bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited review: Role of receptor regulation in opioid tolerance mechanisms
Authors: Loh Horace H. , Tao Pao‐Luh , Smith Andrew P.
Published: January 2005

The molecular basis of opioid tolerance/dependence has long eluded researchers, but recent advances in receptor regulation have suggested a useful conceptual approach to the problem. In NG108‐15 neuroblastoma × glioma hybrid (NG) cells, opioid agonists inhibit adenylate cyclase in a dose‐dependent, naloxone‐antagonizable fashion. Chronic treatment with opioid agonists results in a series of molecular processes that, in a tolerance‐like fashion, counteract this inhibition. These processes include desensitization and down‐regulation of receptors and an increase in adenylate cyclase activity.

Opioid inhibition of adenylate cyclase and opioid receptor down‐regulation also have been observed in the brain. However, most studies have found that the receptors coupled to adenylate cyclase are not of the mu type, which a thought to be the primary mediators of opioid analgesia. Down‐regulation has been observed for both mu and delta opioid receptors in the brain. However, in most case, the time course of down‐regulation is not correlated with that for tolerance development, and chronic morphine treatment does not result in down‐regulation. Thus, opioid receptors in the brain, like those in NG cells, are subject to dynamic regulation by agonists, which probably has an important role in their function. However, it remains to be established that opioid receptor regulation is the basis of opioid tolerance and dependence.
The novel N‐Methyl‐D‐Aspartate (NMDA) antagonist CGS 19755 prevents ischemia‐induced reductions of adenosine A1, NMDA, and PCP receptors in gerbil brain
Authors: Jarvis Michael F. , Murphy Deborah E. , Williams Michael , Gerhardt Susan C. , Boast Carl A.
Published: January 2005

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N‐methyl‐D‐aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30–60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia‐induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755‐treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia‐induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long‐term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.
Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of globus pallidus neurons in the rat
Authors: Pan Helen S. , Walters Judith R.
Published: January 2005

Activities of spontaneously firing neurons in the globus pallidus of intact rats and rats that survived unilateral lesions of the nigrostriatal pathway for 3 days, 1 week, or 6–11 weeks were compared. No significant differences in neuronal firing rate, firing pattern, and number of cells per pass were observed between chloral hydrate‐anesthetized control and lesioned animals. However, in locally anesthetized animals, pallidal cells fired significantly faster than in chloral hydrate‐anesthetized animals, and the lesion caused a decrease in the firing rates of pallidal cells 1 week and 6–9 weeks postlesion. In addition, significant differences in the firing pattern of pallidal cells, as determined by the ratio of the mean to median interspike intervals, were seen between locally anesthetized controls and animals surviving 3 days, 1 week, and 6–9 weeks post lesion. This altered firing pattern tended to return to normal with time. The number of cells per pass was not significantly altered by the lesion. Data from this study suggest that, in locally anesthetized animals, the removal of the tonic dopaminergic input to the basal ganglia causes pallidal cells to decrease their firing rates in a time‐dependent fashion and causes reversable firing pattern changes. This suggests that tonically active dopamine neurons, probably acting through the striatopallidal pathway, regulate the firing rate and mechanisms controlling the temporal ordering of spontaneous discharges of globus pallidus neurons.
Properties of two classes of rat brain acidic amino acid receptors induced by distinct mRNA populations in Xenopus oocytes
Authors: Fong Tung Ming , Davidson Norman , Lester Henry A.
Published: January 2005

The Xenopus laevis oocyte expression system was used to study the molecular composition of mRNAs encoding acidic amino acid (AA) receptors from rat brain. Xenopus oocytes injected with poly(A) mRNA express two general classes of AA receptors. One class consists of AA‐gated cation channels. Responses are evoked by N‐methyl‐D‐aspartate (NMDA), by kainate, and to a lesser extent by L‐glutamate or quisqualate. The second class of receptor is coupled to an intracellular second messenger pathway activating an oocyte‐encoded Ca2+‐activated Cl− conductance. This second messenger‐coupled AA receptor can be activated by L‐glutamate or quisqualate. DL‐2‐amino‐5‐phosphonopentanoic acid and D‐α‐aminohexanedioic acid inhibit the AA‐gated cation conductances activated by NMDA or kainate with different potencies but do not inhibit the second messenger‐coupled AA receptor. Responses to NMDA are enhanced by micromolar level of glycine and are inhibited by Mg2+, Zn2+, or MK‐801. Dose‐response analysis reveals that the AA‐gated cation conductance activated by kainate requires the binding of two agonist molecules. To study the molecular composition, the mRNAs were size fractionated by denaturing agarose gel electrophoresis. About20‐fold purification in specific activity (nA/ng of mRNA injected) of mRNAs encoding the second messenger coupled AA receptor was achieved. In contrast, only a slight enrichment of the mRNAs encoding the AA‐gated channel was observed. This suggests that the second messenger coupled AA receptor is encoded by a single size class of mRNA, whereas the AA‐gated cation channel(s) is encoded by multiple species of mRNAs or by mRNAs whose size distribution is heterogeneous.
Effects of nicotinic agonists and antagonists on N‐methyl‐D‐aspartate‐induced 3H‐norepinephrine release and 3H‐(1‐[1‐(2‐thienyl)cyclohexyl]‐piperidine) binding in rat hippocampus
Authors: Snell Lawrence D. , Johnson Kenneth M.
Published: January 2005

