bluuebunny/crossref_metadata_2025 huggingface dataset:
Microiontophoretic studies of the effects of D‐1 and D‐2 receptor agonists on type I caudate nucleus neurons: Lack of synergistic interaction
Authors: Shen Roh‐yu , Asdourian David , Chiodo Louis A.
Published: December 2004

Several lines of evidence have suggested there may be a physiologically relevant form of synergistic interaction between D‐1 and D‐2 dopamine (DA) receptors located on postsynaptic neurons in the forebrain that receive a dopaminergic innervation. Because of the theoretical importance of such an interaction with respect to understanding the normal physiology of dopaminergic systems, we evaluated effects of D‐1 and D‐2 selective, agonists, applied microiontophoretically, on the spontaneous electrical activity of a single, identifiable subpopulation of neurons within the caudate nucleus, the type I striatal neuron, in locally anesthetized, gallamine‐paralyzed rats. It was observed that the D‐2 receptor agonist quinpirole (QUIN) produced biphasic effects on cell firing rate. Low ejection currents significantly increased firing rate, while higher currents produced an inhibition. Similar effects were observed for the D‐1 agonists SKF 38393; however, the overall excitations observed at low ejection currents were far less than those observed for QUIN. When these two agonists were applied concurrently, a simple additive effect (but not synergism) was always observed. The acute reduction of striatal levels of DA, by as much as 84% (with pretreatment with α‐methyl‐p‐tyrosine, AMPT), did not alter the responsiveness of type I striatal neurons to the DA receptor agonists applied alone or in combination. These observed effects were not altered either by chloral hydrate anesthesia (in which glutamate‐driven activity was studied) or by a more severe depletion of striatal DA levels (98% depletion produced by combined pretreatment with AMPT and reserpine). © Wiley‐Liss, Inc.
Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density
Authors: Lahoste Gerald J. , Marshall John F.
Published: December 2004

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i. e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i. e., behavior was elicited by independent stimulation of D1 or D2 receptors).

In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6‐hydroxydopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6‐hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2 receptor binding. By contrast, when rats with unilateral 6‐hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity.

The results support the hypothesis that two distinct types of dopamine supersensitivity exist: A modest one associated with increased D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.
Somatostatin binding reduced by ammonium acetate in the rat hippocampus can be reversed by treatment with N‐carbamyl‐L‐glutamate plus L‐arginine
Authors: Del Carmen Boyano Maria , Bodega Guillermo , Alvaro Itziar , Arilla Eduardo
Published: December 2004

The effects of short‐term (90 min), mid‐term (5 days), and long‐term (15 days) administration of ammonium acetate (5 mmol/Kg day i. p.) on the somatostatinergic neurotransmitter system of the rat hippocampus have been studied. Scatchard analysis of the binding of 125I‐Tyr11‐somatostatin to hippocampal dissociated cells indicated that administration of ammonium acetate at the times studied were associated with a decrease in the number of somatostatin receptors in this brain area, whereas the affinity of the same receptors remained unchanged. Administration of ammonium acetate did not affect the levels of somatostatin‐like immunoreactivity in the hippocampus. Treatment with N‐carbamyl‐L‐glutamate (1 mmol/Kg, i. p.) plus L‐arginine (1 mmol/Kg), which lead to the conversion of ammonia into urea, prevented the ammonium acetate‐induced changes in somatostatin binding in this brain area. N‐carbamyl‐L‐glutamate plus L‐arginine alone had no observable effect on the somatostatinergic system. The decrease in the number of somatostatin receptors induced by ammonium acetate might reflect a decreased sensitivity of the target cells to somatostatin, a phenomenon that could contribute to the depressed neuronal excitability induced by ammonia in the rat hippocampus. © 1992 Wiley‐Liss, Inc.
Alteration of 5‐HT1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography
Authors: Fanelli Richard J. , McMonagle‐Strucko Katheen
Published: December 2004

Ipsapirone, a high‐affinity ligand for the 5‐hydroxytryptamine1A (5‐HT1A) receptor subtype, has been shown to be a full agonist at presynaptic serotonergic sites and a partial agonist at postsynaptic sites. Several recent studies have examined the effects of chronic treatment with ipsapirone or other structurally related pyrimidinylpiperazine compounds, including buspirone and gepirone, on 5‐HT1A binding sites with mixed results. Since the neural mechanism responsible for the anxiolytic and antidepressant properties of these compounds is currently uncertain, further investigation of this issue appeared warranted. [3H] 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin ([3H] 8‐OHDPAT), a ligand specific for the 5‐HT1A site, has been used successfully to label these sites using both membrane binding assays and autoradiography. Experiments were performed to determine whether chronic treatment with ipsapirone would differentially affect binding to 5‐HT1A receptors at different brain sites. Rats were treated twice daily with ipsapirone (10 mg/kg i. p.) for 1 day or for 1, 2, or 3 weeks. Quantitative analyses were done of autoradiograms of in vitro [3H] 8‐OH‐DPAT binding to selected brain regions. Binding in vehicle‐treated rats was highest in the hippocampus, septal nucleus, interpeduncular nucleus, entorhinal cortex, and dorsal raphe nucleus. Following 3 weeks of treatment with ipsapirone, a large decline in binding was measured in the dorsal raphe nucleus. This decline was not seen with ipsapirone treatments for shorter periods. With the 3‐week treatment, there were less robust declines in [3H] 8‐OH‐DPAT binding in the entorhinal cortex and interpeduncular nucleus. Binding in the other brain regions analyzed was unaltered. These results, together with those in the literature, indicate the importance of dose and length of treatment in producing these alterations. The large decline in binding sites in the dorsal raphe is consistent with the view that the anxiolytic and antidepressant properties of ipsapirone are mediated by a downregulation of the somatodendritic 5‐HT1A autoreceptors. © 1992 Wiley‐Liss, Inc.
Distribution of cocaine recognition sites in monkey brain: II. Ex vivo autoradiography with [3H]CFT and [125I]RTI‐55
Authors: Kaufman Marc J. , Madras Bertha K.
Published: December 2004

