bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of injury on the bi‐affinity α1‐adrenoreceptor binding in rat brain in vivo
Authors: Dyve Suzan , Yang Yu‐Jia , McHugh Michael , Gjedde Albert , Pappius Hanna M.
Published: December 2004

Focal freezing lesions in rats cause a widespread decrease of cortical glucose utilization in the lesioned hemisphere, probably as a reflection of depressed cortical activity. The noradrenergic neurotransmitter system was implicated in these alterations when it was demonstrated that prazosin, a specific norepinephrine (NE) antagonist at β1‐adrenergic receptors, prevented their development. In normal rat brain, specific binding of [125I]HEAT [(±)2‐(3‐[125I]iodo‐4‐hydroxyphenyl)‐ethyl‐aminomethyltetralone], another selective α1‐adrenoreceptor ligand, was demonstrated in vivo at sites consistent with the α1A‐ and α1B‐adrenoreceptor subtypes. In the present study, the effect of a freezing lesion on specific binding of [125I]HEAT in rat brain in vivo was determined three days after traumatization when cortical glucose use suggested the greatest degree of functional depression. The steady‐state volumes of distribution of [125I]HEAT three days after injury were significantly increased in all the cortical areas of the lesioned hemisphere, but not in the subcortical structures. Injury did not modify the binding affinities for HEAT. However, a statistically significant increase in the number of low‐affinity binding sites for this ligand was demonstrated in all cortical areas of the lesioned hemisphere, but not in subcortical structures. The traumatization did not modify Bmax. estimates for the high‐affinity binding of HEAT. The results support the hypothesis that changes in the noradrenergic system are of functional importance in brain injury and that at least some effects of injury are mediated by α1B‐adrenergic receptors. © 1995 Wiley‐Liss, Inc.
Protective effects of MK‐801 on methamphetamine‐induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: An immunohistochemical study
Authors: Pu Cunfeng , Vorhees Charles V.
Published: December 2004

It has been shown previously that methamphetamine induces dopaminergic nerve terminal degeneration, serotonin depletion and striatal reactive astrogliosis, and that the noncompetitive N‐methyl‐D‐aspartate (NMDA) antagonist MK‐801 can block methamphetamine (MA)‐induced depletion of dopamine and serotonin and reduction in activity of their synthetic enzymes. In this study, immunohistochemistry was used to evaluate the effect of MK‐801 on methamphetamine‐induced neuropathological alterations of dopaminergic and serotonergic terminals and striatal astrocytic responses. Adult male rats were treated with methamphetamine (4 injections of 10 mg/kg at 2 hour intervals) in conjunction with MK‐801 which was administered 15 min before each methamphetamine administration at doses of 1 mg/kg or 2 mg/kg. Brains were examined three days following treatment. MK‐801 administration prevented methamphetamine‐induced depletion of 5‐hydroxytryptophan (5‐HT) terminals in the forebrain and depletion of tyrosine hydroxylase‐positive dopaminergic terminals and astrocytic response in the neostriatum in most animals. These results support the concept that excitatory amino acids acting through an NMDA receptor are involved in methamphetamine‐induced neuronal damage on dopaminergic and serotonergic terminal fields. A minor depletion of TH‐positive terminals and astrogliosis in the neostriatum was seen in three of nine MA‐MK‐801‐treated animals. This indicates that the protective effects of MK‐801 on MA‐induced dopaminergic terminal degeneration varies among animals with complete protection in most animals and partial protection in the others using the present doses and dosing regimen. © 1995 Wiley‐Liss, Inc.
6β‐[125Iodo]‐3, 14‐dihydroxy‐17‐methyl‐4, 5α‐epoxymorphinan ([125I]IOXY‐AGO): A potent and selective radioligand for opioid μ receptors
Authors: Xu Heng , Goodman Carl B. , Partilla John S. , Ni Qi , Kayakiri Hiroshi , Rice Kenner C. , Rothman Richard B.
Published: December 2004

The recent cloning and expression of an opioid μ receptor has opened up new opportunities for research in opioid pharmacology. The relatively low level of transient receptor expression in COS cells emphasizes the need for radioligands with high specific activity and low nonspecific binding with which to label receptors. In addition, recent data indicating that agonists and antagonists bind to different domains on the same receptor protein indicate the utility of having both agonist and antagonist radioligands available for the study of opioid receptor mechanisms. Previous studies characterized the binding of the. opioid antagonist 6β‐[125iodo]‐3,14‐dihydroxy‐17‐cyclopropylmethyl‐4,5α‐epoxymorphinan ([125I]IOXY) and showed that this naltrexone analog labels μ and K2 receptors in rat and guinea pig brain with high affinity and low nonspecific binding. In the present study, we synthesized the agonist congener of IOXY, 6β‐iodo‐3,14‐dihydroxy‐17‐methyl‐4,5α‐epoxymorphinan. We named this novel agent IOXY‐AGO for IOXY‐agonist. Competition binding studies showed that IOXY‐AGO has high affinity for δ receptors (Ki = 0.28 nM) and lower affinity for δ (Ki = 18.7 nM) and K1 (Ki = 33.9 nM), K2a (Ki = 38.4 nM) and K2b (Ki = 58.2 nM) binding sites. IOXY‐AGO was radioiodinated to a specific activity of 2,200 Ci/mmol. [125I]IOXY‐AGO binding was rapid, readily reversible, and characterized by low nonspecific binding. Equilibrium binding studies showed that it labeled a single class of binding sites (Kd = 1.46 nM, Bmax = 112 fmol/mg protein) with the characteristics of an opioid μ receptor. Receptor autoradiography experiments showed that [125I]IOXY‐AGO labeled binding sites with the anatomical distribution of μ receptors. Viewed collectively, these studies suggest that [125I]IOXY‐AGO will be a useful radioligand for characterizing opioid μ receptors. © 1995 Wiley‐Liss, Inc.
Anatomical localization of SKF‐38393‐induced behaviors in rats using the irreversible monoamine receptor antagonist EEDQ
Authors: Neisewander Janet L. , Ong Alvin , McGonigle Paul
Published: December 2004

