bluuebunny/crossref_metadata_2025 huggingface dataset:
Bi‐affinity α1‐adrenoceptor binding in normal rat brain in vivo
Authors: Gjedde Albert , Dyve Suzan , Yang Yu‐Jia , McHugh Michael , Pappius Hanna M.
Published: December 2004

The specific binding in rat brain in vivo of [125I]HEAT ([125I]iodo‐2‐[β;‐(4‐hydroxyphenyl)ethylamino methyl)], a selective α1‐adrenoceptor ligand, was analyzed by a method designed to distinguish sites with different affinities. The data indicate at least two sites with different affinities for the α1‐adrenoreceptor in normal rat brain in vivo: A high‐affinity site with Kd (half‐saturation constant) of 3.6 ± 0.7 nM (AV ± SD), and a low‐affinity site with Kd of 668 ± 552 nM. The density (Bmax) of the high‐affinity site in nine brain regions—auditory, visual, sensorimotor (four layers) and frontal cortex and lateral thalamic and medial geniculate nuclei—varied from 2.2 ± 0.8 to 14.6 ± 0.6 pmole/g, while the low‐affinity range was 149 ± 44 to 577 ± 30 pmole/g. The results also revealed a very dynamic relationship between the two sites regulated by the concentration of the ligand ranging from 80% preponderance of the high‐affinity sites at low ligand concentrations to more than 95% preponderance of the low‐affinity sites at high ligand concentrations.
[3H]Paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region
Authors: Dewar Karen M. , Reader Tomás A. , Grondin Louise , Descarries Laurent
Published: December 2004

The high‐affinity binding of [3H]paroxetine to membranes was measured in different regions of the rat and rabbit brain: cingulate, frontal, parietal, piriform, entorhinal, and visual cortical areas; dorsal and ventral hippocampus; rostral and caudal halves of neostriatum (rat) or caudate nucleus and putamen (rabbit); ventral mesencephalic tegmentum; and midbrain raphe nuclei region. The tissue concentrations of serotonin (5‐HT), 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) and 5‐hydroxy‐l‐tryptophan (5‐HTP) were also determined by high‐performance liquid chromatography (HPLC) in the same brain samples. The regional density of [3H]paroxetine binding varied in both species; the highest values (Bmax) were found in the midbrain raphe region and ventral mesencephalic tegmentum. The cortical values ranged from moderate to low, with a significantly higher density in the cingulate cortex of the rat compared with rabbit. In the rat, there was also a higher density in the ventral than dorsal hippocampus, and the caudal than rostral neostriatum. In the rabbit, the hippocampal and neostriatal values were generally lower and more uniform. In both species, there was an excellent correlation between regional 5‐HT levels and specific [3H]paroxetine binding (r = 0.87 in the rat and 0.96 in the rabbit). Considering the available quantitative data on the number of 5‐HT nerve cell bodies and axon terminals in different regions of the rat brain, it appears likely that the high amount of [3H]paroxetine binding in the midbrain raphe region and ventral mesencephalic tegmentum reflects the presence of 5‐HT uptake site on 5‐HT nerve cell bodies and dendrites as well as axon terminals. In other brain regions, the heterogenous distribution of [3H]paroxetine binding parallels that of the number of 5‐HT axon terminals, emphasizing the potential usefulness of this radioligand as a marker of 5‐HT innervation density.
Chronic cocaine administration and withdrawal of cocaine modify neurotensin binding in rat brain
Authors: Pilotte Nancy S. , Mitchell W. Mark , Sharpe Lawrence G. , De Souza Errol B. , Dax Elizabeth M.
Published: December 2004

Neurotensin (NT) is a peptide colocalized with dopamine (DA) within some mesocorticolimbic DA neurons that are affected by cocaine. We assessed whether chronic treatment with cocaine and withdrawal from cocaine would alter NT binding within these and other areas in the brain. Rats were given infusions repeatedly of isotonic saline or cocaine (1 mg/kg i.v. every 12 min for 2 hr over 10 days) and then were killed within 15 min of the last treatment session (“cocaine” or “saline”) or 10 days later (“withdrawal”). Brains were processed for NT receptor autoradiography. Cocaine affected NT binding in the mesocortical regions differently from other areas. Within the mesocorticolimbic system, NT binding in the parabrachial pigmented nucleus of the ventral tegmental area (VTA) was 67% lower in cocaine‐treated rats killed immediately after or 10 days after their final infusion than in rats given saline. In contrast to the perikaryal region, significantly more NT binding occurred postsynaptically in the terminal areas of the VTA (prefrontal cortex [PFC] and substantia nigra, pars compacta) 10 days after withdrawal of cocaine than in the saline controls. NT binding in the nucleus accumbens was unaffected by cocaine or its withdrawal. Cocaine also decreased NT binding in non‐mesocorticolimbic areas, including the dorsal hypothalamic area and the zona incerta, but binding returned toward control levels 10 days after withdrawal from cocaine. These data suggest that in central areas poor in DA uptake sites such as the PFC, NT may be a critical element in the inactivation of DA. Chronic cocaine treatment and its withdrawal appear to uncouple the normal NT‐DA interaction at both the cell bodies and terminals. This may increase dopaminergic neurotransmission, a process that may be important to the development of behavioral sensitization.
Heterogeneous binding of [3H]4‐DAMP to muscarinic cholinergic sites in the rat brain: Evidence from membrane binding and autoradiographic studies
Authors: Araujo Dalia M. , Lapchak Paul A. , Quirion Remi
Published: December 2004