CFT [WIN 35, 428, 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane] and its 4‐iodinated analog RTI‐55 have been proposed as imaging probes for cocaine recognition sites and for dopamine transporters. The central and peripheral distribution of radiolabeled forms of these compounds was studied 30 minutes after intravenous administration in squirrel monkey (Saimiri sciureus). Quantitative ex vivo autoradiography of brain tissue sections from animals receiving [3H]CFT (2.5 nmol/kg) revealed radioligand distribution primarily in dopamine‐rich brain regions, and treatment with cocaine or mazindol substantially reduced [3H]CFT accumulation. The caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle accumulated the highest levels of [3H]CFT, and within the caudate nucleus, medial‐to‐lateral and anterior‐to‐posterior gradients were observed. Low levels of [3H]CFT were found in the cortex, thalamus, hypothalamus, and background levels in white matter and in the cerebellum (striatal: cerebellar ratio > 3). The in vivo distribution of [3H]CFT closely paralleled its in vitro distribution (Synapse, 9:177–187). Although [125I]RTI‐55 (0.2 nmol/kg) also distributed to dopamine‐rich brain regions (striatal: cerebellar ratio of 3.6), high levels also were detected in cortex, thalamus, and in midbrain/brainstem structures. In the periphery, [125I]RTI‐55 accumulation, measured as percent of administered dose, was higher than [3H]CFT in liver and lung, greater than 90% comigrated with [3H]CFT or [125I]RTI‐55 standards. The results support the hypothesis that dopamine‐rich brain regions may be relevant to the effects of cocaine, and that both CFT and RTI‐55 may be suitable imaging probes for these sites.
Both phasic sensory stimulation and tonic pharmacological activation increase Fos‐like immunoreactivity in the rat locus coeruleus
Authors: Grant S. J. , Bittman K. , Benno R. H.
Published: December 2004

Neuronal activation increases levels of Fos protein, the product of the early immediate gene c‐fos. Since most studies used stimuli that evoke sustained elevations in activity; the present study examined Fos‐like immunoreactivity (Fos‐LI) in the nucleus locus coeruleus (LC). Halothane‐anesthetized rats were given either footshock to elicit phasic activation of LC neurons or yohimbine (10 mg/kg, i. p.) to induce a tonic increase in firing. Both treatments markedly increased Fos‐LI in a subpopulation of LC neurons. These results demonstrate that c‐fos induction does not require high tonic levels of neuronal activity and that Fos‐LI may underestimate the proportion of LC neurons neurophysiologically activated by a given stimulus and suggest that factors beyond neuronal activity per se contributes to c‐fos expression. © 1992 Wiley‐Liss, Inc.
LHRH neurons in the medial septal‐diagonal band‐preoptic area do not project directly to the hippocampus: A double‐labeling immunohistochemical study
Authors: Dudley Carol A. , Sudderth Skylar B. , Moss Robert L.
Published: December 2004

While neurons containing immunoreactive luteinizing hormone‐releasing hormone (LHRH) are scattered primarily in the medial septal‐diagonal band of Broca‐medial preoptic area (mS‐dbB‐PO) complex, autoradiographic studies have demonstrated dense concentrations of LHRH receptors in the hippocampus. The route by which LHRH is transported to its hippocampal receptors is unknown. The present study was designed to test the hypothesis that LHRH‐containing neurons in the mS‐dbB‐PO complex project to hippocampal sites containing LHRH receptors, thereby serving as a source of innervation to these receptors.

Large (0.10 m̈l) or small (0.02 m̈l) volumes of the retrograde tracer wheat germ agglutinin (WGA) were injected unilaterally into four separate hippocampal locations in six ovariectomized female rats. In an additional five females, a 0.15 m̈l volume of the retrograde tracer fluorogold (FG) was similarly injected. After a five day survival period, the animals were sacrificed. Vibratome sections of the brain were stained for both WGA and LHRH with a dual immunohistochemical technique. Since FG is a fluorescent chromagen, brains of animals injected with FG only required processing for LHRH immunofluorescence. As a positive control, some sections containing retrogradely labeled cells filled with either WGA or FG were processed for choline acetyltransferase (CHAT) immunoreactivity.