This study was designed to localize the population of dopamine D1‐like receptors involved in grooming and oral movements elicited by systemic administration of the Dl‐selective agonist SKF‐38393. Receptors in specific dopamine terminal regions were inactivated by intracranial injection of the nonselective irreversible antagonist N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ). The effect of these injections on behaviors induced by systemic administration of SKF‐38393 (10 mg/kg) was measured 48 hours later. The specific populations of D1‐like receptors inactivated by the EEDQ injections were identified as a loss of 3H‐SCH‐23390 binding in a given region using quantitative autoradiography. EEDQ (1.5 μg/μl/side) injected into the nucleus accumbens (NAc) did not alter SKF‐38393‐induced behaviors. Similarly, injection of EEDQ into the medial caudate‐putamen (CPu) failed to alter these behaviors. In contrast, EEDQ (0.15‐1.5 μg/μl/side) injected into the lateral CPu decreased both SKF‐38393‐induced grooming and oral movements, with complete blockade of grooming observed at the highest dose. To determine whether this effect of EEDQ was due to inactivation of Dl‐like receptors, separate groups of animals were pretreated with SCH‐23390 (3 mg/kg, S.C.) 15 min prior to injection with EEDQ. Pretreatment with SCH‐23390 prevented the disruption of SKF‐38393‐induced behaviors, as well as the loss of 3H‐SCH‐23390‐labeled binding sites observed after injection of EEDQ into the lateral CPu. EEDQ injections that produced disruption of SKF‐38393‐induced behaviors were associated with a greater loss of binding in the lateral CPu relative to other regions examined including the NAc, medial CPu, and globus pallidus. Furthermore, EEDQ injections that produced the greatest loss of 3H‐SCH‐23390 binding in the latter three regions did not disrupt SKF‐38393 induced behavior. These results demonstrate that stimulation of Dl‐like receptors in the lateral CPu is necessary for behaviors induced by systemic administration of SKF‐38393. The results also demonstrate the utility of this “receptor lesion” technique to localize receptor‐mediated behaviors. © 1995 Wiley‐Liss, Inc.
Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain
Authors: Hjorth Stephan , Suchowski Camille S. , Galloway Matthew P.
Published: December 2004

To gain further insight into the operation of 5‐HT autoreceptor‐mediated feedback control of 5‐HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5‐HT1B and the 5‐HT1A receptor agonists, TFMPP and 8‐OH‐DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5‐HT synthesis (5‐HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5‐HT synthesissuppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1–10 μM) decreased 5‐HT synthesis under basal and stimulated (30 mM K+) conditions, an effect which was unaltered by prior in vivo reserpine‐induced 5‐HT depletion but was attenuated in the presence of 5‐HT1B receptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8‐OH‐DPAT (0.1 mg/kg, s.c.)‐induced decrease of 5‐HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8‐OH‐DPAT (10 μM) did not decrease 5‐HT synthesis in vitro. In conclusion, the present study confirms the importance of 5‐HT autoreceptors in the feedback control of nerve terminal 5‐HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5‐HT synthesis after TFMPP is mediated by 5‐HT1B autoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5‐HT neuronal firing and intact monoamine stores. © 1995 Wiley‐Liss, Inc.
Functional diversity of GABAA receptor ligand‐gated chloride channels in rat synaptoneurosomes
Authors: Ito Yoshihisa , Segawa Katsuya , Fukuda Hideomi
Published: December 2004

Experiments were performed to examine neurochemically the functional diversity of GABAA receptors as measured by muscimol‐, 5α‐pregnane‐3α,21‐diol‐20‐one (THDOC)‐, and pentobarbital‐stimulated 36C1− uptake, and region‐specific changes in muscimol THDOC‐ and THDOC‐induced potentiation of muscimol‐stimulated 36CI– uptake in rats treated acutely or subacutely with a subconvulsive dose of bicuculline. The data, for stimulation of 36C1– uptake by muscimol showed a single binding site interaction in the cerebral cortex, hippocampus and cerebellum. The concentration‐response curves for muscimol in the cerebral cortex and hippocampus were steep and indicated an increase of, approximately 130% at the maximum concentration. In contrast, the curve for the cerebellum was shallow and, exhibited a smaller maximal response (∽60%). Apparent affinity for muscimol also differed among these brain regions. The regional differences in 36CI– uptake induced by THDOC and pentobarbital were not as apparent as those induced by muscimol; however, the maximal modulatory effect of pentobarbital, in the hippocampus was significantly higher than that in the cerebellum. In rats treated subacutely with a subconvulsive dose of bicuculline, a significant increase in muscimol‐stimulated 36C1‐ uptake was observed in the cerebellum but not in the frontal cortex or hippocampus. Analysis of the concentration‐response curves for muscimol‐stimulated 36CI− uptake in the cerebellum revealed that the Vmax for muscimol in the subacutely treated group was significantly higher than those for muscimol in the control and acutely treated groups without any differences in the KD value. In addition, THDOC‐induced potentiation of muscimol‐stimulated 36CI− uptake in the subacutely treated group was significantly higher than those in the control and acutely treated groups when a lower concentration (10 nM) of THDOC was used. These results suggest that regional variation of 36C1− uptake stimulated by muscimol is more apparent than those stimulated by THDOC and pentobarbital. The present results, along with our previous findings, also indicate that region‐specific bicuculline up‐regulation of GABAA receptors in the cerebellum involves changes not only in binding characteristics but also in function of GABA receptor‐gated chloride channel. © 1995 Wiley‐Liss, Inc.
Lack of effect of chronic morphine treatment and naloxone‐precipitated withdrawal on tyrosine hydroxylase, galanin, and neuropeptide Y mRNA levels in the rat locus coeruleus
Authors: Holmes Philip V. , de Bartolomeis Andrea , Koprivica Vuk , Crawley Jacqueline N.
Published: December 2004

