bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleus basalis stimulation facilitates thalamocortical synaptic transmission in the rat auditory cortex
Authors: Metherate Raju , Ashe John H.
Published: December 2004

Nucleus basalis (NB) neurons are a primary source of neocortical acetylcholine (ACh) and likely contribute to mechanisms of neocortical activation. However, the functions of neocortical activation and its cholinergic component remain unclear. To identify functional consequences of NB activity, we have studied the effects of NB stimulation on thalamocortical transmission. Here we report that tetanic NB stimulation facilitated field potentials, single neuron discharges, and monosynaptic excitatory postsynaptic potentials (EPSPs) elicited in middle to deep cortical layers of the rat auditory cortex following stimulation of the auditory thalamus (medial geniculate, MG). NB stimulation produced a twofold increase in the slope and amplitude of the evoked short‐latency (onset 3.0 ± 0.13 ms, peak 6.3 ± 0.21 ms), negative‐polarity cortical field potential and increased the probability and synchrony of MG‐evoked unit discharges, without altering the preceding fiber volley. Intracortical application of atropine blocked the NB‐mediated facilitation of field potentials, indicating action of ACh at cortical muscarinic receptors. Intracellular recordings revealed that the short‐latency cortical field potential coincided with a short‐latency EPSP (onset 3.3 ± 0.20 ms, peak 5.6 ± 0.47 ms). NB stimulation decreased the onset and peak latencies of the EPSP by about 20% and increased its amplitude by 26%. NB stimulation also produced slow membrane depolarization and sometimes reduced a long‐lasting IPSP that followed the EPSP. The combined effects of NB stimulation served to increase cortical excitability and facilitate the ability of the EPSP to elicit action potentials. Taken together, these data indicate that NB cholinergic neurons can modify neocortical functions by facilitating thalamocortical synaptic transmission. © 1993 Wiley‐Liss, Inc.
Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: Assessment of the role of D1 dopamine receptor stimulation
Authors: Rowlett James K. , Mattingly Bruce A. , Bardo Michael T.
Published: December 2004

Previous research has revealed a role of repeated D1 dopamine receptor stimulation in the development of behavioral sensitization to the D1/D2 agonist apomorphine. The present experiments assessed the role of repeated D1 receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D1 stimulation on dopamine synthesis, rats were injected with the D1 agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4‐dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD‐1015. DOPA accumulation, assessed in striatal, nucleus accumbens‐olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D1 agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine‐treated rats, but not the SKF 38393‐treated rats, across the 10 days. On day 11, all rats were injected with NSD‐1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC) and [3H]SCH 23390 binding to D1 receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels. In the VM, DOPAC levels were enhanced following repeated apomorphine, but not repeated SKF 38393, whereas dopamine levels were not affected by either drug treatment. D1 binding was not altered by the repeated drug treatments. Since repeated D1 stimulation by SKF 38393 did not produce the same alterations in dopamine synthesis and DOPAC levels as repeated apomorphine, the neurochemical effects accompanying locomotor sensitization to apomorphine probably are not mediated by D1 receptors. © 1993 Wiley‐Liss, Inc.
Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers
Authors: Volkow Nora D. , Fowler Joanna S. , Wang Gene‐Jack , Hitzemann Robert , Logan Jean , Schlyer David J. , Dewey Stephen L. , Wolf Alfred P.
Published: December 2004

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self‐administration, positron emission tomography and a dual‐tracer approach was used to examine dopamine D2 receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D2 receptor availability which persisted 3‐4 months after detoxification. Decreases in dopamine D2 receptor availability were associated with decreased metabolism in several regions of the frontal of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug‐taking behavior. © 1993 Wiley‐Liss, Inc.
Alterations in striatal and extrastriatal D‐1 and D‐2 dopamine receptors in the MPTP‐treated common marmoset: An autoradiographic study
Authors: Gnanalingham Kanna K. , Smith Lance A. , Hunter A. Jackie , Jenner Peter , Marsden C. David
Published: December 2004

In adult common marmosets (Callithrix jacchus), MPTP (1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine) treatment induced almost total depletion of cells in the substantia nigra pars compacts (SNc) but partial cell loss in the ventral tegmental area (VTA). There was severe depletion of [3H]‐mazindol binding to dopamine (DA) uptake sites in the caudate, putamen, and SNc. The loss of [3H]‐mazindol binding in the nucleus accumbens (NAc) and olfactory tubercle (OT) was less marked. [3H]‐mazindol binding in the body of caudate nucleus showed a small but significant recovery with increasing post‐lesion survival times.

