bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of the role of anti‐opioid peptides in morphine tolerance and dependence
Authors: Rothman Richard B.
Published: December 2004

Studies on the mechanisms of tolerance and dependence have mostly focused on changes at the receptor level. These experiments, conducted with model systems ranging from clonal cell lines to whole animals, have identified a number of important adaptive mechanisms which occur at the receptor level. However, none of these adaptive mechanisms can completely account for the phenomena which serve to define the state of morphine tolerance and dependence, especially the observation that as an animal becomes more tolerant to morphine, less naloxone is required to trigger withdrawal. The data reviewed in this paper provide strong support for the hypothesis that the brain synthesizes and secretes neuropeptides which act as part of a homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. According to this model, administration of morphine releases anti‐opioid peptides (AOP), which then attenuate the effects of morphine. As more morphine is given, more AOP are released, thereby producing tolerance to the effects of morphine. Cessation of morphine administration, or administration of naloxone, produces a relative excess of anti‐opioid, which is in part responsible for the withdrawal syndrome. Since endogenous and exogenous antagonists might together produce synergistic effects, less naloxone might be required to trigger withdrawal in the presence of higher levels of AOPs. Although the study of AOP is in its infancy, a deeper understanding of the central nervous system (CNS) anti‐opioid systems may lead to new treatments for chronic pain, substance abuse, and psychiatric disorders. © 1992 Wiley‐Liss, Inc.
Serotonergic signalling between thyroid cells: Protein kinase C and 5‐HT2 receptors in the secretion and action of serotonin
Authors: Tamir Hadassah , Hsiung Shu‐Chi , Yu Pei‐Ying Y. , Liu Kuo‐Peing , Adlersberg Mella , Nunez Eladio A. , Gershon Michael D.
Published: December 2004

Parafollicular (PF) cells of the thyroid gland are neural crest derivatives, which costore the neurotransmitter, 5‐hydroxytryptamine (5‐HT) with calcitonin. PF cells are located adjacent to follicular (F) cells within the basement membrane of thyroid follicles. It has been proposed that 5‐HT serves an intercellular signalling function in the thyroid and that F cells are its target. This proposal was tested by using cell lines derived from PF (medullary thyroid carcinoma [MTC]) and F (FRTL‐5) cells to study the mechanisms that mediate the secretion and action of 5‐HT. Secretion of 5‐HT by MTC cells was evoked by thyroid stimulating hormone, thyrotropin (TSH), elevated extracellular calcium (↑[Ca2+]e), or by agents that increase intracellular cAMP (↑[cAMP]i). When protein kinase C (PKC) was down‐regulated by prolonged treatment of MTC cells with phorbol 12‐myristate 13‐acetate (PMA), or PKC was inhibited by staurosporin, the TSH‐or PMA‐evoked secretion of 5‐HT was blocked; however, interference with PKC function did not affect 5‐HT secretion evoked by ↑ [Ca2+]e or ↑ [cAMP]i. In the putative targets, FRTL‐5 cells, 5‐HT increased the turnover of phosphoinositides (PI), cytosolic calcium (↑[Ca2+]i), ↑[cAMP]i, and biphasically modified the effect of TSH on cAMP. All of these 5‐HT effects were inhibited by 5‐HT2 receptor antagonists (spiperone and ketanserin) and by pertussis toxin (PTx), suggesting that the actions of 5‐HT are mediated by 5‐HT2 receptors, which are coupled to a G protein. This suggestion was supported by the following additional observations: FRTL‐5 membranes bound the 5‐HT2 agonist, [125I]2,5‐dimethoxy‐4‐iodophenylisopropylamine ([125I]‐DOI), and anti‐idiotypic anti‐bodies, which recognize 5‐HT2 receptors. [125I]‐DOI binding was inhibited by guanosine‐5′‐O‐(3‐thiotriphosphate) (GTP‐γ‐S) and the antibodies were displaced by spiperone. Data are consistent with the hypothesis that 5‐HT serves as a PF to F cell messenger. © 1992 Wiley‐Liss, Inc.
Metabolic mapping of the synergism between MK‐801 and SKF 38393 in rats with unilateral lesions of the dopaminergic nigrostriatal pathway
Authors: Pontieri Francesco E. , Morelli Micaela , Orzi Francesco , Terenzi Riccardo , Di Chira Gaetano
Published: December 2004

In rats with a unilateral lesion of the dopaminergic nigrostriatal pathway with 6‐hydroxydopamine, blockade of N‐methyl‐D‐aspartate receptors by MK‐801 strongly potentiated the turning behavior induced by D‐1 receptor stimulation. To determine the functional consequences of such positive interaction we measured the local rates of cerebral glucose utilization (ICMRglc) in lesioned rats treated with MK‐801 (0.1mg/kg) and the D‐1 agonist SKF 38393 (1.5 mg/kg), either alone or in combination. Treatment with each drug separately did not induce any substantial change in ICMRglc besides an increase in the metabolic activity of the dorsomedial caudate and entopeduncular nucleus (EP) of the lesioned side of MK‐801 treated rats, as compared to the same side of lesioned rats treated with vehicle. Combined administration of MK‐801 + SKF 38393 increased ICMRglc in the EP (+77%) and in the substantia nigra pars reticulata (SNr) (+30%) of the lesioned side as compared with the intact side, while it decreased ICMRglc in the lateral habenula (−26%). These changes were also significant when compared to the lesioned side of vehicle treated rats. The results suggest that while the caudate putamen might be the primary site of MK‐801 and SKF 38393 positive interaction, the EP and SNr are the striatal efferent areas where this positive interaction is expressed. © 1992 Wiley‐Liss, Inc.
Non 5‐HT1A/5‐HT1C[3H]5‐HT binding sites in the hamster, opossum, and rabbit brain show similar regional distribution but different sensitivity to β‐adrenoceptor antagonists
Authors: Waeber Christian , Palacios José M.
Published: December 2004