Morphine dependence was experimentally induced in rats by daily injection of increasing doses of morphine for seven days. Withdrawal was precipitated in half of the morphine‐dependent rats by a single injection of naloxone on day 8. Behavioral signs of withdrawal weret evident in the morphine/naloxone group. Gene expression in locus coeruleus (LC) neurons was investigated using quantitative in situ hybridization analysis. Messenger RNA (mRNA) levels for tyrosine hydroxylase (TH), the rate‐limiting enzyme in catecholamine synthesis, and for precursors to galanin (GAL) and neuropep tide Y (NPY), peptides that coexist with norepinephrine in LC neurons, were not altered by chronic morphine treatment or naloxone‐precipitated withdrawal. In contrast, mRNA levels for c fos were dramatically elevated in the LC following naloxone‐precipitated withdrawal. Chronic morphine treatment caused a small decrease in levels of mRNA encoding the precursor to corticotropin‐releasing factor (CRF) in Barrington's nucleus. Although long‐term adaptations of LC neurons have previously been implicated in the development of morphine tolerance, dependence, and withdrawal, alterations in the levels of TH, GAL, or NPY mRNA in the LC apparently do not underlie this process. © 1995 Wiley‐Liss, Inc.
Lipophilic metabolite of [123I]β‐CIT in human plasma may obstruct quantitation of the dopamine transporter
Authors: Bergström Kim A. , Halldin Christer , Kuikka Jyrki T. , Swahn Carl‐Gunnar , Tiihonen Jari , Hiltunen Jukka , Länsimies Esko , Farde Lars
Published: December 2004

I‐123 or C‐11 labelled 2β‐carbomethoxy‐3β‐(4‐iodophenyl)tropane (β‐CIT) is a recently developed radioligand for the study of dopamine and serotonin reuptake sites in humans with single photon emission tomography (SPET) or positron emission tomography (PET). Determination of the radioligand metabolite pattern is fundamental for a quantitative analysis of radioligand binding. The metabolism of [123I]β‐CIT was determined by a gradient HPLC method in plasma samples of six human subjects. Two metabolites of [123I]β‐CIT were found, a polar and a lipophilic. At 4 h after [123I]β‐CIT injection the percentages of parent compound and polar and lipophilic metabolites were 23 ± 3% (mean ± SD), 33 ± 11%, and 44 ± 8%, respectively. The lipophilic metabolite might pass the blood‐brain barrier and account for a fraction of free and nonspecifically bound radioactivity in brain. The existence of a lipophilic metabolite of [123I]β‐CIT may obstruct the use of simple ratio methods for quantitation of the dopamine transporter in brain. © 1995 Wiley‐Liss, Inc.
Effect of destruction of serotonin neurons on basal and fenfluramine‐induced serotonin release in striatum
Authors: Kirby Lynn G. , Kreiss Deborah S. , Singh Ashish , Lucki Irwin
Published: December 2004

This study examined the relationship between the magnitude of tissue serotonin (5‐HT)depletion produced by treatment with the neurotoxin 5,7‐dihydroxytryptamine (5,7) and basal and fenfluramine‐induced 5‐HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7‐DHT (100μ 76% striatal 5‐HT depletion; or 200μ 93% styriatal 5‐HT depletion). four weeks after treatment 5‐HT release was measured in the ventral striatum using in vivo microdialysis in animals anesthetized with chloral hydrate. Basal 5‐HT levels were not significantly altered in any lesion group, whereas basal 5‐hydroxyindoleacetic acid levels were dosedependently reduced by 5,7‐DHT. In contrast, the increase of 5‐HT release produced by fenfluramine treatement (10 mg/kg) wa diminished significantly after 5‐HT neuronal destruction in correlation with the reduction of striatal tissue 5‐HT content. Fractional 5‐HT efflux, a measure of the 5‐HT release from surviving striatal nerve terminals, was also significantly elevated when tissue depletion of 5‐HT exceeded 95%. This study suggests that compensatory mechanisms may enable surviving 5‐HT terminals to maintain basal 5‐HT levels in th striatum with as little as 5% of the terminals remaining, but those mechanisms are not sufficient to allow the damaged system to respond to a pharmacological challenge. © 1995 Wiley‐Liss, Inc.
Brain somatostatin receptors in a rat model of acute liver failure
Authors: Boyano‐Adánez Maria Del Carmen , Barrios Vicente , Afulla Eduardo
Published: December 2004