The present study shows that [3H]4‐DAMP binds specifically, saturably, and with high affinity to muscarinic receptor sites in the rat brain. In homogenates of hippocampus, cerebral cortex, striatum, and thalamus, [3H]4‐DAMP appears to bind two sub‐populations of muscarinic sites: one class of high‐affinity, low capacity sites (Kd < 1 nM; Bmax = 45–152 fmol/mg protein) and a second class of lower‐affinity, high capacity sites (Kd > 50 nM; Bmax = 263–929 fmol/mg protein). In cerebellar homogenates, the Bmax of [3H]4‐DAMP binding sites was 20 ± 2 and 141 ± 21 fmol/mg protein for the high‐ and the lower‐affinity site, respectively. The ligand selectivity profile for [3H]4‐DAMP binding to its sites was similar for both the high‐ and lower‐affinity sites; atropine = (—)QNB = 4‐DAMP » pirenzepine > AF‐DX 116, although pirenzepine was more potent (16‐fold) at the lower‐ than at the high‐affinity sites. The autoradiographic distribution of [3H]4‐DAMP sites revealed a discrete pattern of labeling in the rat brain, with the highest densities of [3H]4‐DAMP sites present in the CA1 sub‐field of Ammon's horn of the hippocampus, the dentate gyrus, the olfactory tubercle, the external plexiform layer of the olfactory bulb and layers I–II of the frontoparietal cortex. Although the distribution of [3H]pirenzepine sites was similar to that of [3H]4‐DAMP sites in many brain regions, significant distinctions were apparent. Thus, both the ligand selectivity pattern of [3H]4‐DAMP binding and the autoradiographic distribution of sites suggest that although the high‐affinity [3H]4‐DAMP sites may consist primarily of muscarinic‐M3 receptors, the lower‐affinity [3H]4‐DAMP sites may be composed of a large proportion of muscarinic‐M1 receptors.
Integrity of perforant path fibers and the frequency of action potential independent excitatory and inhibitory synaptic events in dentate gyrus granule cells
Authors: Staley Kevin J. , Mody Istvan
Published: December 2004

Whole‐cell voltage clamp recordings in 400 μm thick hippocampal slices revealed discrete excitatory and inhibitory postsynaptic currents which persisted at synapses on granule cells following abolition of action potentials with 1 μM tetrodotoxin (TTX). The conductances associated with excitatory amino acid and GABAA receptor mediated events had mean peaks of 200 and 800 pS, and decayed monoexponentially with time constants of 5.6 and 5.3 ms. At a holding potential close to the normal resting membrane potential of granule cells (−80 to −90 mV), the frequency of glutamate/aspartate mediated spontaneous excitatory postsynaptic currents (sEPSCs) was decresed from 2.04 Hz in slices cut parallel to the plane of the perforant path to 0.87 Hz in slices cut in a plane that disrupted the distal perforant path fibres, suggesting that presynaptic integrity influences the rate of action potential independent neurotransmitter release. The orientation of the slicing had no effect on the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs).
Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories
Authors: Caldecott‐Hazard Sally , Morgan David G. , DeLeon‐Jones Frank , Overstreet David H. , Janowsky David
Published: December 2004

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.
NMDA‐dependent heterosynaptic long‐term depression in the dentate gyrus of anaesthetized rats
Authors: Christie Brian R. , Abraham Wickliffe C.
Published: December 2004

This report examines the inductive mechanism involved in long‐term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non‐associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non‐associative condition, no lateral path stimuli were given during the medial path trains, In both condition, the application of the conditioning stimuli resulted in a long‐term potentiation (LTP) of the medial path evoked responses (P < 0.001), while the lateral path responses showed LTD (P < 0.001). A two‐way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P > 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non‐associative LTD. The N‐methyl‐D‐aspartate (NMDA) receptor antagonist CPP (3‐((+)‐2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid; 10 mg/kg) blocked the appearance of LTP and LTD in both conditions, and in fact, the lateral path responses in the associative condition actually showed a significant degree of enhancement (P < 0.001). This enhancement was also evidenced when the lateral path stimuli were administered alone without prior CPP administration (P < 0.05). The results imply that one set of common mechanisms is utilized in the induction of LTD in the dentate gyrus, whether the medial and lateral paths are activated in an associative or a non‐associative manner.
Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus of suicide victims
Authors: Biegon Anat , Fieldust Sheila
Published: December 2004