The WGA and FG injections covered targeted hippocampal sites and neurons containing retrogradely transported WGA or FG were found in abundance in the mS‐dbB‐PO complex. In accord with previous reports, many CHAT‐positive and fewer LHRH‐positive neurons were found in this complex. Approximately 5–10% of the CHAT‐positive neurons also contained WGA or FG; however, no neurons were found to co‐localize LHRH and either of the retrograde tracers. The results indicate that LHRH neurons in the mS‐dbB‐PO complex do not project directly to hippocampal sites containing LHRH receptors. © 1992 Wiley‐Liss, Inc.
Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats
Authors: See Ronald E. , Chapman Mary Ann , Meshul Charles K.
Published: December 2004

The effects of chronic intermittent administration (7 months) of two neuroleptics, haloperidol (HAL) and raclopride (RAC), were compared using several different measures. Both drugs were administered weekly by subcutaneous injection at 7.0 mg/kg. Both neuroleptics consistently produced catalepsy throughout the treatment period, although HAL was generally more cataleptogenic than RAC. Assessment of dopamine (DA) release in the caudate putamen (CPu), through the use of in vivo microdialysis, showed that chronic HAL or RAC administration caused a prolonged decrease of DA release in response to a low dose of the DA D2 agonist quinpirole (0.03 mg/kg, sc). Injection of the muscarinic agonist pilocarpine (1.0 mg/kg, IP) did not have any significant within‐group effects, although both neuroleptic treatment groups showed decreased DA release when compared to controls. Ultrastructural analysis of the dorsolateral CPu showed that both HAL and RAC treatment resulted in a significant increase in the number of perforated synapses, which contain a discontinuous density along the postsynaptic membrane. These results demonstrate that two different DA D2 receptor antagonists produce a similar effect on DA function and ultrastructural changes within the CPu following chronic, intermittent treatment. © 1992 Wiley‐Liss, Inc.
Sigma receptors are associated with cortical limbic areas in the primate brain
Authors: Mash Deborah C. , Zabetian Cyrus P.
Published: December 2004

Putative sigma receptors are a current target for antipsychotic drug development. Novel antipsychotic agents which possess selective and high affinity for sigma binding sites may serve as an alternative to the principal neuroleptic drugs currently in clinical use which mediate extrapyramidal side effects and dyskinesias through their blockade of dopamine receptors. We have used in vitro autoradiography to localize putative sigma receptors labelled with (+)‐[3H]‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl) piperidine [(+)‐[3H]‐3‐PPP] in the brain of the rhesus macaque. The binding characteristics of (+)‐[3H]‐3‐PPP in the primate brain were comparable to those previously described in the rodent. Saturation analysis demonstrated a single class of sites in cerebellar and hippocampal membranes with a Kd value of 28 nM. Sigma receptors labeled with (+)‐[3H]‐3‐PPP in the primate brain displayed the appropriate rank order of potency and stereoselectivity in competition binding assays. Haloperidol displaced (+)‐[3H]‐3‐PPP binding in the low nanomolar range, and the (+) isomer of pentazocine was 50‐fold more potent than (‐) pentazocine. Computerized densitometric analysis of the autoradiograms demonstrated a striking enrichment of sigma binding sites over the paralimbic belt cortices, including the orbitofrontal, cingulate, insular, parahippocampal, and temporopolar gyri. Peak densities of sigma receptors were seen over the medial and central nuclei of the amygdala and were widely distributed within the hippocampal formation. Sigma binding sites densities were elevated over the suprachiasmatic and supraoptic nuclei of the hypothalamus. Moderate sigma receptor densities were observed over the ventromedial sectors of the caudate and the putamen. Sigma receptors were also elevated over autonomic relay nuclei of the brainstem, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. The distribution of sigma receptors in the primate brain suggests that the paralimbic belt cortices, amygdala, hippocampus, hypothalamus, and autonomic relay nuclei of the brainstem may be interrelated by a topographic chemical linkage. The autoradiographic visualization of sigma receptor distributions in the primate brain provides further support for a role of sigma receptor mechanisms in the functions of the limbic system. © 1992 Wiley‐Liss, Inc.
Multiple metabotropic glutamate receptors regulate hippocampal function
Authors: Desai Manisha A. , Smith Timothy S. , Conn P. Jeffrey
Published: December 2004

Selective activation of metabotropic glutamate receptors withtrans‐1‐amino‐1, 3‐cyclopentanedicarboxylic acid (trans‐ACPD) stimulates phosphoinositide hydrolysis and elicits three major physiological responses in area CA1 of the hippocampus. These include direct excitation of pyramidal cells, blockade of synaptic inhibition, and decreased transmission at the Schaffer collateral‐CA1 pyramidal cell synapse. Physiological effects oftrans‐ACPD are thought to be mediated by activation of phosphoinositide hydrolysis. However, it is now clear that multiple metabotropic glutamate receptor subtypes exist, some of which are not coupled to phosphoinositide hydrolysis. Thus, we performed a series of studies aimed at determining whether the physiological effects oftrans‐ACPD in the hippocampus are mediated by activation of the predominant phosphoinositide hydrolysis‐linked glutamate receptor. We report thatL‐2‐amino‐3‐phosphonopropionic acid (L‐AP3), an antagonist oftrans‐ACPD‐stimulated phosphoinositide hydrolysis, does not inhibit the physiological effects oftrans‐ACPD in area CA1 at concentrations that maximally inhibittrans‐ACPD‐stimulated phosphoinositide hydrolysis in this region. Furthermore, 1S, 3S‐ACPD activates the phosphoinositide hydrolysis‐linked glutamate receptor but does not reduce evoked field excitatory postsynaptic potentials (EPSPs) in area CA1. However, we report that the physiological effects of 1R, 3S‐ and 1S, 3R‐ACPD are consistent with the hypothesis that these effects are mediated by activation of a metabotropic glutamate receptor. Thus, our data are consistent with the hypothesis that the physiological effects oftrans‐ACPD in area CA1 of the hippocampus are mediated by metabotropic glutamate receptors that are distinct from the AP3‐sensitive phosphoinositide hydrolysis‐linked glutamate receptor. © 1992 Wiley‐Liss, Inc.
Systemic and microiontophoretic administration of morphine differentially effect ventral pallidum/substantia innominata neuronal activity
Authors: Napier T. Celeste , Chrobak James J. , Yew Jay
Published: December 2004