The present study examines the effect of acute liver failure induced by a single intraperitoneal (i.p.) injection of D‐galactosamine‐HC1(3 gkg) on somatostatin (SS) binding and levels in the rat frontoparietal cortex and hippocampus. Neurobehavioural changes were evaluated by the method of Zieve et al. (1984)J. Lab. Clin. Med., 1046554641.The rats were decapitated as soon as they reached neurobehavioural stage I or 11. In stage I, rats had lethargy and in stage I1 they showed mild ataxia, mainly in the hind limbs. The administration of D‐galactosamine elevated serum transaminase levels (mean peak level 2,242 IU/1) but hypoglycemia, gross cerebral edema, or signs of sepsis were not detected in any of the animals studied. In addition, D‐galactosamine did not affect somatostatin‐like immunoreactivity (SSLI) levels in either brain area in any of the experimental groups as compared to the control groups. The rats sacrificed in stage I showed no change in the number or affinity of specific 125I‐Tyr11‐somatostatin(125I‐Tyr11‐SS)receptors in synaptosomes from the frontoparietal cortex and hippocampus. The rats sacrificed in stage II showed a decrease in the number of specific 125I‐Tyr11‐SS receptors in synaptosomes from both brain areas, with no change in receptor affinity. Binding studies were also conducted on synaptosomes from the frontoparietal cortex and hippocampus of rats that received D‐galactosamine but did not develop acute liver failure and consequently did not develop neurobehavioural changes. The SS receptors in these synaptosomes did not change in comparison with controls, indicating that the D‐galactosamine was not directly responsible for the changes in the cerebral SS receptors. SS caused a significantly lower inhibition in AC activity in frontoparietal cortex and hippocampal membranes of D‐galactosamine‐treated rats sacrificed in stage II. No significant differences were seen for the basal or for the forskolin (FK)‐stimulated AC activities in all groups. The results of this study indicate that D‐galactosamine‐induced acute liver failure in rats is associated with a decrease of the number of SS receptors and the inhibitory effect of SS on adenylyl cyclase (AC) activity in frontoparietal cortex and hippocampus when the animals showed neurobehavioural stage II from Zieve et al. [(1984)J. Lab. Clin. Med., 104:655‐664]. © 1995 Wiley‐Liss, Inc.
Biochemical and electrophysiological effects of 7‐OH‐DPAT on the mesolimbic dopaminergic system
Authors: Devoto Paola , Collu Maria , Muntoni Anna Lisa , Pistis Marco , Serra Gino , Gessa Gian Luigi , Diana Marco
Published: December 2004

Systemic administration of the putative selective D3 receptor agonist 7‐hydroxy‐2‐(N, N‐di‐n‐propylamino)tetralin(7‐OH‐DPAT) consistently decreased extracellular dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and dopaminergic neuronal activity in the ventral tegmental area. 7‐OH‐DPAT inhibited dopamine release in the nucleus accumbens also when locally perfused through the dialysis probe. The results suggest the possibility that stimulation of dopamine D2 receptors with 7‐OH‐DPAT mimic biochemical and electrophysiological actions previously ascribed to D2 autoreceptor stimulation; however the lack of selective D3 antagonist precludes any firm conclusion in this sense. © 1995 Wiley‐Liss, Inc.
Neuroprotective sigma ligands interfere with the glutamate‐activated NOS pathway in hippocampal cell culture
Authors: Lesage Anne S. , De Loore Katrien L. , Peeters Luc , Leysen Josee E.
Published: December 2004

We studied neuroprotective properties of 12 structurally different sigma site ligands in primary rat hippocampal cell cultures and analyzed whether they interfere with glutamate‐induced activation of the nitric oxide synthase (NOS) pathway. Neurotoxicity was triggered with 1mM glutamate on day 8 of culture. Cells were treated with various concentrations of the compounds for 7 days before glutamate exposure (prolonged pretreatment), or during glutamate exposure (acute treatment). Protection was seen after prolonged pretreatment (long‐term protection) with sabeluzole, opipramole, haloperidol, ifenprodil, fenpropimorph, carbetapentane, and tiospirone, with pIC50S of 7.30, 7.15, 6.87, 6.68, 6.66, 6.39, and 6.34, respectively. There was no protection with PD 128298, 1,3‐ortho‐di‐tolylguanidine, BMY‐14802, (+)3‐(3‐hydroxyphenyl)‐N‐l(propy1) piperidine, or dextromethorphan. Upon acute treatment, only ifenprodil was protective. Interference of the drugs with glutamate activation of the NOS pathway was determined by measuring glutamate‐activated cGMP formation and citrulline levels. Glutamate‐activated cGMP formation was reduced by all neuroprotective sigma ligands after prolonged pretreatment but not after acute treatment. Sigma ligands added to cell culture iysate did not reduce citrulline formation, evidence that there was no direct effect on the NOS enzyme. We conclude that some but not all sigma ligands exert long‐term protective properties against glutamate‐induced neurotoxicity in primary hippocampal cultures, and that this protection is accompanied by attenuation of cGMP formation in the NOS pathway. However, inhibition of cGMP formation by itself appeared not sufficient for obtaining neuroprotective effects, as inhibition of glutamate‐activated cGMP formation by N‐nitro‐L‐arginine, haemoglobin, or PD128298 did not provide neuroprotection. © 1995 Wiley‐Liss, Inc.
Neuropharmacology of the nucleus accumbens: Iontophoretic applications of morphine and nicotine have contrasting effects on single‐unit responses evoked by ventral pallidal and fimbria stimulation
Authors: Hakan R. L. , Eyl C.
Published: December 2004

Extracellular recordings within the nucleus accumbens (NAS) of halothane anesthetized rats have revealed that iontophoretically applied morphine and nicotine have contrasting effects on neuronal responses evoked by fimbria or VP stimulation. Iontophoretically applied morphine inhibited NAS single‐unit responses evoked by VP stimulation but did not affect unit responses evoked by fimbria stimulation. In contrast, iontophoretically applied nicotine had no effect on NAS single‐unit responses evoked by VP stimulation but inhibited single‐unit responses evoked by fimbria stimulation. Spontaneously active NAS units were inhibited by iontophoretically applied morphine but were unaffected by nicotine.

In addition, experiments were conducted to determine whether NAS unit responses to electrical stimulation of the VP were likely to involve cell body as opposed to axonal activations. Selective cell body stimulation by glutamate microinfusions into the VP region excited spontaneously active VP single‐units. Concurrently recorded NAS unit responses to electrical stimulation of the VP were also excited. These results are consistent with the idea that NAS evoked responses to VP electrical stimulation involve somal activation.