The specific binding of [3H]‐SCH 23390 to D‐1 DA receptor sites was increased after MPTP treatment in all subregions of both caudate and putamen but was unaltered in the NAc and OT. Substantia nigra pars reticulata (SNr), frontal cortex, and medial segment of globus pallidus (GPm) all demonstrated moderate levels of [3H]‐SCH 23390 binding in control animals, which were unaffected by MPTP treatment. Specific [3H]‐spiperone binding to D‐2 DA receptor sites was not altered by MPTP treatment in the subregions of caudate‐putamen. Moderate levels of [3H]‐spiperone binding were observed in control animals in the NAc, OT, SNc, and the lateral segment of globus pallidus (GPl). [3H]‐spiperone binding in the SNc and OT was partially decreased in MPTP‐treated animals. The changes in specific [3H]‐spiperone and [3H]‐SCH 23390 binding induced by MPTP‐treatment did not alter with post‐lesion survival times.

These results demonstrate that MPTP treatment causes greater dopaminergic denervation of the caudate‐putamen than in NAc/OT. This resulted in an increase in postsynaptic D‐1 DA receptor sites in the caudate‐putamen but not in the NAc/OT. Also, there appeared to be loss of presynaptic D‐2 DA receptic sites in the SNc and OT. In the caudate‐putamen, the loss of presynaptic D‐2 DA receptor sites may have masked postsynaptic D‐2 DA receptor upregulation. © 1993 Wiley‐Liss, Inc.
Low density of dopamine D4 receptors in Parkinson's, schizophrenia, and control brain striata
Authors: Seeman Philip , Guan Hong‐Chang , Van Tol Hubert H. M. , Niznik Hyman B.
Published: December 2004

The purpose of this study was to determine whether dopamine D4 receptors could be detected in the human brain striatum by means of an indirect ligand‐binding method, because no dopamine D4 receptor‐selective ligand presently exists. The antipsychotic clozapine is more selective for the dopamine D4 receptor than for other dopamine receptors. Although most antipsychotic drugs act in the striatum to elicit Parkinson‐like side‐effects, clozapine is atypical in that it does not produce Parkinsonism. To understand this atypical action of clozapine, it would be helpful to know whether the presumed target for clozapine, the dopamine D4 receptor, is or is not present in the human striatum. We measured dopamine D4 receptors indirectly, using [3H]emonapride

Emonapride (or YM‐09151‐2; eis‐N‐[(2RS,3RS)‐l‐benzyl‐2‐methylpyrrolin‐ 3‐yll‐5‐chloro‐2‐methoxy‐4‐∼methylamino‐benzamide]) contains two asymmetric carbon atoms and is, therefore, a racemate of four enantiomers, two of which, (R,R)YM‐O9151‐2 and (S,S)YM‐09151‐2, are active with identical potency (see Refs. in Seeman et al., 1992).

and [3H]raclopride. Emonapride has a high affinity (K = 90 pM) for the dopamine D4 receptor, while raclopride has a very low affinity for this receptor (K = 240 nM); thus, any difference in the densities of these two [3H]ligands (in the absence of dopamine) could be attributed to the presence of dopamine D4 receptors. Since the binding of [3H]raclopride is sensitive to endogenous dopamine, we used Parkinson‐diseased tissue which has little dopamine. We found that the densities of the two ligands were identical in Parkinson striata, indicating a low density (<1 pmol/g) for dopamine D4 receptors in the human striatum. This low or undetectable density of dopamine D4 receptors in the striatum is consistent with other data indicating that clozapine does not have its major action in the human striatum. Thus, the atypical action of clozapine, insofar as clozapine does not elicit Parkinson side‐effects, may be based on its ability to avoid striatal dopamine D2 receptors and to target dopamine D4 receptors in non‐striatal brain regions. In schizophrenia striata the density of [3H]emonapride was almost two‐fold higher than that of [3H]raclopride. Considering that there are few dopamine D4 receptors in the human striatum, this two‐fold difference is best explained by endogenous dopamine interfering with the binding of [3H]raclopride, but not that of [3H]emonapride. © 1993 Wiley‐Liss, Inc.
Dopamine receptors labelled by PHNO
Authors: Seeman Philip , Ulpian Carla , Larsen Robert D. , Anderson Paul S.
Published: December 2004

Since the high‐affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive agonist to label this high‐affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's disease. We prepared [3H](+)PHNO from allyl‐des‐propyl‐(+)PHNO. In binding to dopamine receptors in homogenates of canine brain striata, [3H](+)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of [3H](+)PHNO at drug concentrations similar to those inhibiting other [3H]ligands at D2 receptors, but not similar to those acting at D4 receptors. Approximately 90% of the total [3H](+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhibited [3H](+)PHNO binding, suggesting that [3H](+)PHNO was binding primarily to the high‐affinity state of dopamine D2 receptors rather than to D3 receptors. The density of the [3H](+)PHNO binding sites was equal to that of [3H]emonapride (or [3H]YM‐09151‐2), both densities of which were 1.5‐ to 2‐fold higher than that of [3H]spiperone, compatible with the idea that [3H](+)PHNO binds to monomers of D2, while [3H]spiperone binds to dimers of D2. Although [3H](+)PHNO has good selectivity and affinity for the high‐affinity state of D2, the [3H]ligand was sensitive to endogenous dopamine, since washing the tissue lowered the dissociation constant. For future in vivo labelling of D2 by an agonist, therefore, it will be essential to search for a related [3H]ligand with an even lower dissociation constant. © 1993 Wiley‐Liss, Inc.
Comparison of immunolocalization patterns for the synaptic vesicle proteins p65 and synapsin I in macaque monkey retina
Authors: Koontz Margaret A. , Hendrickson Anita E.
Published: December 2004