The nicotinic agonists dimethylphenylpiperazinium iodide (DMPP) and carbachol (CARB) as well as (−)nicotine ((−)NIC) were tested alone and in combination with N‐methyl‐D‐aspartate (NMDA) for their abilities to enhance the efflux of 3H‐norepinephrine (NE) from slices of rat hippocampus. CARB and (−)NIC produced small, transient increases in NE efflux, while DMPP produced larger, longlasting increases. Inasmuch as the nicotinic antagonists mecamylamine (MECA) and hexamethonium (C6) did not consistently inhibit the increases in NE efflux produced by these agonists, the role of a nicotinic receptor in mediating these responses is uncertain. CARB and DMPP enhanced the ability of NMDA to stimulate NE release, while (−)NIC did not. MECA, but not C6, was found to selectively antagonize NMDA‐stimulated NE release that did not appear to involve a nicotinic receptor. Binding studies indicated that MECA and the related nicotinic antagonist pempidine produced an inhibition of NMDA‐stimulated NE release by an action at the PCP receptor that is known to be linked to the NMDA receptor‐ionophore complex. These data suggest that the actions of these ganglionic blocking agents on excitatory responses in the hippocampus involve inhibition of excitatory amino acid as well as nicotinic receptors.
Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus
Authors: Steinmetz Joseph E. , Lavond David G. , Thompson Richard F.
Published: January 2005

Classical conditioning of skeletal muscle responses was accomplished by pairing microstimulation of the pontine nuclei as a conditioned stimulus (CS) with microstimulation of the dorsal accessory olive as an unconditioned stimulus (US). A conditioned response identical in form to the behavioral response elicited by the olivary stimulation was established when the CS was forward paired with the US, and behavioral extinction occurred with CS‐alone presentations or unpaired CS‐US presentations. Conditioned responding could not be established or maintained when the CS and US were simultaneously presented or when the US preceded the CS (i.e., backward paired). Complete lesions of the interpositus nucleus abolished both conditioned and unconditioned responses. These findings support the idea that plasticity associated with classical conditioning of skeletal muscle responses occurs in regions of the cerebellum that receive convergent CS and US input.
Detection and characterization of a 5HT1D serotonin receptor‐gtp binding protein interaction in porcine and bovine brain
Authors: Herrick‐Davis Katharine , Titeler Milt
Published: January 2005

Radioligand binding studies were performed to characterize serotonin 5HT1D binding sites in porcine and bovine brain. 3H‐5HT binding, in the presence of 1 μM (+/−)pindolol (to block 5HT1A and 5HT1B receptors) and 100 nM mesulergine (to block 5HT1c receptors), was specific, saturable, and of high affinity. In porcine and bovine cortex and striatum the majority of 5HT1 sites (80%‐90%) were of the 5HT1D subtype. In competition experiments 8‐OH‐DPAT, TFMPP, mesulergine, DOB, and ICS 205‐930 had low affinity for 3H‐5HT‐labeled 5HT1D sites, indicating that the pharmacology of the 5HT1D site is distinct from previously identified 5HT1A, 5HT1B, 5HT1C, 5HT2, and 5HT3 sites. Guanyl nucleotides, GTPgammaS, and Gpp(NH)p, and divalent cations potently modulated the binding of 3H‐5HT to 5HT1D sites in porcine and bovine striatum. Mg+ + ions increased the number and affinity of 3H‐5HT‐labeled 5HT1D sites, while guanyl nucleotides decreased the number of 3H‐5HT‐labeled 5HT1D sites. These results demonstrate the presence of the 5HT1D receptors in porcine striatum and bovine cortex and provide direct demonstration that the radioligand binding assay for the 5HT1D receptor can monitor the interaction of this receptor with a GTP‐binding protein.
Intracellular studies in the facial nucleus illustrating a simple new method for obtaining viable motoneurons in adult rat brain slices
Authors: Aghajanian George K. , Rasmussen Kurt
Published: January 2005

In general, it has been difficult to preserve electrophysiologically viable motoneurons in brain slices from adult mammals. The present study describes a new method for obtaining viable motoneurons in the facial nucleus of adult rat brain slices. The essence of the method was to use a modified artificial cerebrospinal fluid (ACSF) in which NaCl was replaced initially by sucrose; the modified ACSF was used during (1) slice preparation and (2) a 1 hr recovery period. The rationale for the modification is discussed in terms of the proposed acute neurotoxic effects of passive chloride entry and subsequent cell swelling and lysis. The actual recordings were made only after switching back to normal ACSF. Use of this method yielded large numbers of viable motoneurons that were suitable for intracellular recording; no motoneurons survived when normal ACSF (i.e., with NaCl) was used during slice preparation. A survey of some electrophysiological and pharmacological properties of facial motoneurons in this preparation, by means of current‐clamp and voltage‐clamp recording, revealed close similarities to the properties of adult motoneurons previously observed in vivo (e.g., time‐dependent inward rectification, apamin‐sensitive afterhyperpolarization, and serotonin‐induced slow depolarization).
Alterations in local cerebral glucose utilization following central administration of corticotropin‐releaseing factor in rats
Authors: Sharkey John , Appel Nathan M. , De Souza Errol B.
Published: January 2005