Generally, these results suggest a specific neuropharmacological organization of the NAS. Analysis of the effects of morphine and nicotine on other NAS circuits will establish a systems level understanding of NAS responses to reinforcers. © 1995 Wiley‐Liss, Inc.
Corticosteroid‐mediated modulation of carbachol responsiveness in CA1 pyramidal neurons: A voltage clamp analysis
Authors: Hesen W. , Joëls M.
Published: December 2004

Pyramidal neurons in the rat hippocampal CA1 area contain mineralocorticoid (MRs) and glucocorticoid (GRs) receptors for corticosterone. Previous current clamp experiments showed that depolarizations evoked by carbachol(1–3 μM) depend on relative MR/GR occupation: carbachol responses are small with predominant MR‐activation and larger when both receptor types are occupied. Multiple K‐conductances underlie the carbachol‐induced depolarization. In the present study we used the single electrode voltage clamp technique to examine which K‐conductances modulated by carbachol are sensitive to corticosteroid treatment in vitro. We observed that 1 μM carbachol significantly reduced the IK, Leak while the IM was hardly affected; carbachol effects on the IK, Leak were significantly reduced under conditions of predominant MR activation compared to simultaneous activation of MRs and GRs. With a higher (10 μM) carbachol dose, steroid modulation of the IK, Leak showed a similar tendency. The amplitude of the IM was largely reduced by 10 μM carbachol but appeared to be not affected by steroid treatment. We conclude that the previously described suppression of the carbachol‐induced depolarization with predominant activation MRs is caused by an attenuation of the carbachol action on the IK, Leak. © 1995 Wiley‐Liss, Inc.
Time‐dependent changes in dopamine agonist‐induced striatal fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefkontal cortex injury
Authors: Vargo J. M. , Marshall J. F.
Published: December 2004

This study examined interactions between the corticostriatal glutamatergic system and the nigrostriatal dopaminergic system via immunocytochemical examination of dopamine (DA) agonist induction of the striatal immediate early gene product Fos following cortical injury. After unilateral aspiration of the medial agranular cortex (AGm) region of prefrontal cortex, rats were tested for orientation to visual, tactile, and auditory stimuli. Fos immunoreactivity induced by d‐amphetamine (5 mg/kg) or apomorphine (5 mg/kg) was quantified in dorsolateral and ventrolateral regions of caudate‐putamen (CPu) in rats still demonstrating sensory neglect (5 days postsurgery) and in rats recovered from sensory neglect produced by AGm ablation (29+ days postsurgery). The pattern of immunoreactivity of rats still demonstrating neglect differed from that of unlesioned rats or recovered AGm‐ablated rats. In rats demonstrating sensory neglect, d‐amphetamine or apomorphine induction of Fos in the ipsilateral CPu was reduced by about 40% compared to the contralateral CPu or to comparable readings in unlesioned controls. These asymmetries were restricted to dorsolateral CPu, the region receiving the densest input from AGm. In contrast, recovered AGm‐ablated rats had DA agonist‐induced striatal Fos immunoreactivity that was symmetrical between the two hemispheres and comparable to control values. These findings indicate that adaptations involving the striatal medium spiny neuron, a site of convergence of cortical glutamatergic and nigral dopaminergic afferents, may contribute to recovery from behavioral deficits resulting from neocortical injury. © 1995 Wiley‐Liss, Inc.
In vivo characterization of two cell types in the rat globus pallidus which have opposite responses to dopamine receptor stimulation: Comparison of electrophysiological properties and responses to apomorphine, dizocilpine, and ketamine anesthesia
Authors: Kelland Mark D. , Soltis Robert P. , Anderson Lisa A. , Bergstrom Debra A. , Walters Judith R.
Published: December 2004

Extracellular single‐unit recording techniques were used to examine the rat globus pallidus (GP). In both locally anesthetized, paralyzed rats and ketamine‐anesthetized rats, we observed two distinct biphasic extracellular waveforms, which we have labeled Type I (negative/positive waveform) and Type II (positive/negative waveform). No significant differences were observed in the firing pattern or number of cells per track between these cell types, although the Type II neurons had a faster mean firing rate in the locally anesthetized animals. A portion of both cell types could be antidromically activated from the subthalamic nucleus, although Type II neurons had significantly slower conduction velocities. The most striking pharmacological difference between the two cell types was that Type I GP neurons were inhibited by systemic administration of the dopamine agonist apomorphine; previous studies have repeatedly shown that Type II. GP cells are excited by this treatment. Pretreatment with a subthreshold dose of apomorphine reduced the responsiveness of Type I cells to a subsequent high dose of apomorphine, as has been shown for Type II cells. However, pretreatment with the NMDA antagonist dizocilpine (MK 801) produced a significant change in the pattern of response to apomorphine for Type II GP neurons only. Relative to observations in locally anesthetized, paralyzed rats, ketamine anesthesia reduced the firing rate of both cell types, but did not significantly alter their direction of response to apomorphine. Thus, this study has confirmed the existence of two GP cell types with distinct extracellular waveforms and different responses to dopamine receptor stimulation. These data may necessitate a reevaluation of general theoretical models of basal ganglia function in order to account for these opposite effects of dopamine receptor stimulation on pallidal output. © 1995 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Comparison of the action of the stereoisomers of the psychostimulant 4‐methylaminorex (4‐MAX) on midbrain dopamine cells in the rat: An extracellular single unit study
Authors: Ashby Charles R. , Pan Helen , Minabe Yoshio , Toor Alon , Fishkin Lyle , Wang Rex Y.
Published: December 2004

In this study, we examined and characterized the action of the stereoisomers of 2‐amino‐4‐methyl‐Δ2‐5‐phenyl‐oxazoline (4‐methylaminorex, 4‐MAX) on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10) in anesthetized male rats. This was accomplished using the technique of extracellular single unit recording. The intravenous (i.v.) administration of the stereoisomers of 4‐MAX (0.1−6.4 mg/kg) produced a dosedependent suppression of the basal firing rate of A10 DA cells with the following rank order of potency: trans 4S,5S > cis 4R,5S ≈︁ cis 4S,5R ≫ trans 4S,5S 4‐MAX. The rank order of potency of the isomers of 4‐MAX to suppress the firing of A9 DA cells was trans 4S,5S = cis 4R,5S = cis 4S,5R ≫ trans 4R,5R. The trans 4S,5S isomer was 5‐fold more potent in suppressing DA cell firing in the A10 compared to the A9 area.