Antibodies against tyrosine hydroxylase (TH, the rate‐limiting enzyme in norepinephrine synthesis) and dopamine β‐hydroxylase (DBH, the last enzyme in the synthesis) were used for immunohistochemical staining of human brain locus coeruleus sections, obtained postmortem form suicide victims and matched controls. Stain density over individual cells was quantified by a computerized, video‐camera‐based image analysis system. Mean stain density for TH was significantly lower (by about 30%) in the locus coeruleus of suicide victims. There was no difference between suicides and controls in DBH immunoreactivity or in the number of TH immunoreactive cells. Reduced TH availability, either genetically or environmentally determined, may contribute to the noradrenergic insufficiency postulated to occur in depression and the increased β‐adrenergic receptor concentrations observed in prefrontal cortex of suicide victims.
Amphetamine‐stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates
Authors: Innis Robert B. , Malison Robert T. , Al‐Tikriti Mohammed , Hoffer Paul B. , Sybirska Elzbieta H. , Seibyl John P. , Zoghbi Sami S. , Baldwin Ronald M. , Laruelle Marc , Smith Eileen O. , Charney Dennis S. , Heninger George , Elsworth John D. , Roth Robert H.
Published: December 2004

We used the reversibly binding D2 dopamine receptor radioligand [123I]IBZM (iodobenzamide) to test whether the endogenous neurotransmitter dopamine competes in vivo for radiotracer binding measured with single photon emission computed tomography (SPECT). In a series of nonhuman primate experiments (n = 27), the effects of temperature, amphetamine, haloperidol, and reserpine on brain uptake of [123I]IBZM were measured. Specific brain uptake of [123I]IBZM reached a peak by 100 min postinjection of radioligand and demonstrated a gradual, apparent “steady‐state” washout over the next 2 hr. Brain uptake was temperature dependent, with rates of washout of specifically bound radioligand greater under normothermic conditions (26%/hr: core body temperature 35–37°C) than under conditions of controlled hypothermia (11%/hr; 32–34°C). Given the greater retention of radioactivity, low‐temperature conditions were used in all other experiments. Administration of haloperidol (0.02 mg/kg IV) during the period of apparent steady state resulted in a dramatic increase in washout (60%/hr; p < 0.0001), consistent with its potent D2 receptor antagonist properties. d‐Amphetamine (1.0 mg/kg IV), which has negligible affinity for the D2 receptor but mediates the release of endogenous stores of dopamine, also enhanced washout (34%/hr; p < 0.0005). Reserpine pretreatment at doses (1.0 mg/kg) sufficient to cause greater than 90% depletion of striatal dopamine levels blocked this amphetamine‐enhanced washout (10%/hr; p < 0.05). Reserpine did not block the increased washout induced by the direct‐acting D2 receptor antagonist haloperidol. These results are consistent with the hypothesis that endogenous dopamine may effectively compete for radioligand binding in vivo in neuroreceptor imaging studies using PET and SPECT.
Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation
Authors: Hu Xiu‐Ti , White Francis J.
Published: December 2004

Following 6‐hydroxydopamine (6‐OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate‐putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist‐induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the “uncoupling” of functional interactions between the receptors following 6‐OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6‐OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6‐OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6‐OHDA lesions of the nigrostriatal pathway. After a 4‐week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.
Localization of drug reward mechanisms by intracranial injections
Authors: Wise Roy A. , Hoffman Diane C.
Published: December 2004

Intracranial drug injections are useful in localizing brain areas where drugs of abuse initiate their habit‐forming actions. However, serious methodological problems accompany such studies. Pharmacological controls are necessary to assess non‐receptor‐mediated local actions of the drug, anatomical controls are necessary to rule out drug efflux to distal sites of action, and behavioral controls are necessary to separate rewarding from general activating effects of drugs. Five brain sites have been advanced as sites of rewarding opiate actions: the ventral tegmental area (VTA), nucleus accumbens septi (NAS), lateral hypothalamus, periaqueductal gray, and hippocampus. Current evidence appears to confirm two of these—VTA and NAS; evidence is currently incomplete in the case of the hippocampus and is conflicting in the case of the lateral hypothalamus and periaqueductal gray. Two sites have been advanced as sites of rewarding psychomotor stimulant actions: NAS and the frontal cortex; each site seems implicated, but puzzling differences between amphetamine and cocaine findings remain to be resolved. Each of the clearly implicated sites is local to dopamine cell bodies or dopamine terminals that have been implicated in the rewarding effects of brain stimulation, food, and sex.
Morphology and laminar distribution of neuropeptide Y immunoreactive neurons in the human striate cortex
Authors: Berman Nancy E. J. , Fredrickson Eric
Published: December 2004