We have examined the effects of intracerebroventricular administration of corticotropin‐releasing factor (CRF) (5.25 nmol in 10 μl of saline) on glucose utilization, an index of cerebral function, in 65 anatomically discrete regions of rat brain by using the 14C‐2‐deoxyglucose quantitative autoradiographic technique. CRF administration increased plasma glucose concentrations with a temporal onset and magnitude of response similar to those previously reported. CRF differentially affected glucose utilization (GU) in discrete regions of rat brain. Consonant with the hypophysiotropic role for CRF, pronounced increases in GU were seen in median eminence and lateral nucleus of the hypothalamus. CRF also increased GU in brain regions implicated in mediating responses to stress including locus coeruleus and median raphe nucleus. In contrast, reductions in GU were observed in prefrontal cortex and nucleus accumbens. Punctate increases in GU were noted in the cerebellar cortex. Furthermore, large increases in GU occurred in vermis, inferior olive, and red nucleus substantiating a neurotransmitter role for CRF in the olivocerebellar pathway. Additional brain areas showing significant alterations in GU in response to CRF included anteroventral, anterior pretectal, and posterolateral nuclei of the thalamus, fornix, dorsal tegmental nucleus, spinal trigeminal nucleus, and cuneate nucleus. These data demonstrating regional changes in GU in response to CRF administration further elucidate the neuroanatomical substrates underlying the actions of CRF in brain and support the role of this neuropeptide in coordinating responses to stress.
Associative synaptic potentiation and depression: Quantification of dissociable modifications in the hippocampal dentate gyrus favors a particular class of synaptic modification equations
Authors: Lopez Hector S. , Burger Barbara , Dickstein Ruth , Desmond Nancy L. , Levy William B.
Published: January 2005

This report further characterizes associative long‐term synaptic modification of the ipsilateral and contralateral synapses formed by the bilateral entorhinal cortical (EC) projection to the dentate gyrus (DG). The experimental model is the anesthetized hooded rat. The quatntitative results qualify this system as a model for studying the rules of associative synaptic modification formulated in terms of individual synapses. Bilateral DG microelectrodes recorded both ipsilateral and contralateral EC‐DG responses before and after brief, high‐frequency EC conditioning stimulatin. The weak contralateral pathway receivewd high‐frequency coditioning before, during, or after similar conditioning of the strong, converging ipsilateral pathway. Statistical analyses revealed two types of significant, dissociated synaptic modifications, which depend on the relationship of the ipsilateral and contralateral afferents. First, contralateral EC‐DG responses potentiated, depressed, or showed no change when the collateral ipsilateral responses concurrently either potentiated or remained unchanged. Correlation and contingency table analysis indicated that changes in the contralateral synaptic responses are not well predicted by changes at either neighboring synapses of the converging ipsilateral pathway or at synapses of the collateral ipsilateral pathway. The contingencies of associated pre‐ and postsynaptic activation determined by the conditioning paradigm, however accurately predicted the altered synaptic responses of both ipsilateral and contralateral rately predicted the altered synaptic responses of both ipsilateral and contralateral EC‐DG pathways. The results imply that associative synaptic modification in the EC‐DG system is specific to individual synapses and requires both appropriate presynaptic and postsynaptic activation. Because this system provides suitable controls for nonspecific dissociable, the EC‐DG system can be used to study further those rules of activity‐dependent associative modification that are formulated in terms of individual synapses. The discussion briefly considers published rules modification, pointing out several rules that are not consistent with the ecperimental observations and one that agrees with the present results.
GABA and glutamate receptor development of cultured neurons from rat hippocampus, septal region, and neocortex
Authors: Köller Hubertus , Siebler Mario , Schmalenbach Corinne , Müller Hans‐Werner
Published: January 2005

The early development of functionally active GABA and glutamate receptors on neurons from hippocampus, septal region, and neocortex of embrryonic rats were studied using primary dissociated serum‐free cell cultures. The responses to GABA and glutamate, applied to individual neurons by pressure ejection, were tested at different development stages, starting at 1 day in vitro (DIV) until 3 weeks. In all three types of neuronal cultures, the GABAA‐receptor developed prior to the glutamate receptros, and after 9 DIV most of the neurons were sensitive to both GABA and glutamate. N‐methyl‐D‐aspartate (NMDA) and non‐NMDA receptor subtypes of the glutamate receptors could be distinguished in hippocampal cultures. The development of GABA and glutamate receptors on septal region neurons appeared to be delyed as compared to hippocampal neurons. In neucortical cultures the majority of nueorns was sensitive to GABA just after plating, whereas the sensitivity to glutamate was retarded. The differences in GABA and glutamate receptor development among these three neuronal cultures provide evidence that the apearance of tranmitter receptors on cultured neurons is predominantly determined by intrinsic mechanisms rather than by environmental coditions. The proportion of spontaneously active networks in these cultures increased with a time course very similar to the rise in glutamate‐sensitive neurons suggesting that functional active glutamate receptors may be involved in the generation of spontaneous activity.
Subtypes of excitatory amino acid receptors involved in the stimulation of [3H]dopamine release from cell cultures of rat ventral mesencephalon
Authors: Mount Howard , Quirion Rémi , Kohn‐Alexander Judity , Boksa Patricia
Published: January 2005