We have used receptor autoradiography to investigate the distribution and pharmacological profile of non 5‐HT1A/5‐HT1C[3H]5‐hydroxytryptamine binding sites in the brain of rabbits, hamsters and opossums. These data were compared to those found under similar conditions in the brain of rats and guinea pigs, species which are known to possess 5‐HT1B and 5‐HT1D receptors, respectively. In the presence of 100 nM 8‐OH‐DPAT and mesulergine, the regional distribution of [3H]5‐hydroxytryptamine binding sites was very similar in the brain of all species investigated; densest labelling was observed in the globus pallidus, substantia nigra and superior colliculus. In all species, 5‐carboxamidotryptamine competed for the labelled sites in a biphasic manner and metergoline displayed a subnanomolar affinity. In contrast, the β‐adrenoceptor blocking agents (−)propranolol, (−)pindolol, and (±)SDZ 21009 were potent displacers only in the rat, hamster and opossum brains. These data indicate that non 5‐HT1A/5‐HT1C[3H]5‐HT binding sites display a high affinity for these agents in a particular rodent suborder as well as in opossum, a phylogenetically unrelated species. © 1992 Wiley‐Liss, Inc.
Dopaminergic regulation of cortical acetylcholine release
Authors: Day Jamie , Fibiger Hans C.
Published: December 2004

The extent to which the activity of basal forebrain cholinergic neurons is influenced by dopamine (DA) was investigated using in vivo microdialysis of cortical acetylcholine (ACh). Systemic administration of the DA receptor agonist apomorphine significantly increased dialysate concentrations of ACh. Systemic, but not local, administration of d‐amphetamine produced similar effects. Both D1 (SCH 23390) and D2 (haloperidol, raclopride) DA receptor antagonists attenuated the amphetamine‐induced increase in cortical ACh release; however, only the D1 antagonist significantly reduced basal output of cortical ACh. These findings suggest that the activity of cortically projecting cholinergic neurons in the nucleus basalis is regulated in an excitatory manner by central dopaminergic neurons and that both D1 and D2 receptors are involved. © 1992 Wiley‐Liss, Inc.
Interaction of amfonelic acid with antipsychotic drugs on dopaminergic neurons
Authors: Gudelsky Gary A. , Nwajei E. Ewanzani , Defife Kristen , Nash J. Frank
Published: December 2004

The effects of two inhibitors of dopamine (DA) reuptake, amfonelic acid and GBR 12909, on the clozapine‐and haloperidol‐induced increases in DA synthesis, release, and metabolism were investigated in the rat. In the striatum, as well as in the nucleus accumbens, the haloperidol‐induced increase in tissue concentrations of dihydroxyphenylacetic acid (DOPAC) or the accumulation of dihydroxyphenylalanine (DOPA) was potentiated or unaltered, respectively, in rats treated with amfonelic acid. In contrast, amfonelic acid attenuated the stimulatory effects of clozapine on DOPAC concentrations and DOPA accumulation in both brain regions. GBR 12909 also differentially affected the haloperidol‐ and clozapine‐induced increases in DOPAC concentrations. However, the clozapine‐induced increase in DOPA accumulation in the median eminence was not significantly altered by treatment with amfonelic acid. The haloperidol‐induced increase in the extracellular concentrations of DA and DOPAC in the striatum also was potentiated by amfonelic acid, whereas the increase elicited by clozapine was suppressed. The increase in extracellular DA produced by the administration of morphine or the coadministration of ritanserin, a 5‐HT2 antagonist, and haloperidol also was potentiated by amfonelic acid. The ability of amfonelic acid to distinguish between the actions of clozapine and haloperidol on nigrostriatal and mesocorticolimbic DA neurons does not appear to be related to differences in the effects of the drugs on DA autoreceptors or 5‐HT2 receptors. Moreover, the mechanism, through which clozapine activates tuberoinfundibular DA neurons may differ from that which is involved in the activation of nigrostriatal or mesocorticolimbic DA neurons. © 1992 Wiley‐Liss, Inc.
Evaluation of [3H]paroxetine as an in vivo ligand for serotonin uptake sites: A quantitative autoradiographic study in the rat brain
Authors: Biegon Anat , Mathis Chester
Published: December 2004

Paroxetine, a selective inhibitor of serotonin uptake and an antidepressant, was used in conjunction with quantitative ex vivo autoradiography to study the feasibility of imaging serotonin terminals in the living brain. Tritiated paroxetine was injected in the rat tail vein, and the brain was processed for quantitative autoradiography 3 hours later. Animals received either [3H]paroxetine alone (100 μCi/animal) or a mixture of labeled paroxetine (100 μCi) and an excess of unlabeled drug (0.5 or 2 mg/kg intravenously [i.v.]). Computerized image analysis of the resulting autoradiograms revealed high densities of radioactivity in brain regions known to contain high densities of serotonergic terminals and high specific binding of [3H]paroxetine in vitro, such as the raphe nuclei, interpeduncular nucleus, basolateral amygdala, substantia nigra, and some hypothalamic nuclei. Radioactivity uptake in these brain regions was effectively blocked (50‐72%) by coadministration of excess unlabeled paroxetine. However, cortical and hippocampal binding of paroxetine in vivo was moderately high, in contrast to the relatively sparse serotonergic innervation in these regions. Only a relatively small proportion of cortical and hippocampal binding (20‐40%) could be blocked by excess unlabeled paroxetine, indicating that most of the radioactivity in these regions is not associated with serotonin terminals or uptake sites. The usefulness of [3H]paroxetine as an in vivo ligand for imaging serotonin terminals in the human brain is limited by these nonserotonergic binding sites. © 1993 Wiley‐Liss, Inc.
Day/night differences in D1 but not D2 DA receptor protection from EEDQ denaturation in rats treated with continuous cocaine
Authors: Burger Lynn Y. , Martin‐Iverson Mathew T.
Published: December 2004