The morphology, laminar distribution, and distribution relative to cytochrome oxidase patches of neuropeptide‐Y immunoreactive (NPY‐ir) neurons were studied in the human striate cortex. The density of NPY‐ir cells was highest in the white matter. NPY‐ir neurons were sparsely distributed within the cortical layers. NPY‐ir neurons were located in both cytochrome oxidase dense patch and interpatch regions. However, the paucity of NPY‐ir neurons in layer III, where cytochrome oxidase patches are most clearly demonstrated, precluded establishing a clear relationship of NPY‐ir neurons to cytochrome oxidase patches. NPY‐ir neurons exhibited a variety of nonpyramidal morphologies, and many of them had axons with recurrent or looped trajectories. A dense plexus of NPY‐ir axons was located just beneath the pia, and these axons were concentrated at the entry points of pial blood vessels. Other NPY‐ir neurons had cell bodies or processes in close proximity to cerebral capillaries. These results suggest a role of NPY in cortical metabolism, control of cerebral circulation, or activity‐related changes in local blood flow. © 1992 Wiley‐Liss, Inc.
Calcium‐, calcium/calmodulin‐, and calcium/phospholipid‐stimulated protein phosphorylation in the rat anterior pituitary
Authors: Pryor James C. , Cain Scott T. , Nemeroff Charles B.
Published: December 2004

Calcium‐dependent protein phosphorylation may be a critical step in the stimulated secretion of anterior pituitary hormones. We have noted the existence of a number of calcium‐calcium/calmodulin‐, and calcium/phospholipid‐dependent phosphoproteins in the normal rat anterior pituitary. Cell extracts were prepared from anterior pituitary glands of male rats and phosphorylated with [γ32P]ATP in the presence or absence of calcium, calmodulin, and phosphatidylserine. The samples were electrophoresed on SDS‐PAGE gels, autoradiographs prepared, and phosphate incorporation into specific proteins quantitated with microdensitometry. Calcium alone significantly stimulated the phosphorylation of proteins with molecular weights of 80.0‐, 62.0‐, 51.0,‐ 30.5‐, and 25.0‐kDa. The phosphorylation of 21.5‐, 51.0‐, and 80.0‐kDa MW phosphoproteins was found to be phospholipid dependent. The phosphorylation of 62.0‐, 51.0‐, 33.0‐, 30.5‐, and 25.0‐kDa MW phosphoproteins was found to be calcium/calmodulin kinase dependent. Calcium/calmodulin also inhibited phosphorylation of the 80.0‐kDa phosphoprotein. © Wiley‐Liss, Inc.
Long‐Term frontal brain metabolic changes in cocaine abusers
Authors: Volkow Nora D. , Hitzemann Robert , Wang Gene‐Jack , Fowler Joanna S. , Wolf Alfred P. , Dewey Stephen L. , Handlesman Leonard
Published: December 2004

Neurological complications from cocaine use are well recognized. We propose that chronic cocaine use can also cause clinically silent brain dysfunction.

We investigated brain glucose metabolism with positron emission tomography (PET) and 2‐deoxy‐2[18F] fluoro‐D‐glucose (FDG) in 21 neurologically intact chronic cocaine abusers (C) and 18 normal controls (N). The cocaine abusers were tested 1–6 weeks after the last use of cocaine and seven were retested after a 3 month drug‐free period.

Global cerebral glucose metabolism was not significantly different between controls and cocaine abusers (N = 38.4±3, C = 36.5±5 μmol/100 g of tissue, min). However, cocaine abusers had significantly (P< 0.05) lower metabolic activity in 16 of the 21 left frontal regions and 8 of the 21 right frontal regions. These decreases persisted after 3–4 months of detoxification and were correlated with the dose (P ≤ 0.01) and the years of cocaine use (P ≤ 0.05).

This study shows reduced rates of frontal metabolism in neurologically intact cocaine abusers that persist even after 3–4 months of detoxification. © Wiley‐Liss, Inc.
Effects of the novel NMDA receptor antagonist, CGP 39551, on field potentials and the induction and expression of LTP in the dentate gyrus in vivo
Authors: Maren Stephen , Baudry Michel , Thompson Richard F.
Published: December 2004

The effects of the novel competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, CGP 39551 [the carboxyethylester of CGP 37849; DL‐(E)‐2‐amino‐4‐methy‐5‐phosphono‐3‐pentenoic acid], on extracellular field potentials and long‐term potentiation (LTP) induced in the dentate gyrus by stimulation of the perforant path were studied in anesthetized rats. CGP 39551 attenuated the population spike (PS) and excitatory postsynaptic potential (EPSP) amplitude of dentate field potentials, reduced the NMDA receptor‐mediated component of train‐evoked burst potentials, and prevented the induction of LTP. The decrease in PS and EPSP amplitude produced by CGP 39551 was observed mainly in non‐potentiated synaptic populations; potentiated field potentials were only minimally affected by drug treatment. These results are consistent with the in vivo blockade of NMDA receptors by CGP 39551. They also indicate that NMDA receptors may contribute in a tonic manner to the state of dentate granule cell excitability. Finally, the differential modulation of potentiated and non‐potentiated synapses by CGP 39551 suggests that a change in some properties of postsynaptic AMPA receptors is involved in the expression of LTP. © Wiley‐Liss, Inc.
GABAB receptor‐mediated inhibitory postsynaptic potentials evoked by electrical stimulation and by glutamate stimulation of interneurons in Stratum lacunosum‐moleculare in hippocampal CA1 pyramidal cells in vitro
Authors: Williams Sylvain , Lacaille Jean‐Claude
Published: December 2004