In vivo electrophysiological recording techniques were employed to examine responses of ventral pallidum/substantia innominata (VP/SI) neurons to systemic and local administration of morphine. Using a cumulative dosing protocol, intravenous administration (0.1–30 mg/kg i. v.) produced a suppression of firing in 82% of neurons tested. The suppression was dose‐related and blocked by the opioid antagonist, naloxone. In contrast, microiontophoretic applications of morphine resulted in current‐related suppression (32% of neurons tested) or excitation (26%). Concurrent application of naloxone attenuated or blocked both effects of local morphine applicatio. It was demonstrated that acute tolerance did not develop with repeated morphine exposures following either systemic or local administration. The present findings establish the sensitivity of VP/SI neurons to morphine and provide functional relevance at the level of a single neuron for opioid peptides and their receptors in this region. As reported for most other opioid receptive brain areas, neuronal rate suppression was the predominate response observed, and it is proposed that excitations to iontophoresed morphine reflect a disinhibitory phenomenon. The differntial morphine‐induced rate changes, and number of responding neurons, observed with systemic vs. iontophoretic morphine administration suggest that extra‐VP/SI regions that also are opioid sensitive can subsequently direct neuronal responsivensess to opioids within the VP/SI. © 1992 Wiley‐Liss, Inc.
Alcohol inoxication does not change [11C]cocaine pharmacokinetics in human brain and heart
Authors: Fowler J. S. , Volkow N. D. , Logan J. , MacGregor R. R. , Wang G.‐J. , Wolf A. P.
Published: December 2004

There is increasing evidence that the combined use of cocaine and alcohokl produces enhanced behaviroal and toxic effects. We have used PET and tracer doses of [11C]cocaine in 7 normal human volunteers to assess if the dostribution and clearance of cocaine are altered by alcohlol intoxication. Each subject received 2 PET studies with [11C]cocaine (3–11 m̈g), one before and one during alcohol intoxication (1 g/kg). Regions of interest included dthe brain (n= 3) and heart (n = 4). arterial plasma was assayed for unchanged cocaine and for labelaed cocaethylene, a metabolite of cocaine found in individuals usig cocaine and alcohol in combination (hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady‐state distribution volume of [11C]cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detedted in the 10 minute plasma sample. These results suggest that the acute dnhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine's organ distribution or to cocaethylene formation but may be related to an additive effect resulting from the direct actaons of each of these drugs. Published 1992 Wiley‐Liss, Inc.
In vivo studies of [125I]iodobenzamide and [11C]iodobenzamide: A ligand suitable for positron emission tomography and single photon emission tomography imaging of cerebral D2 dopamine receptors
Authors: Wong Dean F. , Wilson Alan A. , Chen Catherine , Minkin Elynne , Dannals Robert F. , Ravert Hayden T. , Sanchez‐Roa Patricia , Villemagne Victor , Wagner Henry N.
Published: December 2004

Iodobenzamide (IMB) labeled with either [11C] or [125I] was studied in mice and baboons. Pharmacological studies demonstrated an in vivo binding profile compatible with D2 dopamine receptors. Mouse biodistribution studies with both [11C]IMB and [125I]IMB showed a similar brain distribution of radioactivity. Mouse [125I]IMB studies with amphetamine and reserpine pretreatment suggested that IMB may be less susceptible to endogenous dopamine competition for D2 receptor binding in vivo as compared to raclopride. Preliminary baboon studies showed haloperidol competition for IMB binding sites. © 1992 Wiley‐Liss, Inc.
Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system
Authors: Guitart Xavier , Beitner‐Johnson Dana , Marby David W. , Kosten Therese A. , Nestler Eric J.
Published: December 2004