The distributions of the two synaptic vesicle proteins p65 [Matthew et al. (1981) J. Cell Biol., 91:257–269] and synapsin I [De Camilli et al. (1983) J. Cell Biol., 96:1337–1354] were compared in macaque monkey retina using pre‐embedding immunocytochemistry for both light and electron microscopy. The monoclonal antibody AB‐48 against p65 labeled ribbon‐containing synaptic terminals of cone, rod, and bipolar cells as well as many conventional synapses of amacrine cells. In contrast, a polyclonal antiserum against synapsin I (SYN I) labeled many amacrine conventional synapses but no photoreceptor or bipolar ribbon synaptic terminals. Horizontal cell pre‐ and post‐synaptic profiles in the outer plexiform layer were not labeled by either antibody. At the light microscopic level, the banding patterns in the inner plexiform layer also differed for the two antibodies, with four bands of AB‐48 immunoreactivity in sublayers S1, S2, S4, and S5 but only three bands of SYN I immunoreactivity in S1, S3, and S5. SYN I also labeled varicose fibers in both the inner nuclear layer and the outer plexiform layer that are probably processes of dopaminergic and GABAergic interplexiform cells. Varicose fibers in the ganglion cell layer were labeled by both antibodies. These results provide the first electron microscopic immunocytochemical labeling for AB‐48 and SYN I in intact retina and confirm that AB‐48 labels both ribbon and conventional synaptic terminals, whereas SYN I labels only conventional synapses. © 1993 Wiley‐Liss, Inc.
Comparison of associative and non‐associative conditioning procedures in the induction of LTD in CA1 of the hippocampus
Authors: Kerr D. Steven , Abraham Wickliffe C.
Published: December 2004

Recent reports have indicated that weak activity in a test input, negatively correlated (out‐of‐phase) with tetanization of a separate, converging input, produces an NMDA‐independent, associative long‐term depression (LTD) of the test input synapses, in hippocampal field CA1 (Stanton and Sejnowski, 1989; Stanton et al., 1991). Associative LTD has also been observed in the dentate gyrus, in vivo, but only following “priming” of the test path with 5 Hz stimulation prior to associative conditioning (Christie and Abraham, 1992b). We have used these stimulus protocols, in vitro, in order to compare the induction of non‐associative and associative LTD in field CA1 of the adult rat hippocampus. Stimulation in normal solution evoked a small non‐associative LTD, but no associative LTD. Addition of picrotoxin to the medium facilitated the induction of NMDA‐dependent non‐associative LTD, but not associative LTD. Previously potentiated pathways were not different from naïve pathways in expression of LTD of either kind. Finally, ‘priming’ stimulation (5 Hz) of the test pathway produced a weak, selective enhancement of associative LTD that was, however, not significantly greater than non‐associative LTD. These results indicate that, for our experimental conditions, negatively correlated co‐activity during afferent tetanization does not induce a substantial associative LTD in area CA1. © 1993 Wiley‐Liss, Inc.
Quantitation and three‐dimensional reconstruction of Ch4 nucleus in the human basal forebrain
Authors: Halliday Glenda M. , Cullen Karen , Cairns Murray J.
Published: December 2004

The basal nucleus of Meynert, incorporating the Ch4 group of cholinergic neurons, was examined in six patients with no signs of neurological abnormalities. The ages of the patients ranged from 20 to 80 years. Despite a number of descriptions of these neurons, few age‐related studies have been dedicated to the analysis of the entire anteroposterior extent of the nucleus. Staining with cresyl violet and acetylcholinesterase histochemistry, alone or in combination, was used to identify the cytoarchitectural organization of the Ch4. Computer‐assisted morphometry was used for three‐dimensional visualization and quantitation. The three‐dimensional computer reconstructions revealed a continuous ribbon of neurons with a highly variable density. Four distinct subregions could be clearly identified in all cases by their cytoarchitecture and cellular morphology, although these subgroups were different to those previously described. There were no quantitative differences between the hemispheres in volume, density or cell number of the Ch4, although equivalent levels varied in area and density. The measures were similar in all cases with the exception of the case aged 80 years old. The data demonstrate individual variability in three dimensions and confirm previous studies that found only a mild decline of the Ch4 in old age. © 1993 Wiley‐Liss, Inc.
Muscarinic potentiation of excitatory amino acid‐evoked dopamine release in mesencephalic cells: Specificity for the NMDA response and role of intracellular messengers
Authors: Allaoua Horia , Chaudieu Isabelle , Alonso Richard , Quirion Rémi , Boksa Patricia
Published: December 2004

