bluuebunny/crossref_metadata_2025 huggingface dataset:
Pet study of [11C] β‐CIT binding to monoamine transporters in the monkey and human brain
Authors: Farde Lars , Halldin Christer , Müller Lars , Suhara Tetsuya , Karlsson Per , Hall Håkan
Published: December 2004

The cocaine congener β‐CIT has been labeled with 11C for positron emission tomographic (PET) studies of the dopamine transporter. In the present autoradiographic study on human' brain sections and PET study on monkey and human [11C]β‐CIT accumulated markedly in the striatum. [11C]β‐CIT binding in the striatum was selective to the dopamine transporter. The binding in the thalamus was on an intermediate level and was displaced by compounds having affinity for norepinephrine and serotonin transporters. The neocortical binding was on a low level and could be displaced only by citalopram, a serotonin uptake inhibitor. A high dose of cocaine intravenously (7 mg/kg) induced a 50% occupancy of specific [11C]β‐CIT binding to the dopamine transporter in the striatum. This dose is much higher than the doses of 0.25‐0.5 mg/kg i.v. for cocaine arousal in human subjects. The finding indicates that cocaine arousal may be induced at a low dopamine transporter occupancy of a few percent. [11C]β‐CIT should be a useful radioligand to explore cocaine actions in humans and to follow the pathophysiological process in vivo by PET in neurodegenerative diseases of the striatum. © 1994 Wiley‐Liss, Inc.
Blockade of D‐1 dopamine receptors in the medial prefrontal cortex produces delayed effects on pre‐ and postsynaptic indices of dopamine function in the nucleus accumbens
Authors: Vezina Paul , Blanc Gérard , Glowinski Jacques , Tassin Jean‐Pol
Published: December 2004

The present experiments assessed the acute and delayed effects of D‐1 dopamine (DA) receptor blockade in the medial prefrontal cortex (mPFC) on pre‐ and postsynaptic indices of DA neurotransmission in the nucleus accumbens (N.Acc). Different groups of rats received intra‐mPFC injections of saline (control animals) or the D‐1 DA receptor antagonist SCH‐23390 (0.25 μg/side). Acutely, intra‐mPFC injections of this antagonist did not affect spontaneous locomotion but significantly increased the locomotion induced by intra‐N.Acc. amphetamine (1.5 μg /side), in agreement with our earlier findings [Vezina et al. (1991) Eur. J. Neurosci., 3:1001‐1007]. When tested two days post‐injection, however, mPFC‐SCH‐23390 preexposed animals showed lower levels of locomotor activity than Control animals in response to intra‐N.Acc. injections of amphetamine. This effect was not observed in other animals preexposed two days earlier to mPFC injections of amphetamine (2.5 tg/side) or the D‐2 DA receptor antagonist sulpiride (1.0 μg/side). Animals preexposed two days earlier to mPFC SCH‐23390 also showed higher levels of locomotor activity (+ 98%) when tested with intra‐N.Acc. injections of the D‐1 DA receptor agonist SKF‐38393 (1.0 μg/side) and a 36% increase in maximal DAsensitive adenylate cyclase activity in comparison to Control animals. These effects were no longer observed in animals tested seven days following the mPFC SCH‐23390 injections. These results demonstrate delayed actions resulting from cortical D‐1 DA receptor blockade. They suggest, in a way consistent with previous findings [Herve et al. (1989) J. Neurosci., 9:3699‐3708] that mPFC D‐1 DA receptors are involved in the presynaptic regulation of DA neuron reactivity as well as the postsynaptic regulation of D‐1 DA receptors in subcortical DA terminal and receptor fields such as the N.Acc. © 1994 Wiley‐Lies, Inc.
Buprenorphine and morphine produce equivalent increases in extracellular single unit activity of dopamine neurons in the ventral tegrnental area in vivo
Authors: Grant Steven J. , Sonti Gayatri
Published: December 2004

Buprenorphine is a synthetic opioid proposed as a potential treatment for drug abuse. Although buprenorphine is widely considered to be a partial agonist at opioid receptors, little is known of its electrophysiological effects in the central nervous system. Because buprenorphine has been reported to have limited hedonic effects in humans, and since activation of the dopaminergic system is thought to be critical to the reinforcing effects of drugs, we compared the ability of buprenorphine and morphine to activate dopamine neurons. We report here that buprenorphine and morphine are equally effective in increasing the impulse flow of dopamine cells in the ventral tegmental area.