Following micropressure application of glutamate (500 μM) in stratum lacunosum‐moleculare (L‐M), inhibitory postsynaptic potentials (glut‐IPSPs) were recorded in CA1 pyramidal cells. These glut‐IPSPs were blocked by tetrodotoxin (1 μM) and, thus, were probably generated by the activation of local interneurons. The effects of pharmacological antagonists on glut‐IPSPs and on electrically‐evoked early and late IPSPs were assessed in the same cells during the same application of the antagonist. Local application of the GABAB antagonist 2‐OH saclofen (1–4 mM) reduced both glut‐IPSPs and late IPSPs but not early IPSPs. In contrast, the GABAB antagonist phaclofen (20 mM) reduced late IPSPs but not early IPSPs or glut‐IPSPs. Early IPSPs were blocked by the GABAA antagonists bicuculline and picrotoxin but late IPSPs and glut‐IPSPs were not. Repetitive electrical stimulation depressed early and late IPSPs as well as glut‐IPSPs, suggesting that interneurons activated with glutamate were also stimulated electrically. Thus, interneurons in str. lacunosum‐moleculare appear to inhibit pyramidal cells via a GABAB receptor‐mediated IPSP. The discrepancy in the pharmacological profile of the GABAB glut‐IPSPs and of the GABAB late IPSPs may suggest the presence of two GABAB mechanisms in CA1 pyramidal cells. © 1992 Wiley‐Liss, Inc.
Induction of long‐term potentiation in the basolateral amygdala does not depend on NMDA receptor activation
Authors: Chapman Paul F. , Bellavance Lisa L.
Published: December 2004

Long‐term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2‐amino‐5‐phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 μM) of DL‐AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low‐frequency stimulation. Furthermore, at 50 μM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 μM 6‐cyano‐7‐nitroquinoxaline‐2, 3‐dione (CNQX), which blocks non‐NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX‐insensitive response did not appear to be mediated by NMDA‐type receptors, since it was not reduced by 50 or 100 μM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors. © Wiley‐Liss, Inc.
Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex
Authors: Cepeda Carlos , Radisavljevic Zivotije , Peacock Warwick , Levine Michael S. , Buchwald Nathaniel A.
Published: December 2004

The responses of human neocortical neurons to iontophoretic application of excitatory amino acids and their modulation by dopamine (DA) were studied in vitro. Brain slices were obtained from children undergoing surgery for intractable epilepsy. Application of N‐methyl‐D‐aspartate (NMDA) to the slices induced slow depolarizations accompanied by decreased input conductances and sustained action potentials in cortical neurons. Glutamate produced rapid depolarizations and firing with few changes in input conductances. Quisqualate also induced depolarization and firing, but input conductances increased during the rising phase of the membrane depolarization. Iontophoretic application of DA alone produced no change in membrane potential or input conductance. However, when DA was applied in conjunction with the excitatory amino acids, it produced contrasting effects. With either bath application of DA or when iontophoresis of DA preceded application of NMDA, the amplitude of the membrane depolarizations and the number of action potentials were increased, whereas the latency of these responses decreased. In contrast, DA decreased the amplitude of the depolarizations and the number of action potentials evoked by glutamate or quisqualate. The fact that DA affects responses to NMDA and glutamate or quisqualate in opposite directions is of considerable importance to the understanding of cellular mechanisms of neuromodulation and the role of DA in cognitive processing and in epilepsy. © Wiley‐Liss, Inc.
Fine structure of presynaptic axonal terminals in sympathetic autonomic ganglia of aging and diabetic human subjects
Authors: Schroer Jo Anna , Plurad Santiago B. , Schmidt Robert E.
Published: December 2004