The effect of chronic cocaine administration on the in vivo occupation of dopamine (DA) receptor subtypes was examined using the irreversible receptor blocker N‐ethoxycarbonyl‐2‐ethoxy‐1, 2‐dihydroquinoline (EEDQ). Rats were given continuous infusions of cocaine (vehicle, 2.5, 7.5, or 22.5 mg/day) via subcutaneous implants of Alzet osmotic minipumps for 14 days. Some groups were also given the D1 antagonist SCH 23390 and/or the D2 antagonist raclopride for this same time period. DA receptor binding techniques were used 24 hours post‐EEDQ injection (Day 15, 5 mg/kg, intraperitoneally [ip]) in order to examine changes in D1 and D2 receptor densities in the striatum. Half of the rats were killed in the day with the other half killed at night in order to examine day/night differences in the effects of cocaine treatment. Results showed that chronic cocaine increased the protection of D1 receptors from EEDQ inactivation in a dosedependent fashion during the day, and decreased D1 protection from EEDQ at night. Since EEDQ has a low affinity for the DA receptor relative to endogenous DA or the exogenous ligands in this study, only receptors that are vacant are inactivated thereby allowing for an estimate of DA receptor occupation in vivo. Cocaine can therefore be said to increase D1 receptor occupation by DA in vivo during the day and decrease it at night. Coadministration of the DA antagonists eliminated this cocaine‐induced day/night difference and, in the case of the D1 antagonist, produced opposite D1 receptor effects when administered alone. Chronic SCH 23390 treatment protected D1 receptors from EEDQ denaturation while D2 receptors were protected by chronic raclopride. In addition, raclopride was found to affect the affinity of both the D1 and the D2 receptors to the [3H]SCH 23390 and [3H] spiperone ligands, respectively. Since no day/night differences were found in D2 receptor density with respect to chronic cocaine treatment these findings have implications for a phasic D1/tonic D2 receptor hypothesis such that cocaine treatment selectively alters the level of DA at sites containing D1 receptors with differential effects depending on the day/night cycle. © 1993 Wiley‐Liss, Inc.
Decamethonium is a partial agonist at the nicotinic acetylcholine receptor
Authors: Liu Yi , Dilger James P.
Published: December 2004

The efficacy of decamethonium as an agonist at the nicotinic acetylcholine receptor has never been determined. Here, we demonstrate how patch clamp recording during rapid perfusion of agonists to outside‐out patches from BC3H‐1 cells can be used to provide an unambiguous estimate of the efficacy of decamethonium. First, we obtain the decamethonium concentration‐response relationship between 10 and 1,000 μM decamethonium. The maximum channel open probability is small (<0.02) and occurs at about 100 μM. This suggests two alternative explanations: decamethonium is a poor agonist or decamethonium is an efficacious agonist but a potent channel blocker. To distinguish between these alternatives, we perfuse mixtures of decamethonium and acetylcholine to generate acetylcholine concentration‐response curves in the presence of 30, 100, and 1,000 μM decamethonium. We use a model for activation and block of the acetylcholine receptor by both agonists to fit these data and determine the binding affinity, efficacy, and blocking affinity of decamethonium. We conclude that the efficacy of decamethonium is low 0.016. Decamethonium is a true partial agonist. © 1993 Wiley‐Liss, Inc.
Ventral tegmental self‐stimulation selectively induces opioid peptide release in rat CNS
Authors: Stein Elliot A.
Published: December 2004

Intracranial self‐stimulation (ICS) is thought to activate neuronal systems involved in processing natural reinforcing agents. Metabolic mapping studies have previously demonstrated a subset of CNS structures specifically engaged by ICS in animals receiving stimulation actively vs. passively. Since opiates are known to enhance JCS behavior and presumably its reinforcing properties, the current study addressed the question of the role of opioid peptides as mediators of ICS. Rats were trained on a fixed ration (FR) 20 schedule of responding maintained by ICS. Following response stabilization, rats were assigned either to an active or a corresponding yoked stimulation group at 1 of 2 schedules of reinforcement (i. e., FR1‐YFR1, FR20‐YFR20, or sedentary control), and opioid peptide release was inferred from in vivo receptor occupancy. Autoradiographic analyses identified 3 groups of structures. Treatment‐induced alterations in occupancy were seen in the medial dorsal nucleus of the thalamus, basolateral amygdala, ventral pallidum, medial habenula, dorsal raphe, posterior hypothalamus, substantia nigra pars compacta, agranular preinsular cortex, and zona incerta. Depending upon the structure, peptide release was dependent upon stimulus contingency (active vs. yoked) and/or schedule (FR1 vs. FR20). Evidence for ICS‐induced inhibition of peptide release was found in the habenula and preinsular cortex. Nine additional structures, all components of, or receiving projections from, the limbic system, revealed complex interactions between ICS treatment and the electrode side. Finally, a widespread ipsilateral increase in receptor binding was seen rostrally from the cingulate, olfactory tubercle, and nucleus accumbens, along the lateral hypothalamus and hippocampus, and extending caudally to the substantia nigra and ventral tegmentum. These later effects appear to be related to stimulation‐induced changes in blood flow and subsequent ligant presentation increases. Collectively, these data point towards the ability of rewarding brain stimulation to activate discrete neuronal opioid systems contingent upon specific behavioral as well as stimulus conditions. © 1993 Wiley‐Liss, Inc.
Light and electron microscopic localization of calcitonin gene‐related peptide immunoreactivity in lamina II of the feline trigeminal pars caudalis/medullary dorsal horn: A qualitative study
Authors: Henry Michael A. , Nousek‐Goebl Nancy A. , Westrum Lesnick E.
Published: December 2004