Of the five cloned muscarinic receptor subtypes, dopamine (DA) neurons in the substantia nigra and ventral tegmental areas have been shown to be selectively enriched with the mRNA: for the m5 subtype, suggesting that muscarinic modulation of DA neurons may have a distinct pharmacology. In the present study we have used dissociated cell cultures of fetal rat ventral mesencephalon to characterize muscarinic modulation of DA neurons. [3H]DA release stimulated by activation of N‐methyl‐Daspartate (NMDA) receptors was potentiated by carbachol, a mixed muscarinic‐nicotinic agonist, and by oxotremorine‐M, a muscarinic agonist. Neither carbachol nor oxotremorine‐M had an effect on [3H]DA release evoked by the non‐NMDA agonists, kainate or quisqualate. A nicotinic agonist, DMPP, had no effect on NMDA‐stimulated release. Potentiation of NMDA‐stimulated [3H]DA release by oxotremorine‐M was inhibited by the broad spectrum muscarinic antagonist, QNB, and by low concentrations of a putative Ml antagonist, pirenzepine, while much higher concentrations of a purported M2 antagonist, AF‐DX 384, were required to reverse the oxotremorine‐M effect. The muscarinic antagonist, 4‐DAMP, was active in a concentration range between that required for pirenzepine and AF‐DX 384. Further experiments examined intracellular messenger mechanisms coupled to the muscarinic receptors modulating NMDA‐stimulated [3H]DA release. In contrast to oxotremorine‐M, two muscarinic agents with only weak partial agonism with respect to phosphoinositide turnover, pilocarpine and arecoline, had no effect on NMDA‐stimulated [3H]DA release. Potentiation of NMDA‐stimulated [3H]DA release by oxotremorine‐M was inhibited by staurosporinc, an inhibitor of protein kinase C, but was unaffected by H8, an inhibitor of cAMP‐ and cGMP‐dependent protein kinases. Pretreatment of cultures with pertussis toxin did not alter oxotremorine‐M potentiation of the NMDA response. Our results indicate that the muscarinic receptors responsible for potentiation of NMDA‐stimulated [3H]DA release in mesencephalic cultures are linked to phosphoinositide hydrolysis and protein kinase C activation via pertussis toxin insensitive G proteins. The data are also consistent with the identification of these receptors as the m5 subtype of cloned receptor, on the basis of the relative potency of muscarinic agonists and antagonists in this system, although involvement of ml receptors cannot be excluded solely on this basis. Taken together with previous reports showing selective localization of m5 receptor mRNA in regions containing DA cell bodies, these studies suggest that use of dissociated cell cultures may thus be an appropriate model for studying direct modulation of dopaminergic neurons by cholinergic agents interacting with putative m5 receptors. © 1993 Wiley‐Liss, Inc.
Loss of striatal histamine H2 receptors in Huntington's: Chorea but not in Parkinson's disease: Comparison with animal models
Authors: Martínez‐Mir M. I. , Pollard H. , Moreau J. , Traiffort E. , Ruat M. , Schwartz J. C. , Palacios J. M.
Published: December 2004

Autoradiographic techniques were used to study the distribution of histamine H2‐receptors as labeled with [125I]iodoaminopotentidine in the brains of patients affected by human neurodegenerative pathologies, as compared with control cases. The highest levels of histamine H2 binding sites in control cases were found in the caudate, putamen, and accumbens nuclei. In Huntington's chorea, the levels of histamine H2 receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis. The loss of binding sites was related to the grade of the disease. Losses were more marked in grade III disease cases. The possible influence of neuroleptic treatment, commonly used in Huntington's patients, was studied by including samples from clinically treated schizophrenic patients. A moderate increase in the densities of [125I]iodoaminopotentidine was found in the globus pallidus of these patients. In Parkinson's disease, the levels of histamine H2‐receptor binding sites were found not to be significantly different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin‐lesioned guinea pigs. Similar losses of binding sites were observed in the quinolinic acid lesioned striatal intrinsic neurons in the guinea pig, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6‐hydroxydopamine did not produce any significant change. These results strongly suggest that histamine H2‐receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striato‐nigral pathway. © 1993 Wiley‐Liss, Inc.
GABAB‐Receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra
Authors: Engberg Göran , Kling‐Petersen Torben , Nissbrandt Hans
Published: December 2004

Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB‐receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB‐receptor agonist baclofen (1–16 mg/kg) was associated with a dose‐dependent regularisation of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16–32 mg/kg), the firing rate of the DA neurons was dose‐dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB‐receptor antagonist CGP 35348 (200 mg/kg, l.v.). The GABAA‐receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a Cecreased regularity. The NMDA receptor antagonist MK 801 (0.4–3.2 mg/kg, i.v.) produced a moderate, dose‐dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3–10 min) did neither promote nor prevent the regularisation of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB‐receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst Firing activity on these neurons. © 1993 Wiley‐Liss, Inc.
Time‐dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats
Authors: Neisewander Janet L. , Lucki Irwin , McGonigle Paul
Published: December 2004