The neuropathologic changes that may underlie autonomic nervous system dysfunction in nondiabetic elderly human subjects or as a complication of diabetes have been systematically examined in sympathetic ganglia of a series of autopsied human subjects. As in animal models of aging and diabetes, enormously swollen terminal axons were found closely apposed to the perikarya of principal sympathetic neurons in prevertebral superior mesenteric sympathetic ganglia of aged and diabetic human subjects. Dystrophic axons consisted of two stereotyped forms: the first was composed of large numbers of misalligned aggregates of neurofilaments surrounded by variable numbers of small dense core vesicles; the second was characterized by large numbers of mitochondria, vacuoles, and dense and multivesicular bodies. The fine structural characteristics of neuroaxonal dystrophy, its predilection for prevertebral rather than paravertebral sympathetic ganglia, and the tendency for multiple dystrophic axons to cluster preferentially around selected neurons were identical in aged and diabetic human ganglia and were similar to changes seen in animal models of aging and diabetes. Neither diabetic nor aging ganglia demonstrated evidence of neuronal degeneration. Such structural changes may represent a degenerative influence of diabetes and aging on the normal remodeling of nerve terminals in autonomic ganglia, i. e., the continually ongoing process of turnover and replacement of axonal terminals. Similarity of lesions in human diabetes and aging suggests the possibility of pathogenetic mechanisms that are common to diabetes and the aging process. The substantial parallels between humans and animal models provide support for the validity of testing some proposed pathogenetic mechanisms directly in animal models. © 1992 Wiley‐Liss, Inc.
High‐affinity binding of [125I]RTI‐55 to dopamine and serotonin transporters in rat brain
Authors: Boja J. W. , Mitchell W. M. , Patel A. , Kopajtic T. A. , Carroll F. I. , Lewin A. H. , Abraham P. , Kuhar M. J.
Published: December 2004

RTI‐55 (3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid methyl ester), one of the most potent inhibitors of dopamine uptake reported to date, was radioiodinated and tested as a probe for the cocaine receptor in Sprague‐Dawley rat brain. Saturation and kinetic studies in the striatum revealed that [125I]RTI‐55 bound to both a high‐ and low‐affinity site. The Kd for the high‐affinity site was 0.2 nM, while the Kd for the low‐affinity site was 5.8 nM. The corresponding number of binding sites in the striatum was 37 and 415 pmol/g protein. The pharmacological profile of specific [125I]RTI‐55 binding in the striatum was consistent with that of the dopamine transporter. Additionally, [125I]RTI‐55 was found to bind with high affinity to the cerebral cortex. Scatchard analysis revealed a single high‐affinity component of 0.2 nM with a density of 2.5 pmol/g protein. The pharmacological profile demonstrated by [125I]RTI‐55 in the cerebral cortex matched that of the serotonin transporter. Autoradiographic analysis of sagittal brain sections with [125I]RTI‐55 binding was consistent with these findings. Specific binding of [125I]RTI‐55 was blocked by dopamine uptake inhibitors in areas rich in dopaminergic nerve terminals. Conversely, serotonin uptake inhibitors blocked the binding of [125I]RTI‐55 in brain areas rich in serotonergic neurons. These results demonstrate that [125I]RTI‐55 may be a very useful ligand for the dopamine and serotonin transporters. Published 1992 Wiley‐Liss, Inc.
Regional distribution of neuropeptide somatostatin gene expression in the human brain
Authors: Mengod G. , Rigo M. , Savasta M. , Probst A. , Palacios J. M.
Published: December 2004

The regional distribution of mRNA coding for the neuropeptide somatostatin has been studied in the human brain by in situ hybridization histochemistry using 32P‐labeled oligonucleotides. We show that somatostatin mRNA‐containing neurons are widely distributed in a number of nuclei and grey areas of the human brain, including neocortex, putamen, nucleus caudatus, nucleus accumbens, amygdala, midbrain, medulla oblongata, hippocampal formation, reticular nucleus of the thalamus, and posterior nucleus of the hypothalamus. No significant hybridization signal was observed in the substantia nigra, claustrum, globus pallidus, thalamus, and cerebellum. The topographic localization of neurons containing SOM mRNA in the human brain is in agreement with previous studies using immunocytochemical or radioimmunoassay techniques. These results show that in situ hybridization histochemistry with oligonucleotide probes can be used to map the distribution of neurons expressing SOM mRNA in human postmortem materials. © 1992 Wiley‐Liss, Inc.
SPECT Imaging of the benzodiazepine receptor: Autoradiographic comparison of receptor density and radioligand distribution
Authors: Sybirska Elzbieta , Al‐Tikriti Mohammed , Zoghbi Sami S. , Baldwin Ronald M. , Johnson Eric W. , Innis Robert B.
Published: December 2004

SPECT imaging of benzodiazepine (BZ) receptor using the antagonist [123I]iomazenil in nonhuman primates was correlated with ex vivo autoradiography and in vitro receptor autoradiography of postmortem tissue sections taken at the time of maximal brain uptake of the radiotracer. Cryostat sections prepred from brain tissue blocks at the orientation of the SPECT imaging plane showed high activity in gray matter regions, with gray to white matter ratios of greater than 30:1. After at least one week decay of 123I, these same tissue sections were used to localize and quantify the distribution of BZ receptors with the standard technique of in vitro receptor autoradiography using [125I]iomazenil. The ex vivo autoradiographic distribution of activity was highly correlated (r = 0.89) with the distribution of BZ receptors, although a few brain regions showed reproducible discrepancies between ex vivo and in vitro results. The ex vivo autoradiograms provided quantitative data from a realistic “biological phantom,” which may be used to assess the accuracy of image reconstruction and to investigate differences between the distribution of an intravenously (i. v.) administered tracer and that of its target in brain tissue. © 1992 Wiley‐Liss, Inc.
Reduction of GABAB inhibitory postsynaptic potentials by serotonin via pre‐ and postsynaptic mechanisms in CA3 pyramidal cells of rat hippocampus in vitro
Authors: Oleskevich Sharon , Lacaille Jean‐Claude
Published: December 2004