Calcitonin gene‐related peptide (CGRP) is a neuropeptide that is associated with a subset of primary afferent fibers and appears to have a role in nociception. The purpose of the present study was to perform a qualitative light, and especially electron microscopic (LM and EM), examination of CGRP‐immunoreactivity (IR) within lamina II (substantia gelatinosa) of the feline pars caudalis/medullary dorsal horn (PC/MDH) of the spinal trigeminal nucleus. The LM investigation revealed massive CGRP‐IR within lamina II outer, with fewer fibers that traversed lamina II inner. The EM preparations showed CGRP‐IR in small, thinly myelinated and unmyelinated axons, preterminal axons, and in axon terminals that formed asymmetric synaptic contacts onto small dendritic profiles. The terminals with CGRP‐IR were often the central element within glomeruli, where the terminal usually formed 2 or more asymmetric synaptic specializations onto 1 or more dendrites. Many of these postsynaptic dendrites contained synaptic vesicles. Other profiles were seen forming presynaptic contacts onto the terminal with CGRP‐IR, and these profiles most likely represent presynaptic dendrites and/or other axon terminals of intrinsic origin. The synaptic association of terminals showing CGRP‐IR with vesicle‐containing dendrites, presynaptic dendrites, and/or other axon terminals suggests that terminals with CGRP‐IR are especially susceptible to modulation. © 1993 Wiley‐Liss, Inc.
MK‐801, phencyclidine (PCP), and PCP‐like drugs increase burst firing in rat A10 dopamine neurons: Comparison to competitive NMDA antagonists
Authors: French Edward D. , Mura Anna , Wang Ting
Published: December 2004

Extracellular single‐unit recordings were used to assess the effects of PCP and PCP‐like drugs (MK‐801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (±)CPP, and to BTCP, a PCP‐derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK‐801, and TCP produced dose‐dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 19755 and (±) CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP‐like drugs, and the resultant hyperdopaminergia within the mesolimbic‐mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists. © 1993 Wiley‐Liss, Inc.
Comparison of the effects of the cholecystokinin‐B receptor antagonist, PD 134308, and the cholecystokinin‐A receptor antagonist, L‐364,718, on dopamine neuronal activity in the substantia nigra and ventral tegmental area
Authors: Meltzer Leonard T. , Christoffersen Curt L. , Serpa Kevin A. , Razmpour Ahmad
Published: December 2004

Extracellular single‐unit recording techniques were used to study the effects of the cholecystokinin‐A (CCK‐A) antagonist, L‐364, 718, and the CCK‐B antagonist, PD 134308, on DA neuronal activity in chloral hydrate anesthetized rats. Neither L‐364, 718 (0.1‐1.6 mg/kg i.v.) nor PD 134308 (0.1‐6.4 mg/kg) altered the basal firing rate of substantia nigra or ventral tegmental area DA neurons. The ability of PD 134308 and L‐364, 718 to alter the apomorphine‐induced inhibition of substantia nigra DA neurons was assessed. Pretreatment with L‐364, 718 (0.6 or 4.16 mg/kg i.v.) did not shift the apomorphine dose‐response curve (0.5‐32 μg/kg i.v.). In contrast, PD 134308 (0.6 or 6.4 mg/kg i.v.) produced dose‐related, significant shifts to the right of the apomorphine dose‐response curve. However, these effects were small in comparison to the haloperidol (0.1 mg/kg i.p.)‐induced shift of the apomorphine curve. These data suggest that in the substantia nigra there may be a tonic level of CCK release that, through actions on CCK‐B receptors, may modulate DA agonist‐induced inhibition of DA neuronal activity. © 1993 Wiley‐Liss, Inc.
Cytoplasmic structure in organotypic cultures of rat hippocampus prepared by rapid freezing and freeze‐substitution fixation
Authors: Miller Lucas D. Pozzo , Landis Dennis M. D.
Published: December 2004