Extracellular single unit activity was recorded from dopaminergic (DA) neurons in the ventral tegmental area (VTA) of chloral hydrate anethestized rats. Standard physiological and anatomical criteria were used to identify DA neurons. Systemic injection of buprenorphine (5–200 μg/kg, i.v.) and morphine (1–10 mg/kg, i.v.) produced equal magnitudes of activation in a similar subset of DA neurons in the VTA (buprenorphine: 173%; morphine: 164%). Unlike morphine, the activation by buprenorphine was not reversed by the opioid antagonist naloxone (50–100 μg/kg, i.v.), but this is consistent with the known pharmacodynamics of buprenorphine at opioid receptors.

These studies demonstrate that acute administration of buprenorphine has morphinelike effects on the impulse activity of DA neurons. The implications for use of buprenorphine as a clinical treatment for drug abuse are discussed. © 1994 Wiley‐Liss, Inc.
Excitatory amino acid‐induced excitation of dopamine‐containing neurons in the rat substantia nigra: Modulation by kynurenic acid
Authors: Wu Hui‐Qiu , Schwarcz Robert , Shepard Paul D.
Published: December 2004

Kynurenic acid (KYNA), an endogenous antagónist of ionotropic excitatory amino acid (EAA) receptors, was tested for its ability to modulate N‐methyl‐D‐aspartate (NMDA)‐ and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA)induced excitation of dopamine (DA)‐containing neurons in the zona compacta of the rat substantia nigra (SNc). Experiments were conducted using extracellular recording techniques in conjunction with an in vitro brain slice preparation. Bath application of NMDA (1–20 μ) or AMPA (0.5–10 μ) produced a concentration‐dependent increase in the firing rate of SNc DA neurons but had no effect on firing pattern. The highest concentration of both agonists produced a rapid and reversible cessation of activity that was attributed to acute induction of depolarization block. Addition of glycino (GLY) (up to 100 μ) to the bathing solution had no effect on either basal firing rate or the increase in activity produced by NMDA. KYNA (10 μ–1 mM) antagonized the excitatory effects of both NMDA (15 μ) and AMPA (3 μ) in a concentration‐dependent fashion (IC50: 102 μ and 64 μ, respectively) without affecting basal firing rate. Perfusion of tissue slices with a modified Ringer's solution containing low Mg2+ (0.12 mM) increased NMDA‐induced excitation but did not affect the antagonist properties of KYNA. D‐serine (100 μ) reversed the ability of KYNA to block the excitatory effects of NMDA, suggesting that KYNA attenuates NMDA‐induced excitation of SNc DA neurons via blockade of the GLY allosteric site on the; NMDA receptor. The ability of KYNA to modulate the excitatory effects of both NMDA and non‐NMDA agonists implies that endogenous KYNA may play a physiological role it regulating DA cell excitability. © 1994 Wiley‐Liss, Inc.
Quantitative autoradiography of the serotonin transporter to assess the distribution of serotonergic projections from the dorsal raphe nucleus
Authors: Hensler Julie G. , Ferry Robert C. , Kovachich Gyula B. , Frazer Alan
Published: December 2004

The binding of 3H‐CN‐IMI to 5‐HT uptake sites, as measured by quantitative autoradiography, was used as a marker of serotonergic neurons. Within the dorsal raphe nucleus the binding of 3H‐CN‐IMI was compared in adjacent coronal sections of rat brain to the binding of 3H‐DPAT to 5‐HT1A receptors, which have a known somatodendritic localization. The heterogeneous pattern of binding of these two radioligands within the dorsal raphe nucleus was similar and corresponded to the distribution of serotonergic cell bodies as visualized by 5‐HT immunohistochemistry. Intracerebroventricular administration of 5,7‐dihydroxytryptamine (5,7‐DHT), which caused a dramatic loss of 5‐HT immunoreactivity and 3H‐DPAT binding to 5‐HT1A receptors, resulted in a marked reduction of 3H‐CN‐IMI binding in this nucleus. Treatment of rats with a dose of parachloroamphetamine (PCA) which has been reported to selectively lesion serotonergic processes arising from the dorsal raphe nucleus, while sparing serotonergic cell bodies and projections from the median raphe nucleus, did not alter the binding of 3H‐DPAT or 3H‐CN‐IMI in the dorsal raphe nucleus; serotonergic cell bodies appeared morphologically unaffected. The lack of effect of PCA treatment on the binding of 3H‐DPAT and 3H‐CN‐IMI is consistent with a somatodendritic localization of the 5‐HT transporter in the dorsal raphe nucleus. PCA treatment appeared to produce a moderate loss of serotonergic innervation in serotonergic terminal field areas as visualized by serotonin immunohistochemistry. The reductions in 3H‐CN‐IMI binding observed in terminal field areas (24 to 69%) following treatment of rats with PCA did not reflect a marked differential innervation of forebrain areas by the dorsal and medial raphe nuclei as expected from previous biochemical studies, and were not entirely consistent with the findings of neuroanatomical studies using histochemical techniques. Site‐specific injection of 5,7‐DHT into the dorsal raphe nucleus produced an 80 ± 11% reduction in the binding of 3H‐CN‐IMI in this nucleus, whereas the binding of 3H‐CN‐IMI in the median raphe nucleus was not reduced. The reductions in 3H‐CN‐IMI binding measured in the caudate putamen, frontal and entorhinal cortex as a result of specific lesion of the dorsal raphe nucleus were suggestive of a heavy innervation of these areas by the dorsal raphe nucleus as indicated in neuroanatomical studies. In the hippocampus, our data were consistent with an overlapping innervation of these areas by both the dorsal and median raphe nuclei and are not reflective of predominantt innervation by the medial raphe nucleus. © 1994 Wiley‐Liss, Inc.
Relationship between asymmetries in striatal dopamine release and the direction of amphetamine‐induced rotation during. The first week following a unilateral 6‐OHDA lesion of the substantia nigra
Authors: Robinson Terry E. , Noordhoorn Maura , Chan Emily M. , Mocsary Zoltan , Camp Dianne M. , Whishaw Ian Q.
Published: December 2004

