aspartate (NMDA) receptor‐mediated component of the synaptic response. This enhancement only occurred when a high stimulus intensity was used to induce the sensory response. A similar increase in responsiveness was observed with stimulation of the nucleus paragigantocellularis (PGi), one of the major direct afferents to LC. This action of BIC was neither mimicked by picrotoxin, penicillin, or the GABA‐B antagonist, 2‐hydroxysaclofen, nor by agents that directly depolarize LC neurons. In addition, the inverse agoinst of the benzodiazepine receptor, methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), did not mimic this effect of BIC. The BIC‐potentiated response component was eliminated by direct application of the neurotransmitter γ‐aminobutyric acid (GABA). These results indicate that BIC, acting at a possibly novel site, unmasks NMDA receptors that can be activated by sensory stimuli. This may reflect a mechanism whereby interactions between two major neurotransmitter systems, excitatory amino acids (EAAs) and GABA, potently modulate signal transmission in the brain.
Activators of protein kinase C increase the phosphorylation of the synapsins at sites phosphorylated by cAMP‐dependent and Ca2+/calmodulin‐dependent protein kinases in the rat hippocampal slice
Authors: Browning Michael D. , Dudek Ellen M. 
Published: December 2004

AbstractPrevious studies have shown that activators of protein kinase C (C kinase) produce synaptic potentiation in the hippocampus. For example, the C kinase activator phorbol dibutyrate has been shown to increase transmitter release in the hippocampus. In addition, a role for C kinase in long‐term potentiation has been proposed. A common assumption in such studies has been that substrates for C kinase were responsible for producing these forms of synaptic potentiation. However, we have recently shown that phorbol dibutyrate increased the phosphorylation of synapsin II (formerly protein III, Browning et al., 1987) in chromaffin cells (Haycock et al., 1988). Synapsin II is a synaptic vesicle‐associated phosphoprotein that is a very poor substrate for C kinase but an excellent substrate for cAMP‐dependent and Ca2+/calmodulin‐dependent protein kinase. We felt, therefore, that activation of C kinase might lead to activation of a kinase cascade. Thus effects of C kinase activation might be produced via the phosphorylation of proteins that are not substrates for C kinase. In this report we test the hypothesis that activators of C kinase increase the phosphorylation of synapsin II and an homologous protein synapsin I. Our data indicate that PdBu produced dose‐dependent increases in the phosphorylation of synapsin I and synapsin II. We also performed phospho‐site analysis of synapsin I using limited proteolysis. These studies indicated that PdBu increased the phosphorylation of multiple sites on synapsin I. These sites have previously been shown to be phosphorylated by both cAMP‐dependent protein kinase and the multifunctional Ca2+/calmodulin‐dependent protein kinase II. The ability of C kinase activators to produce a net increase in the phosphorylation state of these sites on synapsin was confirmed by a “back phosphorylation assay” with exogenous cAMP‐ and Ca2+/calmodulin‐dependent protein kinases. Previous studies have provided direct evidence that synapsin I regulates neurotransmitter release at the squid giant synapse and that this effect is controlled by phosphorylation of synapsin I by Ca2+/calmodulin‐dependent protein kinase II. Accordingly we hypothesize that the phosphorylation of synapsin I and the related protein, synapsin II, may play an important role in mediating the increased transmitter release elicited by activators of C kinase. Moreover, we suggest that the role played by C kinase in long‐term potentiation may involve, in part, the phosphorylation of the synapsins.
Autoradiographic localization of 5HT1 binding sites in the medulla oblongata of the rat
Authors: Thor Karl B. , Blitz‐Siebert Alisa , Helke Cinda J. 
Published: December 2004

AbstractSerotonin (5HT) binding sites in the medulla oblongata of the rat were localized using autoradiographic techniques with radioactive ligands that express high affinity for the 5HT1, (3H‐5HT), 5HT1A (3H‐8OH‐DPAT), or 5HT1B (125I‐CYP with isoproterenol) receptor subtypes. 5HT1A sites were concentrated primarily in certain sensory regions of the medulla and in regions that contain serotonergic neurons. 5HT1B sites were diffusely distributed throughout the reticular formation and motor regions as well as being localized to certain sensory regions. A surprising finding was an association of 5HT1B binding sites with the corticospinal tract. 3H‐5HT binding generally reflected the combined pattern of 5HT1A and 5HT1B sites but was also extremely dense in the choroid plexus, which exhibited virtually no 5HT1A or 5HT1B ligand binding. Presumably this binding, which was blocked by ketanserin, corresponds to 5HT1C sites.Administration of the serotonergic neurotoxin 5,7‐dihydroxytryptamine reduced 5HT1A binding sites in regions of the medulla that contain serotonergic neuronal cell bodies. 5HT1B binding was not significantly altered in any area of the medulla.These studies indicate an important role for 5HT1A ligands in the processing of visceral and somatic sensory information, in regulation of certain cerebellar afferent projections, and in the regulation of serotonergic neuronal activity. 5HT1B ligands would be expected to regulate visceral and somatic efferent activity, as well as sensory information and reticular efferent activity, and might presynaptically regulate cortical inputs to the brain stem and spinal cord.