We studied levels of neurofilament (NF) proteins in the ventral tegmental area (VTA), and other regions of the central nervous system, of two genetically inbred rat strains, Lewis (LEW) and Fischer (F344) rats. These strains represent genetically divergent populations of rats that have been used to study possible genetic factors involved in a variety of biological processes, including drug addiction: compared to F344 rats, LEW rats show a much higher preference for several classes of drugs of abuse. We found 30–50% lower levels of three NF proteins, NF‐200 (NF‐H), NF‐160 (NF‐M), and NF‐68 (NF‐L), in the VTA of LEW compared to F344 rats by use of immunolabeling and Coomassie blue staining. These strain differences were highly specific to this brain region, with no differences observed elsewhere in brain or spinal cord. Interestingly, chronic treatment of F344 rats with morphine decreased levels of these three NF proteins in the VTA, as found previously in outbred Sprague‐Dawley rats (Beitner‐Johnson, D., Guitart, X., and Nestler, E. J.: J. Neurosci., 12:2165–2176,1992), whereas morphine had no effect on NF levels in the VTA of LEW rats. A similar strain difference was observed in chronic morphine regulation of tyrosine hydroxylase, with morphine increasing enzyme immunoreactivity in the VTA of F344 rats (as has been observed previously in Sprague‐Dawley rats [Beitner‐Johnson, D., and Nestler, E. J.: J. Neurochem., 57:344–347, 1991]), but not in LEW rats. In view of the observations that LEW and F344 rats show different levels of preference for several types of drugs of abuse, and of the evidence supporting a central role of the mesolimbic dopamine system in drug reward mechanisms, the results of the current study suggest the possibility that levels of NFs and tyrosine hydroxylase may mediate some aspects of drug reinforcement and contribute to individual genetic differences in vulnerability to drug addiction. © 1992 Wiley‐Liss, Inc.
Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity
Authors: Smith Ian D. , Grace Anthony A.
Published: December 2004

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker‐like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: (1) a 20–50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst‐like pattern, and (2) a short‐latency inhibition lasting 5–25 msec in 75% of non‐DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30–60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two‐fold increase in burst firing 6–14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6–14 minutes. Muscimol‐induced STN inhibition produced complimentary biphasic changes in SN neuron firing: (1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and (2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: (1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and (2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents. © 1992 Wiley‐Liss, Inc.
BMY‐14802, a sigma ligand and potential antipsychotic drug, reverses amphetamine‐induced changes in neostriatal single‐unit activity in freely moving rats
Authors: Wang Zhongrui , Haracz John L. , Rebec George V.
Published: December 2004

The effects of BMY‐14802 (5,10, or 20 mg/kg), a sigma‐receptor ligand showing preclinical evidence of antipsychotic efficacy, were tested on single‐unit activity in the neostriatum of freely moving rats with or without pretreatment with 1.0 mg/kg D‐amphetamine. Relative to resting baseline, amphetamine activated the large majority of neurons that changed firing rate in close temporal association with movement. All doses of BMY‐14802 reversed this neuronal response, but the effect was most pronounced at 20 mg/kg. This dose, however, was equally likely to reverse or to induce a haloperidol‐like potentiation of those neurons inhibited by amphetamine. In contrast, 10 mg/kg BMY‐14802 consistently reversed amphetamine‐induced neuronal inhibitions. All doses of BMY‐14802 attenuated the locomotor effects of amphetamine, but only the higher doses also blocked other aspects of the amphetamine behavioral response. By itself, BMY‐14802 dose dependently inhibited motor‐related neurons, but elicited less behavioral activation than amphetamine. BMY‐14802 (20 mg/kg) also induced hindlimb ataxia and occasional backwards locomotion. Haloperidol (1.0 mg/kg) reliably suppressed both behavior and neuronal activity when injected 30 min after BMY‐14802, whether or not amphetamine pretreatment was given. Thus, BMY‐14802 shares with other neuroleptics the capacity to reverse amphetamine‐induced excitations of neostriatal motor‐related neurons, whereas other effects of BMY‐14802 reveal some haloperidol‐like actions at 20 mg/kg that do not occur at lower doses. © 1992 Wiley‐Liss, Inc.
Glucose regulation of synaptic transmission in the dorsolateral septal nucleus of the rat
Authors: Shoji Shingo
Published: December 2004

Intracellular recordings were made from neurons in the dorsolateral septal nucleus (DLSN) of rat brain slices. Lowering the concentration of extracellular glucose resulted in a concentration‐dependent membrane hyperpolarization associated with a cessation of spontaneous firing. The amplitude of the excitatory postsynaptic potential (EPSP), inhibitory postsynaptic potential (IPSP), and late hyperpolarizing potential (LHP) evoked by a single stimulus applied to the fimbrial/fornix pathway was decreased when the concentration of glucose was reduced to 0–2 mM. Substitution of glucose with 2‐deoxy‐D‐glucose (11 mM), and antimetabolite of glucose substrate, mimicked the effects of glucose depletion. Mannoheptulose (10–20 mM), a potent hexokinase blocker, and dinitrophenol (50 m̈M), a potent inhibitor of oxidative phosphorylation, produced both the hyperpolarization and inhibition of postsynaptic potentials, even in the presence of 11 mM glucose. The sulphonylureas, glibenclamide (10 m̈M) and tolbutamide (1 mM), did not antagonize the hyperpolarization and the inhibition of the postsynaptic potentials produced by glucose deplection. The amplitude of membrane depolarizations produced by pressure application of glutamate (10 mM) and the membrane hyperpolarizations produced by pressure application of either muscimol (1 mM) or baclofen (1 mM) were almost unchanged, even when glucose was reduced to 1–2 mM. These results indicate that intracellular glucose metabolism regulates the function of septal neurons, not only by changing the resting membrane potential, but also by presynaptically affecting neurotransmission between the hippocampal formation and the lateral septum. © 1992 Wiley‐Liss, Inc.
Effects of trifluoperazine on synaptically evoked potentials and membrane properties of CA1 pyramidal neurons of rat hippocampus in situ and in vitro
Authors: Agopyan N. , Krnjević K.
Published: December 2004