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine‐induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine‐induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine‐induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28–60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate‐putamen, and nucleus accumbens. The density of 3H‐SCH‐23390‐labeled D1 receptors was altered in all three regions examined in a time‐dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in 3H‐spiroperidol‐labeled D2 receptors, 125‐pindolol‐labeled β‐adrenergic receptors, or 3H‐ketanserin‐labeled 5‐HT2 receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine. © 1994 Wiley‐Liss, Inc.
Power spectral analysis of electroencephalographic desynchronization induced by cocaine in rats: Correlation with microdialysis evaluation of dopaminergic neurotransmission at the medial prefrontal cortex
Authors: Luoh Hsiang‐Fei , Kuo Terry B. J. , Chan Samuel H. H. , Pan Wynn H. T.
Published: December 2004

We evaluated the effect and action mechanisms of cocaine on electroencephalographic (EEG) activity in adult male Sprague‐Dawley rats anesthetized with chloral hydrate (400 mg/kg, i.p., with 80 mg/kg/h supplements). On‐line and real‐time power spectral analysis of the EEG activity continuously quantified its root mean square (RMS) and mean power frequency (MPF) values, and the power of its spectral frequency components (low frequency: 0–4 Hz; high frequency: 4–20 Hz). Administration of cocaine (1.5 or 3.0 mg/kg, i.v.) dose‐dependently induced EEG desynchronization, as manifested by a reduction in RMS and an elevation in MPF values, coupled with a differential decrease in both high and low frequency components. Samples collected by in vivo microdialysis at the medial prefrontal cortex (mPFC) and analyzed by HPLC showed that the elevation of cocaine and dopamine (DA) level in the dialysate reached its peak during the time interval when maximal activation of EEG occurred. This EEG activation was antagonized by microinfusion into the mPFC via reverse microdialysis of R(+)‐SCH 23390, a selective antagonist for D‐1 receptors; sulpiride, a selective antagonist for D‐2 receptors; or haloperidol, a nonspecific dopamine antagonist. These results suggest that dopaminergic neurotran:3mission at the mPFC may be intimately related to the specific spectral pattern of alteration in EEG activity elicited by cocaine in the rat and that both D‐1 and D‐2 receptors may be involved in the process. © 1994 Wiley‐Liss, Inc.
Gene expression in central cholinergic neurons in response to axotomy and deafferentation
Authors: Weiser Michael , Baker Harriet , Joh Tong H.
Published: December 2004

Although the molecular and cellular responses to injury in the central nervous system (CNS) have been widely investigated, few studies have examined the potential variations between direct and indirect neuronal injury. To differentiate between the response to axotomy and deafferentation, two central cholinergic populations were analyzed: the horizontal limb of the diagonal band of Broca (HLDB) and the interneurons in the corpus striatum (CS). At time points from one hour to eight weeks postinjury the levels of choline acetyltransferase (ChAT) mRNA and protein were assessed by in situ hybridization and immunohistochemistry. Also examined was the expression of the immediate early gene product, c‐fos. One week post axotomy, neurons in the HLDB exhibited an increase in the levels of ChAT mRNA without a concomitant increase in ChAT protein, followed by a steady decrease reaching a nadir in both parameters at eight weeks. In contrast, a transient increase occurred at one week postdeafferentation in the levels of both ChAT mRNA and protein in the interneurons of the CS. Axotomized neurons in the HLDB did not exhibit either c‐fos mRNA or protein expression, while robust fos induction occurred after one hour in deafferented neurons in the CS. These data demonstrate that the molecular and cellular responses differ following direct and indirect neufenal injury. Furthermore, they suggest that in these central cholinergic populations deafferentation may result in cellular hyperactivity and cell survival while axotomy, results in decreased cellular activity and subsequent cellular regression. © 1994 Wiley‐Liss, Inc.
Desensitization and noncompetitive blockade of GABAA receptors in ventral midbrain neurons by a neurosteroid dehydroepiandrosterone sulfate
Authors: Spivak Charles E.
Published: December 2004

Dehydroepiandrosterone sulfate (DHEAS) blocked the GABAA receptor noncompetitively in neurons grown in primary culture from the ventral midbrains of fetal rats. The apparent dissociation constant for this blockade was 4.5 μ, and one molecule of DHEAS was sufficient to block the receptor. The affinity of the blocked receptor for GABA was diminished by about one half. The findings that the DHEAS caused no rectification of chloride currents and that it did not shorten the durations of open ion channels indicated that DHEAS did not act by occluding open ion channels. Neither did it diminish their conductance. DHEAS accelerated desensitization in at least one population of receptors, diminished the amplitudes of inhibitory postsynaptic currents, and shortened their decay time constants in a concentration dependent manner. © 1994 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Modulation of cellular excitability in neocortex: Muscarinic receptor and second messenger‐mediated actions of acetylcholine
Authors: Cox Charles L. , Metherate Raju , Ashe John H.
Published: December 2004