N‐methyl‐D‐aspartic acid (NMDA), quisqualic acid (QUIS), and kainic acid (KAIN), respective agonists for three excitatory amino acid (EAA) receptor subtyes, stimulated [3H]dopamine ([3H]DA) release from dissociated cell cultures of fetal rat ventral mesencephalon. Release evoked by all three agonist was Ca2+‐dependent and inhibited by broad‐spectrum antagonists (D, L‐cis‐2, 3‐piperidine dicarboxylic acid [PDA] and kynurenic acid [KYN]). However, both of these antagonists were more potent against KAIN than against QUIS and only KAIN‐evoked release was blocked by γ‐D‐glutamylaminomethyl sulfonic acid (GAMS, IC50 700 m̈M). NMDA‐stimulated [3H]DA release was selectively inhibited by competitive (3‐[2‐carboxypiperazine‐4‐yl]propyl‐1‐phosphonic acid [CPP] and D, L‐2‐amino‐5‐phosphonvaleric acid [APV]) and non‐competitive (phencyclidine and MK‐801) NMDA receptor antagonists. In 1.2 mM Mg2+, NMDA‐stimulated [3H]DA release was NA+‐dependent and inhibited by tetrodotoxin (TTX, 2 m̈M) or by the local anaesthetic, lidocaine (200 m̈M). However, in 0 Mg2+, NDMA‐evoked release was not inhibited by TTX or lidocaine. Thus, TTX‐sensitivity of the NMDA response in 1.2 mM Mg2+ apparently occurs because Na+‐action potentials are required to alleviate a Mg2+ blockade. Neither QUIS‐nor KAIN‐evoked release was affected by Mg2+ or TTX. When extracellular NaCI was replaced by sucrose or Na2SO4, the QUIS response was increased. KAIN‐evoked release was unaffected by the sucrose substitution and was attenuated in the Na2SO4‐containing buffer.

It is concluded that NMDA and QUIS/KAIN release [3H]DA via separate receptor subtypes.
Neurotensin binding sites in porcine jejunum: Biochemical Characterization and intramural Localization
Authors: Seybold Virginia S. , Treder Bradley G. , Aaonsen Linda M. , Parsons Ann , Brown David R.
Published: January 2005

Neurotensin is present in high concentrations in the mammalian gut, especially in enteroendocrine cells of the mucose. Exogenous neurotensin has been shown to alter ion transport by the mucosa and contractile activity of intestinal smooth muscle. The purpose of this study was to determine the distribution of neurotensin binding sites withing the intestinal wall. Initially, biochemical characteristics of [125I]neurotensin binding sites were determined within two preparations of the distal porcine jejunum: (1) the mucosa and submucosa, and (2) the circular and longitudinal muscle with their intramural plexuses. Ligand binding data for the preparation including the mucosa and submucosa indicated that [125I]neurotensin bound specifically to two sites having apparent equilibrium dissociation constants of approximately 0.46 and 0.37nM. A binding site with a dissociation constant of approximately 0.38 nM was confirmed for the preparation of muscle and associated intramural plexuses. Xenopsin and neurotensin<sb6–13 were approximately 40 times less potent in the preparation of mucosa and submucosa.

Receptor autoradiography was used to determine the distribution of [125I]neurotensin binding sites within the wall of the jejunum. Autoradiograms of [125I]neurotensin bound to cross sections of the proximal and distal jejunum showed that the highest densities of silver grains were associated with the internal submucosal gangilia, external submucosal plexus and myenteric ganglia. A moderate density of silver grains was associated with the circular muscle.

The localization of neurotensin binding sites to submucosal ganglia is consistent with observations that neurotensin effects on active anion secretion by the mucosa are blocked by tetrodotoxin. Immunohistochemical localization of neurotensin in the porcine jejunum demonstrated a limited population of neurotensin immunoreactive cells within the mucosal epithelium. It is possible that neurotensin released from these cells in the mucosa as well as neurotensin‐related peptides released from enteric neurons may be the endogenous ligands for the binding sites visualized in this study.
Autoradiographic localization of delta opioid receptors within the mesocorticolimbic dopamine system using radioiodinated [2‐d‐penicillamine, 5‐d‐penicillamine]enkephalin (125I‐DPDPE)
Authors: Dilts Roger P. , Kalivas Peter W.
Published: January 2005