The effects of trifluoperazine (TFP), a phenothiazine antipsychotic, on hippocampal activity were studied in the CA1 subfield, both in situ and in slices. In the extracellular studies in situ and in vitro, both somatic population spikes and dendritic excitatory postsynaptic potentials (EPSP) fields were depressed reversibly by TFP, applied by microiontophoresis or in the bath (50‐100 μM). Similar effects were also seen during iontophoretic applications of sphingosine in situ. Like TFP (at micromolar concentrations) sphingosine is a dual Ca2+/calmodulin‐dependent kinase and protein kinase C (PKC) inhibitor. In intracellular recordings from slices, 50‐100 μM TFP induced a slow depolarization and a decrease in input resistance (RN), probably through a β‐aminobutyric acid (GABA)‐mediated increase in Cl− conductance (GCl). TFP also reduced the slow afterhyperpolarization (AHP) as well as electrically evoked inhibitory postsynaptic potentials (IPSPs), but EPSPs were augmented in both amplitude and duration. When CA1 neurons were voltage clamped, TFP elicited a corresponding inward current (consistent with depolarization), increased the leak conductance, and enhanced excitatory synaptic currents; whereas inhibitory synaptic currents and high‐threshold Ca2+ currents were reduced. In conclusion, these effects of TFP–which cannot be readily explained by its potent antidopamine action–are in keeping with other evidence that both Ca2+/calmodulin‐dependent kinase and PKC can modulate GCl‐conductance and high‐threshold Ca2+ ‐conductance, as well as inhibitory and excitatory postsynaptic currents. © 1993 Wiley‐Liss, Inc.
The cytochromes P‐450 are not involved in the modulation of the N‐methyl‐D‐aspartate response by sigma ligands in the rat CA3 dorsal hippocampus
Authors: Monnet Françlois P. , Debonnel Guy , de Montigny Claude
Published: December 2004

Recent in vitro radioligand binding studies have shown that several cytochrome P‐450 inhibitors can displace [3H] sigma ligands, suggesting that these ligands might bind to the cytochrome P‐450 superfamily of enzymes. Using an in vivo electrophysiological model of extracellular recordings performed in the CA3 region of the rat dorsal hippocampus, we have previously shown that intravenous administration of low doses of several sigma ligands, such as 1, 3‐di(2‐tolyl) guanidine (DTG), JO‐1784, and (+)pentazocine potentiate the neuronal response induced by microiontophoretic applications of N‐methyl‐D‐aspartate (NMDA) without affecting those induced by quisqualate and kainate, suggesting that they act as sigma agonists. Conversely, the sigma ligands haloperidol, (+)3‐PPP, and BMY‐14802, which have no effect by themselves on the NMDA response, prevent and suppress the potentiating effect of sigma agonists on the NMDA response, suggesting that they act as sigma antagonists. The present studies were undertaken to determine if cytochromes P‐450 could be involved in the modulation of the NMDA response by sigma ligands. For this purpose, two cytochrome P‐450 inhibitors, proadifen (SKF‐525A) and piperonyl butoxide (PB), have been tested in our model.

Unlike sigma agonists, at low doses, neither SKF‐525A nor PB affected the NMDA response of CA3 dorsal hippocampus pyramidal neurons. Unlike sigma antagonists, neither of these drugs reversed or prevented the DTG‐induced potentiation of the NMDA response. In addition, following high doses of SKF‐525A or PB, sufficient to induce a complete inactivation of cytochromes P‐450, DTG still potentiated the NMDA response.

The present data suggest that cytochrome P‐450 inhibitors do not modulate the NMDA response like sigma agonists or antagonists do in this brain region. Furthermore, they rule out the involvement of cytochromes P‐450 in the modulation of the NMDA response by sigma ligands. © 1993 Wiley‐Liss, Inc.
Morphological and electrophysiological evidence for electrotonic coupling of rat dorsolateral septal nucleus neurons in vitro
Authors: Phelan Kevin D. , Twery Michael J. , Gallagher Joel P.
Published: December 2004

Intracellular injections of Lucifer Yellow were utilized to evaluate the incidence of dye‐coupling among dorsolateral septal nucleus (DLSN) neurons recorded from slice preparations of adult rat septal nuclei. Twenty percent of single injections of Lucifer Yellow resulted in pairs of labeled neurons. These dye‐coupled cells were morphologically heterogeneous and did not exhibit any morphological characteristics that could be used to distinguish them from non dye‐coupled neurons. The spatial separation of cell bodies and close apposition of dendrites within each pair indicated that the dye transfer site(s) were situated at dendrodendritic and/or dendrosomatic rather than somatosomatic junctions. The main axon of some dye‐coupled neurons gave rise to intrinsic axon collaterals prior to exiting the nucleus indicating that these coupled neurons function as projection neurons as well as local circuit interneurons.

Electrophysiological recordings of the passive membrane properties and spontaneous activity of individual dye‐coupled neurons revealed no significant difference from non dye‐coupled cells in the DLSN. Some neurons exhibited spontaneously occurring fast potentials which presumably represent electrotonic potentials. These fast potentials were often tightly coupled with action potentials but could be distinguished from synaptic potentials by their shape and their lack of voltage‐dependent changes in amplitude.