Muscarinic‐type acetylcholine (ACh) receptors are involved in a variety of cortical functions. ACh “activates” neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non‐cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate‐mediated membrane depolarizations. Muscarinic receptors of the M1and/or M3subtype, rather than M2or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13‐dibutyrate (4 β‐PDBu), enhanced neuronal responses to glutamate. The effect of 4 β‐PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions ofendogenousACh. Tetanic stimulation of cholinergic afferents elicited voltage‐dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems. © 1994 Wiley‐Liss, Inc.
Divergence of hippocampal mossy fibers
Authors: Frotscher M. , Soriano E. , Misgeld U.
Published: December 2004

By connecting the fascia dentata with the hippocampus proper, the axons of the granule cells, the mossy fibers, represent an important element of the main excitatory, trisynaptic pathway of the hippocampal formation. In this review the various synaptic connections of the mossy fibers are discussed. It turns out that the mossy fibers do not only establish synapses with the pyramidal neurons of regio inferior as traditionally assumed, but a variety of local circuit neurons as well as projection cells are also contacted by the mossy fibers. Thus there is an underestimated divergence of the impulse flow within the “trisynaptic” pathway at the level of the mossy fibers. Similarly, the pattern of afferent input to the granule cells, especially that of GABAergic neurons, is more complex than previously assumed. In this respect the concept of a unidirectional “trisynaptic” pathway certainly is an oversimplification. In particular, the hilus of the fascia dentata, that the 'mossy fibers traverse on their way to regio inferior, is often neglected in this concept. The hilar region comprises a large variety of morphologically and functionally distinct neuronal types that, to a large extent, are targets of hilar mossy fiber collaterals. By focusing on the mossy fiber system, an attempt is made in this review to summarize new data on hippocampal circuitries that have been accumulated since the original description of the trisynaptic pathway. This concept, which originally comprised the synapses of the perferant path fibers on dentate granule cells, the mossy fiber synapses on CA3 pyramidal neurons, and the synapses of the Schaffer collaterals on CA1 pyramidal cells, has been of great heuristic value but needs to be modified in view of recent morphological and physiological data. © 1994 Wiley‐Liss, Inc.
Mercuric chloride and p‐chloromercuriphenylsulfonate exert a biphasic effect on the binding of the stimulant [3H]methylphenidate to the dopamine transporter
Authors: Schweri M. M.
Published: December 2004

Mercuric chloride was found to have a biphasic effect on the binding of the radiolabeled stimulant [3H]methylphenidate to membranes from a crude synaptosomal preparation of rat striatal tissue. Binding was enhanced at low concentrations of HgCl2, reaching a maximum of 62% above control values at 2.5 μ HgCl2. It was inhibited in a dose‐dependent manner at concentrations greater than 5 μ HgC12, with an IC50 of 7.2 μ. The increase in binding observed at the low concentrations of HgC12 was shown by Scatchard analysis to be due to an increase in the affinity of [3H]methylphenidate for its binding site on the dopamine transporter, while a decrease in both affinity and Bmax accompanied the reduction of [3H]methylphenidate binding observed at the higher concentrations of the inorganic mercury compound. The sodium salt of the organic mercurial p‐chloromercuriphenylsulfonic acid also caused an increase in [3H]methylphenidate binding (159% above controls at 2,000 μ), followed by an immediate decrease in binding at higher concentrations of the reagent. Because both of these mercury‐containing compounds have a high propensity for interacting with sulfhydryl groups, these data suggest that the cysteine residues in the dopamine transporter molecule may play an important role in the regulation of stimulant binding to the uptake complex. © 1994 Wiley‐Liss, Inc.
Effects of supplemental choline on extracellular acetylcholine in the nucleus accumbens during normal behavior and pharmacological acetylcholine depletion
Authors: Rada Pedro V. , Mark Gregory P. , Hoebel Bartley G.
Published: December 2004

Brain microdialysis was used to determine whether systemic or local application of choline would modify the extracellular concentration of acetylcholine (ACh) in the nucleus accumbens (NAc) of freely moving rats. Supplemental choline given intraperitoneally or into the NAc of normal rats did not increase extracellular ACh. When local ACh interneurons in the NAc were treated pharmacologically to deplete the intracellular stores of ACh, then systemic choline (80 mg/kg) was an effective treatment. Specifically, )1) blockade of the high‐affinity choline transporter with hemicholinium‐3 (HC‐3) to reduce ACh synthesis caused a decrease in extracellular ACh, but choline supplementation restored ACh toward its normal level in the NAc. (2) Local bicuculline treatment released ACh to the point of depletion, but systemic choline or locally infused choline helped maintain normal ACh levels. These results suggest that choline supplementation might be useful in preventing depletion of ACh in the nucleus accumbens during pathological conditions. © 1994 Wiley‐Liss, Inc.
Occupancy of the serotonin transporter by fluoxetine, paroxetine, and sertraline: In vivo studies with [125i]rti‐55
Authors: Scheffel Ursula , Kim Stanley , Cline Elizabeth J. , Kuhar Michael J.
Published: December 2004