The enkephalin analog [2‐D‐Penicillamine, 5‐D‐Penicillamine]enkephalin was radioiodinated 125I‐DPDPE and shown to retain a pharmacological selectivity characteristic the delta opioid receptor in in vitro binding studies. The distributions of 125I‐DPDPE binding, using in vitro autoradiographic techniques, were similar to those previously reported for the delta opioid receptor. The nucleus accumbens, striatum, and medial prefrontal cortex contain dense gradients of 125I‐DPDPE binding within particular regions of the mesocorticolimbic dopamine system. Unilateral lesions of dopamine perikarya (A9 and A10) within the ventral tegmental area nd substantia nigra produced by mesencephalic injection of 6‐hydroxydopamine resulted in significant (20–30%) increase in 125I‐DPDPE binding contralateral to the lesion within the striatum and nucleus accumbens. Lesions of the perikarya (dopaminergic and nondopaminergic) of the ventral tegmental area, induced by aquinolinic and injections, caused increases of less magnitude within these same nuclei. No significant alteratons in 125I‐DPDPE binding were observed within the mesencephalon as a result of either treatment. The specificity of the lesions was confiremed by immunocytochemistry for tyrosine for tyrosine hydroxylase. These results suggest that the enkephalins and opioid agonists through delta opioid receptors do not dircetly modulate dopaminergic afferents but do regulate postsnaptic targets of the mesocorticolimbic dopamine system.
Electrosensory systems in fish
Authors: Heiligenberg Walter
Published: January 2005

A close integration of behavioral, neurophysiological, and neuroanatomical approaches has guided research on the neural basis of electrosensation and the generation of behaviors associated with this modality. By postulating neuronal implementaions of specific computations in sensory information processing, behavioral studies have been curcial in focusing studies at the neuronal level onto behaviorally relevant structural and functional aspects. Physiological and anatomical studies have analyzed (a) neural networks underlying the distributed processing of sensory information, (b) the role of descending recurrent pathways and eference copy mechanisms for the filtering of incoming information, c) the significance of multiple topographic representations for sensory information processing, and d) the modulation of sensory and motor structures through various transmitters and receptor subtypes. Developmental studies have explored the significance of steroid hormones for the tuning of electroreceptors to the frequency of an endogenous neuronal oscillator which drives the electric current pulses necessary for their stimulation. Embryological studies have revealed that the development of mechanoreceptors and electroreceptors in the fish's skin is induced by the innervation of primary afferent nerve fibers which are specific with regard to their central connections as well as with regard to the type of receptor induced in the periphery.
Synaptic remodelling of perforated synapses during development and maturation in a visual projection area in birds
Authors: Nixdorf Barbara E.
Published: January 2005

Perforated synapses are characterized by the appearance of one or more discontinuities in the postsynaptic density (PSD). These synapses are thought to represent intermediate stages in synaptic remodelling and turnover. To determine the dynamic level of these processes, the development of perforated synapses at different ages was examined in the neuropil of the ectostriatum, a visual projection area in birds. The overall number of perforated synapses per unit volume increases during development. Single and multeple perforated synapses, however, show a differnt developmental trend. Between 20 and 100 days, when the number of multiple perforated synapses decreases by 46%, single perforated synapses increase by 83% in number per unit volume. No significant changes in single or multiple perforated synapses can be observed at younger ages (i.e., 5 or 10 days). Various parameters increase between 10 and 20 days, followed by a reduction at 100 days: The relative frequency of perforations per synaptic contact, the length of the postsynaptic density including the size of the perforation, the length of the synaptic contact zone in perforated synapses excluding the size of the perforation, and the size of the perforation follow the same trend.
Paradoxical anticonvulsant acitivity of the γhyphen;Aminobutyrate antagonist bicuculline methiodide in the rat striatum
Authors: Turski Lechoslaw , Diedrichs Stefan , Klockgether Thomas , Schwarz Michael , Turski Waldemar A. , Sontag Karl‐Heinz , Brotolotto Zuner A. , Chlderazzo‐Filho Lineu S. , Cavalheiro Esper A.
Published: January 2005

Bicuculline methiodide (BMI), a γ‐aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles amygdala, hippocampus thalamus, neocortex and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mg/kg, i.p.), with an ED50 of 94 fmol (range 45–195 fmol). No topogrphical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA‐mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA‐mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocorpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.
Chemically distinct rat olivocochlear neurons
Authors: Vetter Douglas E. , Adams Joe C. , Mugnaini Enrico
Published: January 2005

We have produced a neurochemical map of the cell bodies of origin of the cochlear efferent terminals in rat by combining glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT) or calcitonin gene‐related peptide (CGRP)immunocytochemistry with retrograde transport of horseradish peroxidase.

The location of cochlear efferent cell bodies are in general agreement with the medial and lateral systems described by White and Warr (J. Comp. Neurol. 219:203–214, 1983) with some minor modifications. The lateral system consists of at least two pools of chemically distinct neurons located within the lateral superior olive (LSO) ipsilateral to the injected cochlea. One pool immunostains with an antibody to GAD while the other immunostains with antibodies to ChAT and to CGRP. The medial efferent system consists of periolivary neurons that are almost exclusively large and ChAT‐positive but CGRP‐negative. They are located both ipsilateral and contralateral to the cochlea they project to. There are a few GAD‐positive small neurons in the medioventral and rostral periolivary regions that project ipsilaterally, but these may prove to be ectopic neurons. The ipsilateral lateroventral periolivary region (LVPO) contains some efferent neurons, all of which are ChAT‐positive but CGRP‐negative. Additional cochlear efferent neurons, some of which are ChAT‐positive and others GAD‐positive, are present within and immediately dorsal to the fiber capsule surrounding the medial limb, and to a lesser extent the lateral limb, of the ipsilateral LSO. Not all GAD‐positive or ChAT‐positive olivary cells project to the cochlea.