We have compared rapid freezing followed by freeze‐substitution fixation with conventional aldehyde fixation as preparative methods for the electron microscopic study of organotypic cultures of neonatal rat hippocampus. Rapid freezing by contact with a copper block chilled by liquid helium was accomplished without mechanical distortion of superficial structures, and preserved structure to a depth of at least 20 μM without visible ice crystals. Freeze‐substitution fixation in acetone/osmium tetroxide, followed by en bloc staining with tannic acid and uranyl acetate, provided satisfactory staining of cytoplasm and organelles. While both preparative techniques yielded generally satisfactory results, rapid freezing provided much better preservation of astrocytic lysosomal inclusions, and afforded new views of intermediate filament substructure. Rapid freezing and freeze‐substitution fixation seemed especially well suited to the preservation of short filamentous proteins, such as those forming the membrane cytoskeleton of dendritic spines or those associated with synaptic vesicles. The combination of rapid freezing methods and organotypic culture provides an opportunity to examine cytoplasmic structure in tissue from deep regions of the brain which had previously been inaccessible to rapid freezing techniques. © 1993 Wiley‐Liss, Inc.
Quantitative autoradiographic mapping of delta‐opioid receptors in the rat central nervous system using [125I][D.Ala2]deltorphin‐I
Authors: Gouarderes Christine , Tellez Stephane , Tafani Jean André M. , Zajac Jean‐Marie
Published: December 2004

The distribution of β‐opioid binding sites was studied by quantitative autoradiography in rat brain and spinal cord using the highly selective ligand [125I][D. Ala2]deltorphin‐I. The binding properties of [125I][D. Ala2]deltorphin‐I were investigated by microdensitometry of autoradiographic films with the aid of a computerassisted image‐analysis system. [125I][D. Ala2]deltorphin‐I appeared to interact with a single class of sites in all brain areas (KD = 0.9 nM). In 23 regions tested, whatever the δ site concentration, DTLET, a δ agonist, appears to be 2 orders of magnitude more effective than DAGO, a μ agonist, in inhibiting specific [125I][D. Ala2]deltorphin‐I binding. The distribution of [125I][D. Ala2]deltorphin‐I sites is globally consistent with that of other δ ligands and does not support the existence of a δ‐receptor subtype recognized by [D. Ala2]deltorphin‐I. [125I][D. Ala2]deltorphin‐I binding sites were highly confined, exhibiting selective localization in the neocortex and a diffuse pattern in the striatum, accumbens nucleus, claustrum, layer of bulb, amygdaloid nucleus, pontine nuclei, and inferior colliculus. In several areas a rostro‐caudal gradient of site concentration was indicated. [D. Ala2]deltorphin‐I binding sites were also present in the substantia gelatinosa at all levels of the spinal cord and, unexpectedly, in deeper laminae and the ventral horn. These results demonstrate the ability of [125I][D. Ala2]deltorphin‐I to characterize low concentrations of binding sites and to reveal new localizations of δ receptors. © 1993 Wiley‐Liss, Inc.
Local cerebral glucose utilization after D1 receptor stimulation in 6‐OHDA lesioned rats: Effect of sensitization (priming) with a dopaminergic agonist
Authors: Morelli Micaela , Pontieri Francesco E. , Linfante Italo , Orzi Francesco , Di Chiara Gaetano
Published: December 2004

In rats bearing unilateral 6‐hydroxydopamine (6‐OHDA) lesions of the dopaminergic nigro‐striatal neurons, a single administration of a D‐2 agonist (LY 17155) potentiates the contralateral turning induced by a D‐1 agonist (SKF 38393). To identify the neural substrate of this form of sensitization (priming), we studied the local cerebral glucose utilization (lCMRglc) in 6‐OHDA lesioned animals treated, 3 days apart, as follows: (1) saline‐saline, (2) LY 171555‐saline, (3) saline‐SKF 38393 and (4) LY 171555‐SKF 38393. The unilateral 6‐OHDA lesion per se (Sal‐Sal) produced increases in lCMRglc in the globus pallidus (GP) and in the lateral habenula (LH) of the lesioned hemisphere. lCMRglc in LY‐Sal group were similar to those measured in the Sal‐Sal group. Administration of SKF 38393 to drug‐naïve rats (Sal‐SKF) abolished the lesion‐induced metabolic asymmetry in the LH but did not have any effect on the GP; furthermore, it increased lCMRglc in the substantia nigra pars reticulata (SNr) of the lesioned side. After priming with LY 171555, administration of SKF 38393 (LY‐SKF) produced marked metabolic asymmetries by increasing lCMRglc in the SNr and entopeduncular nucleus (EP), and decreasing it in the LH of the lesioned side. These changes were also significant when compared to the corresponding values of the other experimental groups. Again, in LY‐SKF group no modification of the lesion‐induced metabolic asymmetry in the GP was found. These results indicate that priming exerts a facilitatory influence on the ability of D‐1 receptors to stimulate the striato‐nigral and striato‐entopeduncular pathway, suggesting that changes in the effectiveness of dopamine in activating its postsynaptic target elements might contribute to the mechanism of sensitization to drugs stimulating dopaminergic transmission. © 1993 Wiley‐Liss, Inc.
Electrophysiological characterization of rat striatal neurons in vitro following a unilateral lesion of dopamine cells
Authors: Twery M. J. , Thompson L. A. , Walters J. R.
Published: December 2004