The action of serotonin (5‐HT) on GABAergic synaptic transmission was investigated with intracellular recordings in CA3 pyramidal cells of rat hippocampal slices. Local application of 5‐HT (500 m̈M) hyperpolarized CA3 pyramidal cells, decreased cellular input resistance, and reduced slow afterhyperpolarizations. Serotonin attenuated the late (GABAB) component of polysynaptic inhibitory postsynaptic potentials (IPSPs; 47% of control) without affecting the early (GABAA) component. During bath application of the excitatory amino acid antagonists 6‐cyano‐7‐nitroquinoxaline‐2, 3‐di‐one (CNQX) (20 m̈M) and 2‐amino‐5‐phosphonovalerate (AP‐5) (40 m̈M), 5‐HT similarly decreased the amplitude of the late (GABAB) component (17% of control) of monosynaptic IPSPs but did not affect the early (GABAA) component. The mean reversal potentials of poly‐ and monosynaptic IPSPs were unaffected by 5‐HT. The conductance increases associated with the late component of poly‐ and monosynaptic IPSPs were reduced by 5‐HT.

Hyperpolarizing responses evoked in CA3 pyramidal cells by somatic applications of gamma‐aminobutyric acid (GABA) were unaffected by 5‐HT. During bath application of bicuculline (20–50 m̈M), hyperpolarizing responses elicited by dendritic GABA application were reduced by 5‐HT (71% of control). The effect of 5‐HT on these direct GABAB hyperpolarizations (29% decrease in response) does not appear sufficient to fully account for the effect of 5‐HT on late GABAB IPSPs (53–83% decrease in response). Therefore, 5‐HT may reduce GABAB IPSPs in CA3 pyramidal cells 1) by a postsynaptic action on pyramidal cells and 2) by a selective presynaptic action on GABAergic interneurons mediating the GABAB IPSP. This presynaptic action of 5‐HT does not appear to involve excitatory afferents onto inhibitory interneurons. © 1992 Wiley‐Liss, Inc.
Involvement of the nigrotectal and nigrothalamic pathways in kappa opioid‐induced circling
Authors: Thompson Lisa A. , Walker J. Michael
Published: December 2004

The relationship between kappa opioid‐induced movement and output stations of the substantia nigra pars reticulata (SNpr) was examined using the rodent circling model. Contralateral rotation produced by intranigral microinjection of the kappa opiate U50,488 was lower in animals with ibotenic acid lesions of either the ipsilateral ventromedial thalamus or superior colliculas than in control animals without lesions. These results suggest that endogenous kappa opioids in the SNpr may influence movement through action on the nigrothalamic and nigrotectal pathways. In contrast, animals with ipsilateral lesions of the striatum showed an increase in circling relative to controls, possibly due to kappa receptor supersensitivity in the SNpr. © 1992 Wiley‐Liss, Inc.
Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain
Authors: Fowler J. S. , Volkow N. D. , MacGregor R. R. , Logan J. , Dewey S. L. , Gatley S. J. , Wolf A. P.
Published: December 2004

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self‐administering 2 drugs. We have used positron emission tomography (PET) and carbon‐11 (t1/2: 20.4 min) labeled cocaine and cocaethylene to compare the short‐term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5–8 mCi and 4–6 m̈g, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady‐state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one‐third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl‐cholinesterase (EC 3. 1. 1. 8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity. © 1992 Wiley‐Liss, Inc.
Chronic treatment with sabeluzole protects cultured rat brain neurons from the neurotoxic effects of excitatory amino acids
Authors: Pauwels Petrus J. , Van Assouw Harrie P. , Peeters Luc , Moeremans Marc , Leysen Josée E.
Published: December 2004