We have complemented the results in the brainstem by demostrating two immunocytochemically distinct populations of efferent terminals in the cochlea simultaneously, one CGRP‐positive and the other GAD‐positive. Approximately, equal numbers of boutons immunoreactive for both markers are present beneath inner hair cells throughout the entire length of the cochlea. Surprisingly high numbers of GAD‐positive and CGRP‐positive boutons are also present on outer hair cells, with each class having its spatially and morphologically ditinct features. The lack of CGRP‐positive periolivary cells that are retrogradely labeled by cochlear injections of HRP suggests that the lateral olivocochlear system sends projections to outer hair cells. Our results raise questions about species differences in the organization of targets of the lateral and medial olivocochlear systems.
Contribution of the amygdala and nucleus accumbens to ventral pallidal responses to dopamine agonists
Authors: Napier T. Celeste
Published: January 2005

Neurons recorded from ventral pallidum/substantia innominata (VP) of the basal forebrain respond to dopaminergic agonists that activate either the D1 or D2 the receptor subtype. Major afferent systems to the VP originate within amygdaloid nuclei (AMN) and the nucleus accumbens (NA). Since both the AMN and the NA are dopaminoceptive, the present study sought to analyze the contribution of these afferent systems to VP responses to dopaminergic agonists. Single VP neurons were electrophysiologically recorded in vivo from chloral hydrate‐anesthetized rats, and the following determinations were made. (1) Effects of pharmacologic inactivation of an afferent system were assessed by monitoring VP neurons during intracerebral microinjections of the local anesthetic procaine, administered directly into either the AMN or the NA. (2) With procaine‐induced VP rate changes used to indicate an afferent influence on the recorded neuron, VP responses to apomorphine (an agonist that acts at D1 and D2 receptor subtypes), SKF38393 (a D1 agonist), or quinpirole (a D2 agonist) were determined and compared with responses in rats not receiving the procaine pretreatment. Following pharmacologic inactivation of either the AMN or the NA, approximately 80% of the VP neurons monitored demonstrated rate changes, illustrating that spontaneous neuronal firing in the VP is dependent on tonically active input systems. Following afferent cessation, responses to apomorphine and quinpirole remained intact, suggesting that the AMN or NA is not necessary for VP responding to the systemic administration of dopaminergic agonists that act at D2 receptors. In contrast, the number of neurons that responded to SKF38393 was diminished follow intra‐AMN (but not intra‐NA) procaine. This suggests that D1‐induced VP responses are mediated, at least in part, via the AMN.
Iontophoretically administered drugs acting at the N‐methyl‐D‐aspartate receptor modulate burst firing in A9 dopamine neurons in the rat
Authors: Overton Paul , Clark David
Published: January 2005

Extracellular single‐unit recording and iontophoresis were used to examine the effect of N‐methyl‐D‐aspartate (NMDA) and the competitive NMDA antagonist (+/−)‐4‐(3‐phosphonopropyl)‐2‐piperazine carboxylic acid (CPP) on the firing rate and firing pattern of A9 dopamine (DA) neurons in the rat. Administration of NMDA produced a dose‐dependent increase in firing rate (up to nearly 300% of baseline at the highest ejection current), which could be blocked by iontophoretic CPP. Low currents (<10 nA) were sufficient to induce apparent depolarisation inactivation in some neurons. In addition to this effect on firing rate, NMDA also caused a dramatic increase in burst firing, which was also dose dependent; cells made more bursts, and each burst consisted of more spikes. The only measured aspect of burst morphology that was not affected was the mean burst interspike interval. All nonbursting cell (n = 10) were converted to burst firing by the drug. CPP administered alone was found to reduce burst firing, without affecting the firing rate. These data suggest that a tonically active excitatory amino acid input to A9 DA neurons is responsible for inducing burst firing in vivo and that this input seems to operate via the NMDA receptor, possibly by virtue of its link to a Ca2+ ionophore.
Clinical and biochemical aspects of depressive disorders: III. Treatment and controversies
Authors: Caldecott‐Hazard Sally , Schneider Lon S.
Published: January 2005

The present document is the final of three parts of a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various treatments for depression, including psychotherapy, pharmacological, and somatic treatments, will be described in this third part. Also, some of the controversies in the field, as well as a summary of the most salient points of the review, will be discussed. Previous sections of this review dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders (Part I) and various transmitter/receptor theories of depressive disorder (Part II).
Direct muscarinic and nicotinic receptor‐mediated excitation of rat medial vestibular nucleus neurons in vitro
Authors: Phelan Kevin D. , Gallagher Joel P.
Published: January 2005