The effects of a unilateral 6 to 19‐week lesion of dopamine cells on the excitability of rat striatal neurons were investigated in vitro using the intracellularly recorded membrane properties of neurons obtained ipsilateral and contralateral to 6‐hydroxydopamine (6‐OHDA) injection sites. Neurons ipsilateral to the lesion site and in striatal tissue depleted of dopamine exhibited resting membrane potentials and membrane resistances similar to those recorded in contralateral striatal neurons. Denervation appeared to have no appreciable effect on the proportion of neurons exhibiting various patterns of neuronal spiking (repetitive, bursting, or single spike) evoked by depolarizing current pulses. Current‐voltage determinations revealed nominal rectification in the majority of neurons and marked nonlinearty consistent with inward rectification at potentials hyperpolarized and depolarized to rest in a large proportion of the remaining neurons. Neurons ipsilateral to 6‐OHDA lesion sites exhibited these relationships in the same proportion as contralateral control cells. However, ipsilateral neurons with nominal rectification exhibited an average rate constant for the early onset of small hyperpolarizing membrane transients which was significantly smaller than that of controls. This finding suggests that intrinsic membrane parameters regulating the excitability of certain striatal neurons may be under the influence of dopamine or other factors closely associated with nigrostriatal nerve terminals. Published 1993 Wiley‐Liss, Inc.
Expression of c‐fos protein in the experimental epilepsy induced by pilocarpine
Authors: Barone Paolo , Morelli Micaela , Cicarelli Giulio , Cozzolino Alberto , DeJoanna Gabriella , Campanella Giuseppe , DiChiara Gaetano
Published: December 2004

The expression of the c‐fos proto‐oncogene, as estimated by immunohistochemistry of the FOS nuclear protein, was studied in both focal and generalized seizures induced in rats by systemic administration of pilocarpine. Focal seizures, as indicated by the occurrence of stereotyped oral movements, chewing and sniffing, were evoked by either a subconvulsant dose of pilocarpine (200 mg/kg) or the association of a convulsant dose of pilocarpine (400 mg/kg) with SCH 23390, a selective D‐1 dopamine receptor antagonist. This seizure pattern resulted in FOS accumulation in certain limbic areas, namely, the piriform cortex, amygdala, and olfactory tubercle. On the other hand, in rats developing generalized seizures, accumulation of FOS was also found in hippocampus, cingulate cortex, frontal cortex, striatum, accumbens, as well as in certain thalamic nuclei. Generalized seizures, including motor limbic seizures and status epilepticus, were induced by either a convulsant dose of pilocarpine (400 mg/kg) or a low dose of pilocarpine (15–200 mg/kg) combined with either lithium or the D‐1 selective agonist SKF 38393. These findings indicate a close correlation between the sequence of behavioural alterations induced by pilocarpine and the proto‐oncogene activation. The results provide the basis for mapping the areas of origin and the pathways of generalization of seizure activity. As shown by the effects of dopamine receptor agonists and antagonists, the process of generalization appears to be controlled by the dopamine system. © Wiley‐Liss, Inc.
Robustness of G protein changes in cocaine sensitization shown with immunoblotting
Authors: Striplin Caryn D. , Kalivas Peter W.
Published: December 2004

Daily cocaine administration has been shown to alter G proteins in mesolimbic nuclei, and these changes have been implicated in the initiation and expression of behavioral sensitization. To evaluate the robustness of changes in G proteins induced by daily cocaine treatments capable of producing behavioral sensitization, the levels of Gi1α, Gi2α, Goα, Gsα, and Gβ protein were measured by immunoblotting at 1 hr after an acute injection of cocaine or saline given 1 or 14 days following the last injection of daily cocaine or saline. A significant decline in Gi1α was seen in the nucleus accumbens at 14 days following daily cocaine administration regardless of whether they received an acute challenge with cocaine or saline 1 hr prior to decapitation. No alterations were observed in the ventral tegmental area, substantia nigra, dorsolateral striatum, or prefrontal cortex in the levels of Gi1α, Gi2α, or Goα. No change in G protein immunoreactivity was measured in the nucleus accumbens or ventral tegmental area of rats decapitated 1 hr after discontinuing daily cocaine. The possibility that a long‐term change in Gi1α in the nucleus accumbens may be related to cocaine‐induced behavioral sensitization is discussed. © Wiley‐Liss, Inc.
Endogenous GABA release from rat striatal slices: Effects of the GABAB receptor antagonist 2‐hydroxy‐saclofen
Authors: Mayfield R. Dayne , Zahniser Nancy R.
Published: December 2004

The reproducibility of endogenous GABA release evoked by multiple periods of electrical field stimulation was examined in rat striatal slices. In these experiments, NO‐328 was used to block GABA uptake, and evoked GABA release (overflow) was completely Ca2+ dependent. A seemingly invariant observation in these experiments was that spontaneous GABA release (outflow) progressively decreased as a function of superfusion time and that GABA overflow decreased 25–30% in response to the second of two periods of stimulation (S2/S1 ratios = 0.70 to 0.75). The attenuation of GABA release was not explained by the amount of GABA lost to the superfusion buffer (fractional release), direct depletion of releasable pools of GABA, or slice viability. Furthermore, the decreases in GABA release were not dependent on stimulation frequency (5–15 Hz) or the absolute amount of GABA evoked by electrical stimulation. However, the GABAB receptor antagonist 2‐hydroxy‐saclofen (2‐OH‐saclofen; 316 μM) not only enhanced GABA overflow, when superfused throughout both periods of stimulation, but also resulted in S2/S1 ratios of unity. When 2‐OH‐saclofen was superfused throughout the second stimulation period only, GABA overflow was almost two‐fold greater than that evoked by the initial period of stimulation (2‐OH‐saclofen‐free). In addition, these S2 responses were ∼30% greater than S1 responses that were observed when 2‐OH‐saclofen was present throughout the entire superfusion period. These results indicate that activation of GABAB receptors was involved in the progressive attenuation of GABA release and further emphasize that GABAB receptors play an important role in modulating endogenous GABA release from striatal slices. © Wiley‐Liss, Inc.
Autoradiographic distribution of [3H]neurotensin receptors in the brains of superoxide dismutase transgenic mice
Authors: Cadet Jean Lud , Kujirai Kayoko , Carlson Elaine , Epstein Charles J.
Published: December 2004