In animals with a large unilateral 6‐hydroxydopamine (6‐OHDA) lesion of the nigrostriatal dopamine (DA) system the traditional “rotational behavior model” states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine‐stimulated DA release and greater DA receptor stimulation. It is puzzling, therefore, why amphetamine induces contraversive rotation in rats tested 4 days after a unilateral 6‐OHDA lesion, despite a 90‐95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamine‐induced rotation by 8 days post‐lesion and turn in the ipsiversive direction thereafter. To try and resolve this paradox, bilateral striatal microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6‐OHDA lesion of the substantia nigra. On Day 4 post‐lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellular concentration of DA in the denervated striatum. This amphetamine‐releasable pool of DA was exhausted by a single amphetamine challenge, because a second injection of amphetamine given 3 h after the first did not produce a comparable increase in DA. It is suggested that on Day 4 post‐lesion the amount of DA released by amphetamine in the denervated striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post‐lesion, amphetamine induced DA release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefore, DA receptor stimulation would be greatest in the intact striatum, leading to ipsiversive rotation. In conclusion, it is suggested that the seemingly paradoxical reversal in the direction of amphetamine‐induced rotation that occurs over the first week following a unilateral 6‐OHDA lesion is consistent with the traditional rotational model, and is due to time‐dependent changes in the ability of amphetamine to release DA in the denervated striatum. © 1994 Wiley‐Liss, Inc.
The effects of chronic haloperidol administration on GABA‐immunoreactive. Axon terminals in rat medial prefrontal cortex
Authors: Vincent Stephen L. , Adamec Emil , Sorensen Ingrid , Benes Francine M.
Published: December 2004

Several reports have suggested that chronic haloperidol (HAL) treatment induces ultrastructural changes in synapses of substantia nigra, corpus striatum, and medial prefrontal cortex (mPFC) of rat brain. The effects of HAL on specific cortical transmitter systems, however, are not well characterized. Recent studies have indicated that there may be a loss of gamma‐aminobutyric acid (GABA)ergic cells in anterior cingulate cortex of schizophrenic subjects and this hypothesis has prompted interest in the question of whether dopamine receptor antagonists, such as HAL, may influence the activity of this transmitter system. This current report describes a quantitative light microscopic analysis of GABA‐immunolabeled axosomatic terminals in mPFC of rats treated with HAL decanoate (0.5 mg/kg/day, i.m.) for a period of 4 months. GABA‐containing terminals were visualized with an avidin‐biotin immunoperoxidase method for localizing anti‐GABA antibodies. Computer‐assisted image processing was employed to determine the total number of pixels representing GABA‐immunoreaction product in axon terminals that were in direct apposition to pyramidal cell bodies. Drug‐treated animals showed a significant increase in the number of pixels representing GABA‐immunoreaction product in axosomatic terminals of layers II, III, V, and VI (93%, 63%, 31%, and 43%, respectively). These data are consistent with the idea that chronic HAL administration may be associated with a significant increase in the amount of GABA present in terminals surrounding pyramidal neurons of rat mPFC. The fact that GABA‐containing terminals showed the greatest increase in layer II is not consistent with the known distribution of dopamine afferents to this region which is lowest in superficial laminae. Based on the laminar distribution of non‐dopaminergic receptor types that have a high affinity for HAL, the effect of this drug on GABAergic transmission could potentially involve changes that are mediated through mechanisms in which 5‐HT2 or sigma opiate receptors play a role. © 1994 Wiley‐Liss, Inc.
Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: Electrophysiological and behavioral studies
Authors: Hu Xiu‐Ti , White Francis J.
Published: December 2004