We have utilized intracellular recording techniques to investigate the cholinoceptivity of rat medial vestibular nucleus (MVN) neurons in a submerged brain slice preparation. Exogenous application of the mixed cholinergic agonists, acetylcholine (ACh) or carbachol (CCh), produced predominantly membrane depolarization, induction of action potential firing, and decreased input resistance. Application of the selective muscarinic receptor agonist muscarine (MUSC), or the selective nicotinic receptor agonists nicotine (NIC) or 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP) also produced membrane depolarizations. The MUSC‐induced depolarization was accompanied by decreased conductance, while an increase in conductance appeared to underlie the NIC‐ and DMPP‐induced depolarizations. The muscarinic and nicotinic receptor mediated depolarizations persisted in tetrodotoxin and/or low Ca2+/high Mg2+ containing media, suggesting direct postsynaptic receptor activation. The MUSC‐induced depolarization could be reversibly blocked by the selective muscarinic‐receptor antagonist, atropine, while the DMPP‐induced depolarization could be reversibly suppressed by the selective ganglionic nicotinicreceptor antagonist, mecamylamine. Some neurons exhibited a transient membrane hyperpolarization during the depolarizing response to CCh or MUSC application. This transient inhibition could be reversibly blocked by the γ‐aminobutyric acid (GABA) antagonist, bicuculline, suggesting that the underlying hyperpolarization results indirectly from the endogenous release of GABA acting at GABA receptors. This study confirms the cholinoceptivity of MVN neurons and establishes that individual MVN cells possess muscarinic as well as nicotinic receptors. The data provide support for a prominent role of cholinergic mechanisms in the direct and indirect regulation of the excitability of MVN neurons.
Prenatal cocaine produces deficits in serotonin mediated neuroendocrine responses in adult rat progeny: Evidence for long‐term functional alterations in brain serotonin pathways
Authors: Cabrera Theresa M. , Yracheta Joseph M. , Li Qian , Levy Andrew D. , Van De Kar Louis D. , Battaglia George
Published: January 2005

Cocaine produces biochemical alterations in brain serotonin (5‐HT) neurons. Since 5‐HT is critical to the development of fetal 5‐HT neurons and target tissues, we hypothesized that in utero exposure to cocaine could result in long‐term alterations in postnatal 5‐HT systems. Pregnant Sprague‐Dawley rats were administered either saline or (−)cocaine (15 mg/kg, s.c., b.i.d.) from gestational day 13 to 20. Prenatal cocaine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny by measuring changes in 5‐HT mediated plasma hormones following a single 8 mg/kg injection of the 5‐HT releaser p‐chloroamphetamine (PCA). Cocaine exposed male progeny exhibited significant reductions in adrenocorticotropic hormone (ACTH, −43%) and renin (−62%) responses to PCA. However, no alterations were observed in the corticosterone or prolactin response to PCA. In utero exposure to cocaine did not alter basal levels of ACTH, renin, corticosterone, or prolactin. There were no significant differences in the density of either hypothalamic or cortical 5‐HT uptake sites. Likewise, there were no significant differences in the densities of any of the 5‐HT1 receptor subtypes or in the density of 5‐HT2 receptors in cortex. These data, which provide the first demonstration of deficits in 5‐HT mediated neuroendocrine function in adult progeny following in utero exposure to cocaine, indicate long‐term functional alterations of brain 5‐HT systems. © 1993 Wiley‐Liss, INe.
Further characterization of the effects of BMY 14802 on dopamine neuronal activity
Authors: Zhang Jing , Chiodo Louis A. , Freeman Arthur S.
Published: January 2005

Further evaluation of the effects of BMY 14802 on dopamine (DA) neuronal activity in the rat substantia nigra pars compacta (A9) was conducted with single‐unit recording and microiontophoresis in anesthetized rats. Microiontophoretic administration of BMY 14802 (sigma, serotonin (5‐HT)‐1A and α‐1 adrenoceptor ligand) had no effect on DA neurons. Microiontophoretic administration of (+)‐3‐PPP (weak D2 agonist with high affinity for sigma receptors) and quinpirole (D2/D3 agonist) inhibited A9 DA neuronal activity. Coiontophoresis or i.v. pretreatment with BMY 14802 had no effect on the current‐response curves for the effects of microiontophoretic (+)‐3‐PPP or quinpirole on A9 DA neurons. Coiontophoretic administration of (−)‐sulpiride, a selective D2 antagonist, blocked the inhibitory effects of microiontophoretic (+)‐3‐PPP. The effects of BMY 14802 (0.25‐8 mg/kg, i.v.) on DA neurons (increased firing rate, increased burst‐firing, reduced regularity of firing pattern) were not altered by acute brain hemitransection, but were blocked by pretreatment with NAN‐190, an antagonist of 5‐HT‐1A and α‐1 receptors. The α‐1 receptor antagonist, prazosin, did not block these effects of BMY 14802.