Superoxide dismutase (SOD) plays an important role in the protection of cells against the deleterious effects of free radicals by dismutating the toxic superoxide anion radical. Although oxygen‐based radicals have been implicated in the process of aging and in neurodegenerative disorders such as Parkinson's disease, the contribution of these free radicals to the pathology of these entities has yet to be clarified. It is also not certain that increased levels of free radical scavenging enzymes would attenuate the molecular and cellular processes that lead to these pathological states. In order to asses the contribution of increased SOD gene dosage to the pathogenesis of Down's syndrome, transgenic mice have been constructed that overexpress the human CuZnSOD. We are also using this model to evaluate the role of free radicals in age‐associated changes in brain neurotransmitters and their receptors. In the present study, transgenic mice and their nontransgenic littermates, aged 6 weeks and 21 months, were used in an autoradiographic receptor study of the distribution of brain neurotensin receptors. At 6 weeks of age, there were no significant differences between the two groups of mice in most brain regions. In addition, [3H]NT binding sites showed parallel age‐related decreases in the majority of the areas examined in both groups. However, significant age‐related decreases in the septum, the diagonal band of Broca, and in some subdivisions of the caudate‐putamen were observed only in SOD‐Tg mice. In contrast, significant age‐related decreases in the core area of the nucleus accumbens and the dorsal aspect of the dentate gyrus of the hippocampus were seen only in non‐Tg mice. Interestingly, there were increases in NT binding sites in the CA2 area of the hippocampus in both groups of mice. These results suggest that oxygen‐based radicals might play a role in the biochemical changes that occur in NT receptors during the process of aging since these receptors were differentially affected in some regions of the brains of SOD‐Tg mice and of their littermates, which contrast in their ability to scavenge the superoxide radical. Published 1993 Wiley‐Liss, Inc.
Discrete expression of Ca2+/calmodulin‐sensitive and Ca2+ ‐insensitive adenylyl cyclases in the rat brain
Authors: Mons Nicole , Yoshimura Masami , Cooper Dermot M. F.
Published: December 2004

Physiological studies and inferences from invertebrate models implicate Ca2+/calmodulin‐sensitive adenylyl cyclase with memory processes. However, Ca2+/calmodulin‐insensitive adenylyl cyclase also occurs in brain, and its neuronal functions are less clear. Two oligonucleotide probes, based on rat cDNAs for Types I and II adenylyl cyclase, which appear to correspond to these functional forms, were used to conduct in situ hybridization analysis of the relative abundance and localization of these two species in the rat brain as a first step in evaluating their neuronal role. Quite discrete patterns of expression were encountered; in some areas, both species were co‐expressed, but in others, little overlap was observed. The differential expression of the two mRNAs suggests that discrete roles may be fulfilled by the two adenylyl cyclases in neural tissues. © Wiley‐Liss, Inc.
Drug‐ and behavior‐associated changes in dopamine‐related electrochemical signals during intravenous heroin self‐administration in rats
Authors: Kiyatkin Eugene A. , Wise Roy A. , Gratton Alain
Published: December 2004

High‐speed chronoamperometry was used to monitor dopamine‐related electrochemical signals in the nucleus accumbens of rats allowed to self‐administer heroin intravenously and rats that received similar injections passively. Rats self‐administered 100 μg/kg of heroin at ∼20‐min intervals. Dopamine‐related electrochemical signals increased monotonically after the first injection of each day; the effect was weaker on the first than on the second and subsequent days. The second and subsequent injections in each session caused biphasic effects: the initial effect was a decrease in signal‐a minor one when compared to the increase caused by the first injection‐and this was followed by an increase that brought the signal back to or somewhat higher than the level at the time of the injection. Over the course of each 4‐h session, the electrochemical signal reached and fluctuated around an elevated plateau; doubling the injection dose did not elevate this plateau but did cause larger phasic decreases and subsequent increases. Qualitatively similar electrochemical changes were seen in the animals passively receiving the drug, but there were two notable quantitative differences. First, in the passive animals the initial depressions in signal were of shorter duration. Second, in the passive animals (which were injected at intervals determined by the self‐administering animals) the electrochemical signal reached a maximum and began to fall prior to the time of the next injection; in the animals that self‐administered the drug, the signal was still rising at the time of the next injection. The changes in electrochemical signal are unlikely to represent fluctuations of ascorbate or dopamine metabolites; thus it appears that whereas self‐administered heroin injections cause a slow and long‐lasting elevation of extracellular dopamine concentration, short‐term increases in dopamine concentration are associated with the behavioral activation that precedes the injections and it is short‐term decreases that appear to be associated with the period usually thought to be most significant for positive reinforcement. © 1993 Wiley‐Liss, Inc.
Kinetic and pharmacological examination of stimulation‐induced increases in synaptic efficacy in the chick ciliary ganglion
Authors: Poage Robert E. , Zengel Janet E.
Published: December 2004