[125I]RTI‐55 was used in tracer doses to label serotonin (5‐HT) transporters in vivo in the mouse brain. Fluoxetine, paroxetine, and sertraline, potent antidepressants and selective inhibitors of serotonin transporter sites, were administered in various doses and at various times. The doses and times that result in significant binding of the drugs to transporters correspond to doses and times where they are reported to have physiological effects. Estimates of occupancy rate and duration of binding to serotonin transporters were made. The rate of occupancy of the 5‐HT transporter site was fastest for sertraline, intermediate for paroxetine and slowest for fluoxetine. Similarly, the duration of occupancy was significantly shorter for sertraline and paroxetine (approximately 10 h) than for fluoxetine (approximately 50 h). The results indicate that in competition studies, [125I]RTI‐55 can be used to identify doses of drugs that are physiologically effective, to determine their relative rate of occupancy, and most importantly, to measure the residency time on the central serotonin transporter in vivo. © 1994 Wiley‐Liss, Inc.
Modeling the integrative properties of dendrites: Application to the striatal spiny neuron
Authors: Martiel Jean‐Louis , Mouchet Patrick , Boissier Marie‐Dominique
Published: December 2004

The role of the striatum in the control of movements and in the processing of cortical information has received much attention in the recent years. We set out a simple biophysical model for the medium‐spiny neuron (msn), the most abundant cell in striatum. This neuron receives two main kinds of inputs, namely, cortical excitatory inputs and dopaminergic inputs coming from the substantia nigra pars compacta. The msn axon impinges directly onto the globus pallidus and onto the substantia nigra pars reticulata neurons and onto striatal neurons through recurrent branches of the axon. The msn is characterized by spiny dendritic trees with a high density of spines (1 to 4 spines/μ) and the probable existence of dendritic spikes. The model predicts that the neuron can integrate excitable inputs in a linear or a nonlinear mode. In the nonlinear mode, the neuron allows the detection of simultaneous (or almost simultaneous) synaptic inputs; it facilitates either a slowing down or a speeding up of the information transfer between the synaptic input location and the soma and is sensitive to inhibition‐excitation pairing. Conversely, in the linear integrative mode, the somatic voltage is determined by a weighted summation of the synaptic inputs. Several geometrical, electrical, or temporal factors can control the switch between these behaviors: the density of excitable dendritic elements, the dendritic radius, the resistance of the spine stem, the membrane resistance, the time between excitations, and the distance between synaptic sites. Finally, the signification of this behavior is discussed in connection with the putative role of dopamine and with the striatal net organization. © 1994 Wiley‐Liss, Inc.
Alpha 1‐antichymotrypsin is strongly immunolocalized at normal human and rat neuromuscular junctions
Authors: Bilak Masako , Askanas Valerie , Engel W. King
Published: December 2004

α1‐Antichymotrypsin (α1‐ACT) is an early‐stage acute‐phase plasma protein and a serpin that preferentially inactivates chymotrypsin, cathepsin G, and chymase. Using immunofluorescence with four rabbit polyclonal and two monoclonal specific antibodies against human α1‐ACT, we have localized α1‐ACT at human and rat neuromuscular junctions (NMJs). Strong α1‐ACT immunoreactivity (IR) was present at all NMJs identified by bound α‐bungarotoxin (α‐BT). α1‐ACT immunoreactivity typically extended slightly deeper into the muscle fiber than α‐BT, and it closely co‐localized with immunoreactivities of post‐synaptic desmin, beta‐amyloid precursor protein, and dystrophin at the same double‐ or triple‐labeled NMJs. Topography of α1‐ACT‐IR was the same at human and rat NMJs. The muscle non junctional sarcolemma was either not immunoreactive or was only very slightly so. When the primary antibody was omitted, absorbed, or replaced by a non‐immune serum, there was no immunostaining. Thus, αl‐ACT is a novel component of the NMJ. Although its role in the postsynaptic domain of the NMJ is unknown, it might be involved in the interaction between the presynaptic and postsynaptic components and/or inhibit excessive or unwanted serine proteases that may exist in the region of the NMJ. © 1994 Wiley‐Liss, Inc.
Pet studies of cocaine inhibition of myocardial norepinephrine uptake
Authors: Fowler Joanna S. , Ding Yu‐Shin , Volkow Nora D. , Martin Thomas , MacGregor Robert R. , Dewey Stephen , King Payton , Pappas Naomi , Alexoff David , Shea Colleen , Gatley S. John , Schlyer David J. , Wolf Alfred P.
Published: December 2004