In conclusion, the effects of BMY 14802 on DA neuronal firing rate and firing pattern are indirect, perhaps due in part to the occupation of 5‐HT‐1A receptors. © 1993 Wiley‐Liss, Inc.
Development of dopamine‐beta‐hydroxylase—positive fiber innervation in co‐cultured hippocampus‐locus coeruleus organotypic slices
Authors: Moudy Anna M. , Kunkel Dennis D. , Malouf Alfred T. , Schwartzkroin Philip A.
Published: January 2005

Development of the noradrenergic innervation of the rat hippocampus by the nucleus locus coeruleus was examined immunohistochemically in the roller tube organotypic cultured slice preparation. Slices of rat hippocampus and locus coeruleus were co‐cultured on glass coverslips for 2–6 weeks and evaluated for the presence of dopamine‐beta‐hydroxylase (DBH) and tyrosine hydroxylase (TH) immunoreactive cells and fibers. Large, multipolar DBH‐ and TH‐positive cells were visible within the locus coeruleus; an occasional cell appeared near or just within co‐cultured hippocampal tissue and in connecting fiber tracts. DBH‐positive cells tended to concentrate near the edges of locus coeruleus tissue. Locus coeruleus slices cultured alone showed little indication of fiber outgrowth in any direction. In co‐cultures, however, beaded DBH‐ and TH‐positive fibers were directed toward the hippocampus. The majority of these fibers entered the hippocampus in the hilar/CA3 region and formed extensive collateral branches. Light microscopy suggests that DBH‐positive fiber growth was densest at or near the pyramidal cell layer in CA3b and CA3c and in the infragranular region of the dentate hilus. This pattern of noradrenergic innervation of hippocampus by co‐cultured locus coeruleus in vitro appears very similar to the pattern established in vivo (see Moudy et al., companion article, this issue). © 1993 Wiley‐Liss, Inc.
GABAergic projection from the ventral pallidum and globus pallidus to the subthalamic nucleus
Authors: Bell Ken , Churchill Lynn , Kalivas Peter W.
Published: January 2005

There exists a topographically organized projection from the globus pallidus and ventral pallidum to the subthalamic nucleus and adjacent lateral hypothalamus. The participation of GABA as a neurotransmitter in this projection was evaluated by retrograde labeling of cells in the pallidal area from an iontophoretic deposit of Fluoro‐Gold in the subthalamus combined with in situ hybridization for mRNA of the GABA synthetic enzyme, glutamate decarboxylase (GAD). A rostrocaudal gradient in the contribution of GABA to the projection was demonstrated with a relatively small percentage of retrogradely labeled cells in the rostra1 ventral pallidum containing GAD mRNA (7%) compared to the caudal globus pallidus which had over 70% of the Fluoro‐Gold containing cells double‐labeled for GAD mRNA. Overall the ventral pallidum contribution to the subthalamic nucleus was less GABAergic than the portion arising from the globus pallidus (35% vs. 61%, respectively). © 1995 Wiley‐Liss, Inc.
Synaptic transmission blockade increases plasminogen activator activity in mouse skeletal muscle poisoned with botulinum toxin type A
Authors: Tian Wen‐Hao , Festoff Barry W. , Blot Stéphane , Diaz Jorge , Hantaï Daniel
Published: January 2005

Experimental denervation, either by nerve crush or axotomy, leads to a dramatic increase in muscle plasminogen activator (PA) activity, suggesting a regulation of muscle PA levels by some neural influence (Festoff et al., 1986, J. Cell Biol., 103:1415–1421; Hantaï et al., 1990, Proc. Natl. Acad. Sci. U.S.A., 87:2926–2930). The Botulinum toxin (BoTx) type A is known to selectively interrupt the release of acetylcholine without structurally altering synaptic morphology. In the present study we have used acute BoTx poisoning of hind limb muscles to further explore the neural regulation of muscle PA activities directly after poisoning and during the process of collateral reinnervation. Electromyographic recording and study of ultraterminal sprouting after zinc iodideosmium and silver‐cholinesterase staining were used to monitor “denervation” and reinnervation. Muscle choline acetyltransferase activity did not decrease, as is observed after experimental denervation, but in contrast increased and, therefore, reflected the functional integrity of intramuscular nerve endings. Within 2 days of BoTx poisoning, muscle urokinase‐PA, and to a lesser extent, tissue‐PA activities, rose in muscle extracts as shown by an amidolytic assay and fibrin zymography. When reinnervation occurred, muscle urokinase‐PA activity decreased but did not return to baseline levels within the 80 days of our study. These results suggest that cholinergic transmission‐regulated events determine activity of muscle PAs and that PAs likely have a role in neuromuscular formation and plasticity. © 1995 Wiley‐Liss, Inc.
Increase in synaptic vesicle proteins in synapsin‐transfected NG108‐15 cells: A subcellular fractionation study
Authors: Fried Gabriel , Han Hui‐Quan
Published: January 2005

We have examined the subcellular distribution of synapsins and synaptophysin in density gradients from synapsin‐ and vector‐transfected NGlO8‐15 cells, since we recently found that transfection of synapsin IIb cDNA into neuroblastoma X glioma hybrid cells (NG108‐15) resulted in cell lines that had a more neuronal phenotype than controls. The increase in synapsins and synaptophysin in the transfected cells was maximal in the region of the gradient containing small synaptic vesicles. The transferrin receptor, a marker for early endosomes, did not increase in the synapsin‐containing fractions in the transfected cells. Secretogranin I, a soluble protein stored in and secreted from large dense cored vesicles, showed a very pronounced increase in the dense regions of gradients from transfected cells. These subcellular fractionation data suggest a possible role for the synapsins in the regulation of synaptic vesicle function. © 1995 Wiley‐Liss, Inc.