The suppressant action of the isomers on A9 and A10 DA cells was reversed by the i.v. administration of haloperidol and the D2/D3receptor antagonists (−)‐sulpiride and (−)‐eticlopride but not by the D1receptor antagonists SCH 23390 and SCH 39166. In addition, the suppressant action of the trans 4S,5S isomer on A10 DA cells was not antagonized or reversed by the i.v. administration of the receptor antagonists granisetron (5‐HT3), ritanserin (5‐HT2A, C), idazoxan (α2), phentolamine (peripheral α1), (±)‐pindolol (5‐HT1A, Bβ) or prazosin (α1). The pretreatment of animals with either α‐methyl‐p‐tyrosine (AMPT) or reserpine, but not p‐chlorophenylalanine (PCPA), (±)‐fluoxetine or tomoxetine, significantly attenuated the suppression of A10 DA cell firing produced by trans 4S,5S 4‐MAX. Overall, our results suggest that the suppressant action of 4‐MAX on midbrain DA cell firing may be mediated by the release of DA, which subsequently interacts with D2/D3receptors. © 1995 Wiley‐Liss, Inc.
Regulation and functional characterization of a rat recombinant dopamine D3 receptor
Authors: Cox Barbara A. , Rosser Mary P. , Kozlowski Michal R. , Duwe Kevin M. , Neve Rachael L. , Neve Kim A.
Published: December 2004

We stably expressed a rat D3 receptor cDNA in C6glioma cells (C6‐D3 cells), quantifying receptor expression with the radioligands [125I]epidepride (KD= 0.1 nM) and [3H]spiperone (KD= 0.7 nM). As reported previously for D2 receptors, quinpirole induced a 9–16% increase in the rate of extracellular acidification by C6‐D3 cells. The acidification was inhibited by epidepride and by the Na+/H+antiporter inhibitors, amiloride and methylisobutylamiloride, but pertussis toxin treatment had no effect on quinpirole‐induced extracellular acidification. These data suggest that D3 receptor stimulation of Na+/H+exchange in C6glioma cells is not mediated by the pertussis toxinsensitive G proteins, Gior Go. Overnight treatment of C6‐D3 cells with N‐propylnorapomorphine, dopamine, or quinpirole resulted in large concentration‐dependent increases (up to 500%) in the density of D3 receptors on membranes prepared from the cells. Antagonists had smaller, variable effects on the density of D3 receptors in C6‐D3 cells, except for domperidone, which significantly increased the density of D3 receptors. Treatment with pertussis toxin had no effect on the agonist‐induced receptor up‐regulation, indicating that an interaction with pertussis toxin‐sensitive G proteins was not required. Densitometry analysis of Northern blots of RNA prepared from C6‐D3 cells showed no significant N‐propylnorapomorphine‐induced increase in D3 receptor message. Treatment with cycloheximide, however, completely prevented receptor up‐regulation by N‐propylnorapomorphine. Pretreatment of C6‐D2 cells with 1'0 pM DA resulted in a substantial heterologous sensitization, in which isoproterenol‐stimulated adenylyl cyclase activity was enhanced more than twofold. In contrast, isoproterenol‐stimulated enzyme activity was inhibited by greater than 50% in C6‐D3 cells pretreated with dopamine. These results confirm one functional response to activation of D3 receptors and demonstrate that the density of D3 receptors, like D2 receptors, is increased after incubation of intact cells with agonists. © 1995 Wiley‐Liss, Inc.

This article is a US Government work and as such, is in the public domain in the United States of America.
Identification of age‐related changes of dopamine D1‐like receptors in the rat cerebellar cortex
Authors: Ricci Alberto , Zaccheo Damiano , Amenta Francesco
Published: December 2004

The present study was designed to characterize the pharmacological profile of dopamine D1‐like receptors in the rat cerebellar cortex and to assess if these receptor sites undergo age‐related changes. Cerebella of young (3 months), adult (12 months), and old (27 months) male Wistar rats were examined by using radioligand binding techniques and light microscope autoradiography. The non‐selective dopamine D1‐like radioligand [3H]SCH 23390 was specifically bound to sections of rat cerebellum. The findings that dopamine displaced [3H]SCH 23390 binding in the submicromolar range suggest the labelling of a dopamine D5 (or D1B) receptor subtype. The affinity of [3H]SCH 23390 for dopamine D1‐like receptors was similar in the cerebellar cortex of the three animal groups investigated, whereas radioligand binding techniques revealed a gradual age‐related reduction of the density of binding sites. Light microscope autoradiography showed the localization of [3H]SCH 23390 binding sites primarily in the molecular layer and to a lesser extent in the Purkinje neuron layer of the cerebellar cortex. Aging was accompanied by a loss of [3H]SCH 23390 binding sites affecting mainly the molecular layer. The age‐dependent loss of dopamine D1‐like receptors is more pronounced if detected with radioligand binding techniques than with light microscope autoradiography. This suggests that the decrease of dopamine D1‐like receptors observed in aging rat cerebellar cortex may depend in part on changes in the receptor expression and in part on cortico‐cerebellar structural changes. © 1995 Wiley‐Liss, Inc.
Ontogeny of fos protein‐like immunoreactivity in the suprachiasmatic nucleus
Authors: Joyce Myra P. , Barr Gordon A.
Published: December 2004