Positron emission tomography (PET), [11C]cocaine, and (–)‐6‐[18F]fluoronorepinephrine [(‐)‐6‐[18F]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents binding to the norepinephrine transporter and to characterize the functional consequences of cocaine administration on the norepinephrine transporter. Peak heart binding of [11C] cocaine was high (0.038‐0.055%/g) and clearance was rapid (t1/2 from peak: 2.5–9 min) for both tracer doses and a pharmacological dose. The binding of a tracer dose of labeled cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose of [11C]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with cocaine profoundly inhibited norepinephrine uptake as assessed by (–)‐6‐[18F]NE. Recovery was slow with only 48% of the baseline (–)‐6‐[18F]NE uptake being recovered by 78 minutes after cocaine administration. [11C]Benzoylecgonine, a vasoactive metabolite of cocaine, showed negligible retention in heart. The results of this study (i.e., the rapid clearance of cocaine from the heart, the inability to inhibit cocaine binding with desipramine and tomoxetine, and its relatively long‐lasting effects on norepinephrine uptake) reinforce the need to understand the link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity. © 1994 Wiley‐Liss, Inc.
Receptor‐receptor link in membranes revealed by ligand competition: Example for dopamine D1 and D2 receptors
Authors: Seeman Philip , Sunahara Roger K. , Niznik Hyman B.
Published: December 2004

An interaction or link between dopamine D1 receptors and dopamine D2 receptors was found by a ligand competition method, using [3H]raclopride to label dopamine D2 receptors and SCH 23390 to block dopamine D1 receptors. In the presence of endogenous or exogenous dopamine, SCH 23390 increased the binding of [3H]raclopride in post‐mortem human striata homogenates or in tissue culture cells containing human dopamine D1 and D2 receptors. In order to reveal such intramembrane receptor‐receptor interactions in general, therefore, it appears essential to add two agonists, one for each receptor, and then to block one of the receptors when measuring the binding of a ligand to the second receptor. © 1994 Wiley‐Liss, Inc.
Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats
Authors: Quirion Remi , Richard Jean , Wilson Amy
Published: December 2004

The aim of the present study was to investigate, using in vivo dialysis, the existence of muscarinic and nicotinic receptors controlling acetylcholine release in the cortex of freely behaving rats. Various muscarinic receptor antagonists, including the nonselective blocker atropine, and a variety of M2 drugs (AF‐DX 116, AF‐DX 384, AQ‐RA 741) potently stimulated, in a concentration‐dependent manner, the in vivo release of acetylcholine in the rat cortex. The effects of all these antagonists were long lasting. The nature of these putative muscarinic autoreceptors is likely of the pharmacologically defined M2subtype on the basis of the high potency of the antagonists of the AF‐DX series and the variability and shorter duration of action of the effects of the prototypic M1 blocker, pirenzepine. 4‐DAMP, a purported M3 blocker, also potently stimulated in vivo cortical acetylcholine release, but this likely relates to its now established, rather limited selectivity for any given muscarinic receptor subtypes. Peripheral and central injections of nicotine also induced the in vivo release of acetylcholine in the rat cortex, albeit with a lower potency and shorter duration of action than muscarinic antagonists. Interestingly, the combination of a muscarinic antagonist, such as atropine, AF‐DX 116, or AF‐DX 384, in the presence of nicotine, induced tremendous releases of cortical acetylcholine up to 8‐to 10‐fold over basal values. This is clearly more than a simply additive effect, and it reveals the great capacity of cortical cholinergic nerve terminals to synthesize and release acetylcholine. Optimal pharmacological manipulations of these putative muscarinic and nicotinic autoreceptors could thus be useful in disorders in which the activity of cholinergic inputs is decreased, such as in Alzheimer's disease. © 1994 Wiley‐Liss, Inc.
Brain uptake of α‐[14C]methyl‐para‐tyrosine in the rat
Authors: Cumming P. , Venkatachalam T. K. , Rajagopal S. , Diksic M. , Gjedde A.
Published: December 2004

The blood‐brain permeabilities of L‐[3H]tyrosine and the tyrosine hydroxylase (TH) inhibitor β‐[14C]methyl‐para‐tyrosine ([14C]AMPT) were determined in rat striatum, a brain region rich in TH activity, and in other brain regions containing relatively little TH activity. In striatum, the unidirectional clearance rate (K1) for L‐[3H]tyrosine (6.2 ml hg‐ −1 min−1) was significantly greater than the rates for L‐[14C]AMPT (2.8 ml hg−1 min−1) and D‐[14C]AMPT (0.8 ml hg−1 min−1). The apparent volume of distribution (Vf) for L‐[14C]AMPT in striatum (72.5 ± 4.0 ml hg‐1) did not differ from the Vf in other brain regions. The homogeneous distribution of L‐[14C]AMPT in rat brain indicates that labeled AMPT is unsuitable for the study of TH in vivo by quantitative autoradiography. © 1994 Wiley‐Liss, Inc.