We have characterized the kinetic and pharmacological properties of stimulation‐induced increases of synaptic efficacy in the embryonic chick ciliary ganglion. We found what appear to be four components of increased ganglionic efficacy with average time constants of decay of about 60 msec, 400 msec, 30 sec, and 200 sec. These time constants are similar to the those describing the decay of the four components of stimulation‐induced increases in neurotransmitter release characterized at other synapses. These components have been termed first and second components of facilitation, augmentation, and potentiation. We found that the addition of small amounts of Ba2+ to the low Ca2+ bathing solution led to an increase in the magnitude of the augmentation‐like component, whereas Sr2+ enhanced the magnitude and time course of the component resembling the second component of facilitation. These effects of Ba2+ and Sr2+ are similar to the effects of these same divalent cations on augmentation and the second component of facilitation, respectively, at the frog neuromuscular junction and rabbit superior cervical ganglion. Based on these similar kinetic and pharmacological properties, we conclude that the four components of stimulation‐induced increases in release that have been described in other synaptic preparations also appear to be present in the chick ciliary ganglion. Published 1993 Wiley‐Liss, Inc.
Septal efferent axon terminals identified by anterograde degeneration show multiple sites for modulation of neuropeptide Y‐containing neurons in the rat dentate gyrus
Authors: Milner Teresa A. , Veznedaroglu Erol
Published: December 2004

The ultrastructure and cellular associations of septal efferent terminals identified by anterograde degeneration with neurons containing neuropeptide Y (NPY) in the rat dentate gyrus were examined quantitatively. For this, the septal complex (i. e., medial septal and diagonal band nuclei) of adult male rats was injected with the neurotoxin ibotenic acid (1%; 150 nl) and following a 2–4‐day survival period, the hippocampal formation was processed for the electron microscopic immunocytochemical demonstration of NPY using the avidin‐biotin complex method.

Terminals with the morphological characteristics of anterograde degeneration, in particular an increase in osmiophilia, and neurons containing NPY‐like immunoreactivity (NPY‐LI) were most abundant in the hilus of the dentate gyrus. In this region, degenerating terminals (n = 109) were usually small (0.2–0.4 μm in diameter) and formed both asymmetric and symmetric synapses with small (distal) dendrites. The degenerating terminals contacted either single NPY‐containing (19%) perikarya or dendrites or unlabeled (48%) perikarya or dendrites. Some degenerating terminals contacted the same perikarya or dendrites as an NPY‐containing terminal (11%); these neurons were either immunoreactive for NPY or unlabeled. The remaining degenerating terminals were either directly apposed without glial intervention to unlabeled and NPY‐labeled terminals (11%) or lacked associations with any neuronal processes in the plane of section analyzed (11%). The findings demonstrate that ibotenic acid injections in the septal complex can identify septal efferent terminals by degeneration and provide cellular substrates for the direct synaptic regulation as well as presynaptic modulation of hippocampal NPY‐containing neurons by septal efferent terminals. © 1993 Wiley‐Liss, Inc.
Quantitative autoradiography of Gpp(NH)p sensitive and insensitive [3H]quinpirole binding sites in the rat brain
Authors: Gehlert Donald R.
Published: December 2004

Recent advances in the cloning of dopamine receptor subtypes have resulted in the detection of at least 5 genetically distinct subtypes of the dopamine receptor. The dopaminergic agonist, quinpirole, has relatively high affinity for the cloned D‐2, D‐3, and D‐4 receptor subtypes. The D‐3 receptor is unique within these 3 subtypes in that it does not appear to have sensitivity to guanine nucleotides. In order to localize the brain regions containing these subtypes of the dopamine receptor, the distribution of [3H]quinpirole binding sites in the rat brain was mapped by autoradiography. Labelling in the absence and presence of the nonhydrolyzable GTP analog, guanylyl‐5′‐imidodiphosphate (Gpp(NH)p) allowed differentiation between the high affinity agonist conformation of the D‐2 receptor and the D‐3 receptor. The highest densities of [3H]quinpirole binding were found in the caudate‐putamen, nucleus accumbens, islands of Calleja, and olfactory tubercle which is consistent with the distribution of dopamine receptors seen with “classical D‐2” receptor agonist and antagonist radioligands. In the presence of 10 μM Gpp(NH)p, binding was reduced in all these areas with the exception of the islands of Calleja. Additional areas which exhibited no change in binding when incubated with Gpp(NH)p included the nodulus and floculus of the cerebellum. Several areas exhibited a partial reduction in binding including the glomerular layer of the olfactory bulb, nucleus accumbens, and the superior colliculus. The distribution of these subtypes is consistent with the distribution of mRNA for the D‐2 and D‐3 receptor in the brain. Therefore, [3H]quinpirole binds to the high affinity agonist conformation of the D‐2 and the D‐3 receptor. © 1993 Wiley‐Liss, Inc.
In vivo imaging of monoaminergic nerve terminals in normal and MPTP‐lesioned primate brain using positron emission tomography (PET) and [11C]tetrabenazine
Authors: DaSilva Jean N. , Kilbourn Michael R. , Domino Edward F.
Published: December 2004

The first successful in vivo imaging of monoamine vesicular transporters in the living primate brain is described, using [11C]tetrabenazine ([11C]TBZ) and Positron Emission Tomography (PET). Radioligand uptake into brain is rapid, and at short time periods (10‐30 minutes) the higher uptake and retention of the radiotracer in the more densely dopaminergic innervated striatum is clearly visualized. Specific binding in striatum can be entirely blocked with co‐administration of a pharmacological dose (1 mg/kg i. v.) of tetrabenazine. In a unilaterally MPTP‐lesioned monkey, specific binding of radioligand was absent in the striatum on the lesioned side, with no effect on radiotracer distribution in the cortex, cerebellum or contralateral striatum. PET imaging with [11C]TBZ provides a new approach to the in vivo study of monoaminergic neurons and their loss in neurodegenerative diseases. © 1993 Wiley‐Liss, Inc.