These morphological and supportive electrophysiological data provide the first indirect evidence for electrotonic coupling of dorsolateral septal neurons. The functional significance of this coupling may lie in the potential for synchronization of the output of the DLSN which could play an important role in the septal maintenance and modulation of hippocampal Theta rhythm. © 1993 Wiley‐Liss, Inc.
Calcium‐dependent serine phosphorylation of synaptophysin
Authors: Rubenstein James L. , Greengard Paul , Czernik Andrew J.
Published: December 2004

The phosphorylation of synaptophysin, a major integral membrane protein of small synaptic vesicles, was found to be regulated in a Ca2+ ‐dependent manner in rat cerebrocortical slices, synaptosome preparations, and highly purified synaptic vesicles isolated from rat forebrain. K+‐induced depolarization of slices and synaptosomes prelabeled with 32P‐orthophosphate produced a rapid, transient increase in serine phosphorylation of synaptophysin. In synaptosomes, the depolarization‐dependent increase in synaptophysin phosphorylation required the presence of external Ca2+ in the incubation medium. The addition of Ca2+ plus calmodulin to purified synaptic vesicles resulted in a 4‐fold increase in serine phosphorylation of synaptophysin, and this phosphorylation was antagonized by a peptide inhibitor of Ca2+/calmodulin‐dependent protein kinase II (CaM kinase II). Purified rat forebrain CaM kinase II phosphorylated both purified synaptophysin and endogenous, vesicle‐associated synaptophysin, and the resulting 2‐dimensional chymotryptic phosphopeptide maps were similar to those derived from synaptophysin phosphorylated in cerebrocortical slices. These data demonstrate that Ca2+‐dependent phosphorylation of synaptophysin, mediated by CaM kinase II, occurs under physiological conditions. © 1993 Wiley‐Liss, Inc.
Long‐term potentiation in the avian hippocampus does not require activation of the N‐methyl‐D‐aspartate (NMDA) receptor
Authors: Wieraszko Andrzej , Ball Gregory F.
Published: December 2004

Evoked potentials recorded from slices of pigeon hippocampus were reversibly attenuated by 2 mM kynurenic acid. High frequency stimulation (3 × 200 Hz for 1 sec, with 1 sec intervals) evoked a persistent increase in the evoked potential, lasting in a nondecremental form for at least 2 hr. This increase in the magnitude of the potential was not blocked by antagonists of the NMDA receptor (APV and MK‐801). These data suggest that the synaptic facilitation observed in the pigeon hippocampus, which appears to be a form of long‐term potentiation, does not depend on the activation of NMDA receptors. © 1993 Wiley‐Liss, Inc.
Beta‐adrenergic receptors in the hippocampal and retrohippocampal regions of rats and guinea pigs: Autoradiographic and immunohistochemical studies
Authors: Booze Rosemarie M. , Crisostomo Edgardo A. , Davis James N.
Published: December 2004

Species differences in the distribution of β‐adrenergic receptors in the hippocampal and retrohippocampal regions of rats and guinea pigs were examined using in vitro autoradiographic techniques. β1‐receptors were found in the hippocampal area CA1 of both species, although guinea pigs had significantly lower receptor densities in comparison to rats. In guinea pigs, β2‐adrenergic receptors were predominant in hippocmpal area CA1. Hippocampal area CA3 had very low levels of β1‐ and β2‐receptors in both species. The retrohippocampal area was also found to have a distinct topographic distribution of β‐receptors. In rats, the subiculum and parasubiculum (layers II‐III) were heavily labeled for β1‐receptors; in contrast, guinea pigs had few receptors in these regions. β2‐receptors were particularly prominent in the parasubicular region in rats. The entorhinal cortex laminae was found to contain β‐receptors in both rats and guinea pigs. Immunohistochemical techniques were used to compare the pattern of catecholaminergic innervation with the receptor distribution within each hippocampal subregion. Despite the general lack of β‐receptors in area CA3, abundant catecholamine immunoreactive fibers were observed in CA3 of rat and guinea pig hippocampus. Significant species differences were found in the distribution of hippocampal β‐adrenergic receptor subtypes, and moreover, in both species the distribution of hippocampal β‐adrenergic receptors did not coincide with the pattern of hippocampal adrenergic innervation. © 1993 Wiley‐Liss, Inc.
Repeated administration of Sigma ligands alters the population activity of rat midbrain dopaminergic neurons
Authors: Zhang Jing , Chiodo Louis A. , Wettstein Joseph G. , Junien Jean‐Louis , Freeman Arthur S.
Published: December 2004