Many effects resulting from D2 dopamine (DA) receptor stimulation are manifest only when D1 DA receptors are stimulated by endogenous DA. When D1 receptor stimulation is enhanced by administration of selective D1 receptor agonists, the functional effects of selective D2 agonists are markedly increased. These qualitative and quantitative forms of D1/D2 DA receptor synergism are abolished by chronic DA depletion when both D1 and D2 DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D1 and D2 renaptnr supersensitivity, induced by repeated administration of selective D1 or D2 receptor antagonists, on the synergistic relationships between D1 and D2 receptors. Daily administration of the selective D2 antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate‐putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D2 agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D1 agonist SKF 38393 to potentiate quinpirole‐induced inhibition, and relieved D2 receptors from the necessity of D1 receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride‐pretreated, but not saline‐pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D1 receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole‐induced inhibition and the necessity of D1 receptor stimulation for such inhibition. However, both quinpirole‐induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390‐pretreated rats. When such Dl‐sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline‐pretreated rats with acute DA depletion and SCH 23390‐pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D1‐sensitized rats are due to a heterologous sensitization of D2 receptors rather than to enhanced enabling resulting from supersensitive D1 receptors. It is suggested that supersensitivity of either D1 or D2 receptors can lead to an uncoupling of normal qualitative and quantitative D1/D2 synergisms and that the heterologous regulation of D2 receptor sensitivity by D1 receptors may be related to uncoupling of functional D1/D2 synergisms.
Metabotropic glutamate receptor agonist ACPD inhibits some, but not all, muscarinic‐sensitive K+ conductances in basolateral amygdaloid neurons
Authors: Womble Mark D. , Moises Hylan C.
Published: December 2004

Muscarinic agonists produce membrane depolarization and losses of spike frequency accommodation and the slow afterhyperpolarization (AHP) when applied to neurons of the basolateral amygdala (BLA). Underlying these changes are the muscarinic‐induced inhibitions of several K+ conductances, including the voltage‐activated M‐current (IM), a slowly decaying Ca2‐activated current (IAHP), a voltage‐insensitive leak current (ILeak), and the hyperpolarization‐activated inward rectifier current (IIR) Similar depolarizations and losses of the slow AHP have been observed in other neuronal cell types following stimulation of metabotropic glutamate receptors. Therefore, we tested the effects of the metabotropic glutamate receptor agonist, 1‐aminocyclopentanels, 3r‐dicarboxylic acid (ACPD), on pyramidal neurons impaled with a single microelectrode for current‐ and voltage‐clamp recordings in a brain slice preparation of the rat BLA. Application of ACPD (20 or 100 μM) to BLA neurons inhibited IM and IA HP, resulting in membrane depolarization and reductions in the amplitude and duration of the slow AHP. However, ACPD did not inhibit the muscarinic‐sensitive current IIR, nor was ILeak blocked in the majority of neurons examined. These findings suggest the possibility that muscarinic cholinergic and metabotropic glutamatergic receptor agonists may activate separate intracellular transduction pathways which have convergent inhibitory effects onto IM and IAHP in BLA pyramidal neurons. © 1994 Wiley‐hiss, Inc.
Ethanol acts via the ventral tegmental area to influence hippocampal physiology
Authors: Criado Jose R. , Steffensen Scott C. , Henriksen Steven J.
Published: December 2004