This study examined the normal development of neuronal activity in the suprachiasmatic nuclei (SCN) of rats between age 3–60 days, using Fos protein‐like immunoreactivity (Fos‐LI) as a marker. At age 3 days, Fos‐positive nuclei are sparsely distributed throughout the SCN. Between age 3–10 days, the density of labeled nuclei increases significantly. Fos‐LI labeling is maximal at 10 days. Between age 10–14 days, the number of labeled nuclei decreases and remains relatively constant thereafter, although the intensity of the reaction product diminishes as the animal matures. By age 60 days, the number of Fos‐LI labeled nuclei in the SCN is substantially decreased and is essentially the same as in the 3‐day‐old rat. The appearance of Fos‐LI nuclei in the SCN during development appears to reflect the development of visual system afferents to the nucleus as well as the development of intrinsic SCN synaptology. © 1995 Wiley‐Liss, Inc.
Effects of the putative antidepressant, ABT 200, on the clearance of exogenous norepinephrine in rat cerebellum
Authors: Cass Wayne A. , Friedema Marilyn N. , DeBernardis John F. , Kerkman Daniel J. , Gerhardt Greg A.
Published: December 2004

ABT 200 [(RR,SS)‐3‐phenyl‐l‐[l′,2′,3′,4′‐tetrahydro‐5′,6′‐methylenedi‐ oxy‐1′‐naphthalenyl‐methyl]‐pyrrolidine methanesulfonate] is a potent alpha2‐adrenoceptor antagonist (Ki = 1.2 nM) with modest norepinephrine uptake‐blocking activity (IC50 = 841 nM) that is currently under clinical evaluation as an antidepressant. The effects of ABT 200, nomifensine (an inhibitor of catecholamine uptake), and rauwolscine (a selective alpha2‐adrenoceptor antagonist) on the clearance of exogenous norepinephrine in the cerebellum of urethane‐anesthetized rats was investigated using a vivo electrochemistry. Chronoamperometric recordings were continuously made at 5 Hz using Nafion‐coated, single carbon fiber electrodes. When a calibrated amount of norepinephrine was pressure‐ejected at 5‐min intervals from a micropipette adjacent (290–330 μM) to the electrode, transient and reproducible norepinephrine signals were detected. In response to systemic ABT 200 (30 mg/kg i.p.) or nomifensine (30 mg/kg i.p.1, the signals increased in both amplitude and time course, indicating significant inhibition of the norepinephrine transporter. A lower dose (15 mg/kg i.p.) of either ABT 200 or nomifensine had no effect in this paradigm. Local application of ABT 200 (400 μM) or nomifensine (400 μM) prior to pressure‐ejection of norepinephrine also significantly increased the amplitude and time course of the norepinephrine signals. In contrast, systemic administration of rauwolscine (30 mgkg i.p.) or vehicle solution, and local application of vehicle solution, had no effect on the norepinephrine signals. These data indicate that at the higher dose evaluated, both ABT 200 and nomifensine inhibit cerebellar norepinephrine uptake in vivo. © 1995 Wiley‐Liss, Inc.
Anesthetics decreased the microdialysis extraction fraction of norepinephrine but not dopamine in the medial prefkontal cortex
Authors: Pan Wynn H. T. , Lai Yu‐Jun
Published: December 2004

We evaluated the effects of chloral hydrate and pentobarbital sodium on the basal extracellular concentrations of dopamine (DA) and norepinephrine (NA) as well as their in vivo extraction fraction (relative recovery) at the medial prefrontal cortex (mPFC) in rats by using zero‐net flux microdialysis method. Adult, male Sprague‐Dawley rats anesthetized with either chloral hydrate (400 mg/kg, i.p., with 80 mg/kg i.v. supplements) or pentobarbital sodium (50 mg/kg, i.p., with 10 mg/kg i.v. supplements) were used as treatment groups. Conscious rats were used as a control group. The basal extracellular concentration and in vivo recovery of DA in the conscious group were 2.38 ± 0.70 nM and 41 ± 6%. In comparison with the chloral hydrate group (1.51 ± 0.55 nM and 41 ± 9%) and the pentobarbital sodium group (2.81 ± 1.20 nM and 42 ± 4%), there were no significant effects of anesthesia on the basal extracellular concentration and the in vivo recovery of DA at the mPFC. Additionally, the basal extracellular concentration and the in vivo recovery of NA in the conscious group were 1.59 ± 0.37 nM and 51 ± 8%. There also were no significant differences of the basal extracellular concentration of NA among these three groups (chloral hydrate group: 4.38 ± 1.39 nM; pentobarbital group: 3.67 ± 0.90 nM). However, the conscious group had a higher in vivo recovery than the two anesthetized groups (chloral hydrate group: 16 ± 2%; pentobarbital group: 27 ± 5%). Based on these findings, we then concluded that pentobarbital sodium and chloral hydrate selectively suppressed NA's active processes (such as release, reuptake, and metabolism) but not DA's yet do not affect the basal extracellular concentrations of NA and DA at the mPFC. Therefore, anesthesia was accompanied by a selective change of the active processes of certain types of neurons but not by altering their basal extracellular concentrations. However, more studies are necessary to draw a relationship between these findings and the action of general anesthesia. © 1995 Wiley‐Liss, Inc.
PET examination of the monoamine transporter with [11c]β‐CIT and [11c]β‐CFT in early parkinson's disease
Authors: Rinne Juha O. , Laihinen Arto , Någren Kjell , Ruottinen Hanna , Ruotsawnen Ulla , Rinne Urpo K.
Published: December 2004