Acute and repeated administration of antipsychotic drugs produce distinctive profiles of electrophysiological effects on the population activity of midbrain dopaminergic (DA) neurons which correlate with their clinical effects. Sigma receptors have been hypothesized to be involved in psychosis and in the efficacy of antipsychotic drugs, but little is known about the effects of repeated treatment with sigma ligands on the activity of midbrain DA neuronal populations. In the present study, the cells‐pertrack cell‐sampling method was used to evaluate the effects of 3 sigma ligands on the numbers of spontaneously active A9 and A10 DA neurons in chloral hydrate‐anesthetized rats. One‐hour pretreatment with either (+)‐pentazocine (10 mg/kg, i.p.), DTG (2 mg/kg, i.p.), or JO 1784 (1 or 10 mg/kg, s.c.) did not alter the number of spontaneously active DA neurons encountered per electrode track. Repeated treatment (21 daily injections) with (+)‐pentazocine (1 or 10 mg/kg) or DTG (0.2 or 2 mg/kg) increased the number of A10 DA cells per track; JO 1784 (10 mg/kg but not 1 mg/kg) moderately decreased the number of active A9 DA cells and increased the firing rate of A10 DA neurons. The effect of JO 1784 on A9 DA neurons was not due to depolarization inactivation. The effects of all 3 sigma ligands differ from those of antipsychotic drugs, all of which inactivate A10 DA neurons after repeated treatment. Clinical studies are necessary to determine if selective sigma ligands will provide a novel alternative to DA antagonists in the treatment of psychosis. © 1993 Wiley‐Liss, Inc.
In utero methamphetamine effects: I. Behavior and monoamine uptake sites in adult offspring
Authors: Weissman Arthur D. , Caldecott‐Hazard Sally
Published: December 2004

Chronic in utero methamphetamine treatment, throughout gestation in rats, resulted in alterations in both behavior and brain monoamine function in the adult offspring. The higher dose of methamphetamine (10 mg/kg/b.i.d.) caused a significant decrease in square crossing and rearing in an open field, as well as a region increase of serotonin and dopamine uptake sites. In contrast, the lower dose of in utero methamphetamine (2 mg/kg/b.i.d.) resulted in a significant decrease in regional densities of serotonin and dopamine uptake sites, and only decreased rearing behavior. Across treatment groups, there were significant correlations between open‐field square crossing activity and the number of uptake sites in specific brain areas. Other measured behaviors, such as the neonate righting reflex and the adult Morris water maze performance, were unaffected by either in utero drug regimen. These results are discussed in terms of the known neurotoxicity of amphetamines and the ability of the immature nervous system to compensate for fetal exposure to methamphetamine. © 1993 Wiley‐Liss, Inc.
Selective induction of Fos and FRA immunoreactivity within the mesolimbic and mesostriatal dopamine terminal fields
Authors: Dilts Roger P. , Helton Todd E. , McGinty Jaqueline F.
Published: December 2004

The influence of the mesencephalic dopaminergic projections on the neurons within the basal forebrain and prefrontal cortex is not well understood although it has been intensely investigated. The purpose of this study was to evaluate the expression of Fos‐like and FRA‐like (Fos Related Antigens) immunoreactivity (IR) as a qualitative and quantitative marker of neuronal activity within the mesolimbic and mesostriatal dopamine terminal fields. Following the administration of apomorphine (5.0 mg/kg S.C.), a rapid increase in FRA‐IR, accompanied by Fos‐IR, was observed within the striatum in a patchy distribution. Apomorphine also induced the expression of FRA‐IR within the nucleus accumbens, cortex, septum, and the islands of Calleja complex. This broad pattern of activation contrasts with the limited expression of Fos‐IR and FRA‐IR within the dorsolateral striatum, dorsomedial shell of the nucleus accumbens, and cingulate cortex following haloperidol administration (2.0 mg/kg, S.C.). Finally, it was observed that nuclei expressed Fos‐IR rapidly and transiently within the striatum following haloperidol, whereas the number of FRA‐IR nuclei remained elevated but changed in distribution and intensity over time. In conclusion, different regions within the dopamine terminal fields express varying concentrations of Fos‐IR and FRA‐IR after stimulation or blockade of dopamine receptors. These data indicate that Fos, as well as selective FRAs, can be used to delineate populations of neurons with altered metabolic activity resulting from the administration of dopaminergic agents. Furthermore, the data support the concept of segregated mesostriatal and mesolimbic projections, in particular the divison of the nucleus accumbens into the shell and core compartments. © 1993 Wiley‐Liss, Inc.
Electrophysiological evidence for the existence of NMDA and non‐NMDA receptors on rat ventral tegmental dopamine neurons
Authors: Wang Ting , French Edward D.
Published: December 2004

In vitro extracellular single‐unit recordings from rat midbrain slices were used to assess the effects of excitatory amino acid agonists on the activity of A10 dopamine neurons. N‐methyl‐D‐aspartic acid (NMDA), kainic acid (KA), and β‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) elicited dose‐dependent increases in firing rates. The relative potencies for the 3 compounds was AMPA > KA > NMDA. None of the excitations was accompained by burst firing, but frequently periods of nonrecordable activity occurred following pronounced stimulation. Concurrent application of the excitatory amino acid antagonist CGS 19755 (cis‐4‐phosphonomethyl‐2‐piperidine carboxylate) selectively blocked the excitations elicited by NMDA but not by KA or AMPA. Likewise the selective non‐NMDA antagonist NBQX [2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(F)quinoxaline] blocked only the excitatory effects of AMPA and KA but not those elicited by NMDA. NBQX appeared to be less optent at antagonizing KA than AMPA. These results suggest that mesolimbic‐mesocortical dopamine neurons possess both NMDA and non‐NMDA receptors, and possibly distinct AMPA and KA recognition sites. © 1993 Wiley‐Liss, Inc.