The neuroprotective properties of the cognitive enhancer sabeluzole were investigated in rat brain neuronal cultures derived from the hippocampal formation of 17‐day‐old rat embryos. Measurement of the neuronal cytoskeletal microtubule‐associated protein, MAP2, was used to assess survival of neurons after exposure of neuronal cultures to glutamate. MAP2 was quantified in neuronal cell homogenates by means of an enzyme‐linked immunosorbent assay (ELISA) using a mouse monoclonal MAP2 antibody, peroxidase‐labeled goat anti‐mouse Jg antiserum, and 2,2′‐azido‐di‐[3‐ethylbenzthiazoline] sulphonate (ABTS) as substrate. Exposure of 7‐day‐old neuronal cultures to 1mM glutamate for 16 hours led to a three‐fold increase in released lactate dehydrogenase (LDH) and a 40% decrease in cellular MAP2 content. Acute treatment of neuronal cultures with 10m̈M sabeluzole yielded a 40% drop in released LDH induced by glutamate. Cultures treated chronically with 0.1 m̈M sabeluzole on days 1 and 4 in culture showed, after 1 week in culture, a MAP2 content and total LDH activity that was not different from control cultures. A 16‐hour exposure to 1mM glutamate did not induce LDH release or changes in MAP2 levels in sabeluzole‐treated cultures. A single treatment with 0.1 m̈M sabeluzole between day 1 to 5 induced a 70–80% drop in glutamate‐induced released LDH in 7‐day‐old neuronal cultures. Full and partial neuronal protection after chronic sabeluzole treatment at 0.1m̈M was also observed for neurotoxicity induced by 5mM N‐methyl‐D‐aspartate (NMDA) and 1mM kainic acid or 30 m̈M veratridine, respectively. Within a series of compounds such as Ca++and Na+ channel antagonists, glutamate receptor antagonists and various neurotransmitter receptor antagonists, sabeluzole, chronically given, were the most potent for inhibition of released LDH induced by 1mM glutamate (IC50‐ value: 34 ± 13nM). In conclusion, chronic sabeluzole treatment protects cultured rat brain neurons from excitotoxic aggression. © 1992 Wiley‐Liss, Inc.
Effect of differential rearing on synapses and soma size in rat medial amygdaloid nucleus
Authors: Ichikawa Masumi , Matsuoka Masato , Mori Yuji
Published: December 2004

The effects of differential rearing on synaptic morphology and neuronal size were examined in the medial amygdaloid nucleus (MAN) of adult rats. Forty‐day‐old male rats were housed in one of three ways: individually (isolated condition, IC); with four males per cage (unisexual condition, UC); or with two males and two females per cage (social condition, SC). After 2 months, the animals were prepared for electron and light microscopy Although there was no statistically significant difference in number of synapses per unit volume in MAN, the number of perforated (P) synapses, which are characterized by discontinuities in the postsynaptic density, were significantly greater in the UC and the SC than in the IC. The length of synaptic contact zone of P synapses was also longer in both the UC and the SC compared with the IC, whereas the length of nonperforated synapses was longer only in the SC. Some area was also larger in the SC compared with the IC. These results demonstrate that exposure to different rearing conditions, in which the pheromonal environment can be substantially different, can induce striking morphological changes in both synapses and neurons in the MAN of adult rats. © 1993 Wiley‐Liss, Inc.
The GABAA receptor channel mediated chloride ion translocation through the plasma membrane: New insights from 36Cl− ion flux measurements
Authors: Kardos J.
Published: December 2004

GABAA receptors in plasma membranes of neurons are integral oligomers which form chloride channels. The binding of GABA molecules at recognition sites for channel opening triggers a transient increase in transmembrane chloride ion flux. The multiplicity and drug specificity of GABAA receptor, kinetics of channel opening, and desensitization of GABAA receptor and its short‐ and long‐term regulation have been investigated by the use of tracer amounts of the radioactive chloride isotope, 36Cl− ion. Results and new insights from 36Cl− ion flux measurements have been reviewed. © 1993 Wiley‐Liss, Inc.
LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: Intracellular studies in rat facial motoneurons
Authors: Garratt Jennifer C. , Alreja Meenakshi , Aghajanian George K.
Published: December 2004

The effects of LSD (d‐lysergic acid diethylamide) on rat facial motoneurons were compared to those of 5‐hydroxytryptamine (5‐HT) in brain slices by means of current clamp and single‐electrode voltage‐clamp recordings. As previously reported, 5‐HT, in part by decreasing a resting potassium conductance, produced a reversible depolarization (∼5 mV), an increase in input resistance, and an enhancement in electrical excitability. LSD also produced an increase in electrical excitability, although with a much slower onset and longer duration. However, in contrast to 5‐HT, LSD produced only a slight depolarization (1‐2 mV). Moreover, in the presence of LSD the depolarizing effect of 5‐HT was markedly attenuated. The 5‐HT2/5‐HT1c agonist 1‐(2,5‐dimethoxy‐4‐io‐dophenyl)‐2‐aminopropane (DOI) produced effects intermediate between LSD and 5‐HT. The LSD‐induced increase in electrical excitability was completely reversed by spiperone, a 5‐HT2/5‐HT1A antagonist, and by ritanserin, a 5‐HT2/5‐HT1c antagonist; the effects of 5‐HT were also reduced by these 2 antagonists, but complete blockade did not occur at the concentrations and durations tested. Surprisingly, LSD was found to enhance the hyperpolarization‐activated nonspecific cation current Ih to a greater extent than did 5‐HT; this enhancement was blocked by both spiperone and ritanserin. These results indicate that, despite having low efficacy relative to 5‐HT in decreasing resting potassium conductance, LSD has high efficacy in enhancing the Ih current in rat facial motoneurons; possible mechanisms for this difference are discussed. © 1993 Wiley‐Liss, Inc.