The monoamine transporter was studied in 4 healthy controls and 5 patients with early Parkinson's disease (PD), who had not received any antiparkinsonian medication, by means of positron emission tomography (PET) using two novel ligands, [11C]β‐CIT and [11C]β‐CFT. Both ligands showed highest uptake in the striatum. There was intermediate accumulation of activity in the thalamus and midbrain, which was more marked for [11C]β‐CIT than for [11C]β‐CFT. In the cortical areas, uptake of both ligands was not different from that seen in the cerebellum. In the controls, the putamen‐to‐cerebellum and caudate‐to‐cerebellum ratios for [11C]β‐CFT were higher than those for [11C]β‐CIT (putamen: 3.15± 0.39 for [11C]β‐CFT, and 1.84 ±0.10 for [11C]CIP‐CIT caudate: 3.15±0.31 for [llC]P‐CFT, and 1.95±0.17 for [11C]β‐CIT). Reduction from mean control value in PD patients was greater for [11C]β‐CFT (45% in the putamen contralateral to the predominant symptoms, P < 0.001) than for [11C]β‐CIT(20%, P > 0.05). [11C]β‐CFT uptake in the caudate nucleus was also diminished in PD patients (to 80% of the control mean, P < 0.05), whereas [11C]β‐CIT was within normal range (reduced to 90% of the control mean). These results indicate that both [11C]β‐CIT and [11C]β‐CFT are useful PET ligands to study brain monoamine transporter in healthy controls and in patients with PD. However, [11C]β‐CFT seems superior to [11C]β‐CIT in this respect. © 1995 Wiley‐Liss, Inc.
Protein kinase C inhibitors enhance the 5‐HT2A receptor‐mediated excitatory effects of serotonin on interneurons in rat piriform cortex
Authors: Marek Gerard J. , Aghajanian George K.
Published: December 2004

Previously it has been shown that excitatory effects of 5‐hydroxytryptamine (5‐HT) upon interneurons in the rat piriform cortex are mediated by 5‐HT2A receptors. This receptor is linked to phosphoinositide turnover, and one consequence of stimulating this receptor is the activation of protein kinase C (PKC). In the present study, the effect of PKC inhibitors on the 5‐HT excitation of piriform cortical interneurons was examined by extracellular recording in a rat brain slice preparation. Bath application of the selective PKC inhibitors, bisindolylmalemide and chelerythrine, and the nonselective protein kinase inhibitor, H‐7, all enhanced the excitatory effects of 5‐HT. Two other nonselective protein kinase inhibitors, H‐8 and HA 1004, which are 2.5‐fold and 6.7‐ fold less potent than H‐7 at inhibiting PKC, produced a slight or no enhancement, respectively, of the excitatory effect of 5‐HT. Bisindolylmalemide, chelerythrine, and H‐7 did not enhance the excitatory effects of norepinephrine or carbachol on the same interneurons. The PKC activator phorboll2,13‐diacetate (PDA) decreased the excitatory effect of 5‐HT this decrease was rapidly reversed by H‐7. As inhibitors of PKC selectively enhanced rather than blocked the excitation by 5‐HT mediated by 5‐HT2A receptors, we conclude that activation of PKC does not mediate the excitation by 5‐HT of piriform cortical interneurons. Instead, we propose that PKC may have a negative feedback role in modulating the excitation by 5‐HT of piriform cortical interneurons. © 1995 Wiley‐Liss, Inc.
Biochemical adaptations in the mesolimbic dopamine system in response to heroin self‐administration
Authors: Self David W. , McClenahan Amanda W. , Beitner‐Johnson Dana , Terwilliger Rose Z. , Nestler Eric J.
Published: December 2004

Previous studies have shown that chronic, forced exposure to opiates produces specific biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc). The functional consequences of these adaptations have been hypothesized to contribute to certain motivational aspects of drug addiction. In this study, the possibility that similar adaptations could occur in response to intermittent heroin self‐administration was tested by comparing homogenates of VTA and NAc from rats self‐administering heroin, rats receiving yoked injections of heroin, and rats receiving yoked injections of saline (controls). Tyrosine hydroxylase (TH) immunoreactivity was increased (31–38%) in the VTA and decreased (11%) in the NAc of heroin‐exposed rats relative to controls. Heroin exposure also increased cAMP‐dependent protein kinase (PKA) activity in both particulate (19–27%) and soluble (17–20%) fractions of the NAc, and decreased (16–17%) the level of Giα, immunoreactivity in this brain region. In contrast, no significant biochemical changes were found in the substantia nigra or caudate‐puta‐men, indicating a selective effect on the mesolimbic dopamine system. Overall, adapta‐tions in the VTA and NAc of heroin‐exposed rats were similar to, but generally smaller in magnitude than, adaptations produced by chronic morphine administration. However, in contrast to morphine‐treated animals, heroin‐exposed animals failed to display overt signs of opiate physical dependence, suggesting that adaptations in motivational systems may occur more readily than adaptations in brain regions associated with physical dependence. © 1995 Wiley‐Liss, Inc.
Stimulation of cortical acetylcholine efflux by FG 7142 measured with repeated microdialysis sampling
Authors: Moore Holly , Stuckman Scott , Sarter Martin , Bruno John P.
Published: December 2004

The effects of the benzodiazepine receptor partial inverse agonist β‐carboline FG 7142 on cortical ACh efflux were determined using in vivo microdialysis in freely‐moving rats. Additionally, a within‐subjects, repeated‐dialysis experimental design (four microdialysis sessions; removable dialysis probe) was evaluated as a method for measuring changes in basal and FG 7142‐stimulated ACh efflux in the frontoparietal cortex. FG 7142 (4.0, 8.0, and 16.0 mg/kg) produced a 150–470% increase in cortical ACh efflux, with a dose‐dependent effect on the duration of the increase in efflux. Basal cortical ACh efflux was lower in session 4 than in session 1. However, the ability of FG 7142 to stimulate efflux was unchanged by repeated dialysis testing. The ability of tetrodotoxin (1.0 μM) to suppress both basal and FG 7142‐stimulated ACh efflux was also unaffected by repeated dialysis testing. These results demonstrate that systemically administered benzodiazepine receptor inverse agonists stimulate cortical ACh efflux, and that repeated‐measures experimental designs can be valid for determining certain changes in cortical ACh efflux with in vivo microdialysis. © 1995 Wiley‐Liss, Inc.