Ethanol selectively alters hippocampal dentate physiology, in part by increasing recurrent inhibition and suppressing long‐term potentiation (LTP), a result of ethanol modulation of subcortical inputs. One of these inputs includes the ventral tegmental area (VTA) in the midbrain, whose neurons have been shown to discharge faster following systemic ethanol. To further understand how subcortical inputs regulate hippocampal physiology and their modulation by ethanol, we studied the effects of acute intoxicating levels of ethanol on VTA facilitation of the perforant path to dentate (PPD) responses. Furthermore, to test the role of the VTA on known pharmacological effects of ethanol on hippocampal physiology, we studied the effects of disruption of the VTA‐dentate inpute on ethanol actions on recurrent inhibition. Stimulation of the perforant path produced well‐characterized evoked responses in the ipsilateral dentate gyrus. Whereas VTA stimulation had no effect on PPD population EPSPs, VTA conditioning markedly increased perforant path‐evoked PS amplitudes (140%). The maximum facilitation was observed at VTA conditioning intervals of 30‐40 ms. PS amplitudes returned to baseline levels immediately following cessation of VTA conditioning. Intraperitoneal injections of ethanol (1.2 g/kg) markedly decreased VTA facilitation of PPD PS amplitudes. Lesions of the VTA blocked the ethanol‐mediated increase in PPD paired‐pulse inhibition. These results demonstrate that, to a great extent, the effects of intoxicating doses of ethanol on hippocampal physiology are mediated by remote pharmacological effects on the ventral tegmental area, whose direct or indirect influences on dentate physiology are described. © 1994 Wiley‐Liss, Inc.
No direct correlation between behaviorally active doses of the dopamine D2 agonist LY 171555 and displacement of [123I]IBZM as measured with SPECT in MPTP monkeys
Authors: Vermeulen R. Jeroen , Drukarch Benjamin , Verhoeff N. Paul L. G. , Goosen Cornelis , Sahadat M. C. Rob , Wolters Erik Ch. , Van Royen Eric A. , Stoof Johannes C.
Published: December 2004

Almost no information is available concerning the link between clinical effects of dopamine D2 receptor agonists in the treatment of Parkinson's disease (PD) and the extent of D2 receptor occupancy in the brain. Therefore, we investigated the possible correlation between adminis tration of behaviorally active doses of the selective D2agonist LY 171555 and in vivo D2 receptor occupancy in the unilateral 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine(MPTP)‐lesioned rhesus monkey model of PD. Single photon emission computed tomography (SPECT) with the D2 receptor antagonist (123I)IBZM (iodobenzamide) as radioligand was used to estimate the receptor occupancy.

The MPTP‐lesioned monkeys consistenty showed signs of unilateral parkinsonism. LY 171555 (0.01 or 0.3 mg/kg) significantly increased contralateral rotation (away from the lesion), being most effective at the lower dose.

In the MPTP‐lesioned monkeys [123]IBZM activity in the left (lesioned) striatum was significantly higher as compared to that in the right striatum. Only upon administration of 0.3 mg/kg LY 171555 a significant amount of receptor occupancy by LY 171555, as measured with [123I]IBZM SPECT, at both lesioned and non‐lesioned side, was detected. Using D2 receptor mediated inhibition of the evoked release of [3H]acetylcholine from rat striatal tissue as a functional model, we showed that the lack of effect with 0.01 mg/kg LY 171555 was not due to non‐competitive interaction between LY 171555 and IBZM at the D2 receptor.

We conclude that the D2 antagonist [123I]IBZM is not a suitable SPECT ligand to study the relationship between behavioral effects of the selective D2 agonist LY 171555 in unilaterally MPTP‐lesioned monkeys and the D2 receptor occupancy in vivo in this animal model of PD. © 1994 Wiley‐Liss. Inc.
Localization and developmental pattern of vasoactive intestinal polypeptide binding sites in the human hypothalamus
Authors: Sarrieau Alain , Najimi Mohamed , Chigr Fatiha , Kopp Nicolas , Jordan Daniel , Rostene William
Published: December 2004

Using a quantitative in vitro autoradiographic approach, vasoactive intestinal polypeptide (VIP) binding site densities were compared in the post‐mortem hypothalamus of human neonate/infant and adult. The densities were similar during development in most of the hypothalamic nuclei and areas examined underlying the stability of 125I‐VIP binding sites in the post‐mortem hypothalamus of young and adult individuals. However, the ventral part of the medial preoptic area, the medial, lateral, and supramammillary nuclei were characterized by an increase of 125I‐VIP binding with age. In young and adult individuals, the highest densities of hypothalamic 1251‐VIP binding sites were detected in the supraoptic and infundibular nuclei; the ependyma; the organum vasculosum of the lamina terminalis; the horizontal limb of the diagonal band of Broca; the ventral part of the medial preoptic area (in adult); the suprachiasmatic, paraventricular, and periventricular nuclei; and the medial and lateral mammillary nuclei in adult. Moderate densities were found in the vertical limb of the diagonal band of Broca, the bed nucleus of the stria terminalis, the ventral part of the medial preoptic area in neonate/infant, the medial and lateral mammillary nuclei in neonate/infant, the supramammillary nucleus in adult, the dorsal hypothalamic area, and the ventromedial nucleus. Low to moderate binding site densities were observed in the other hypothalamic regions of young or adult individuals. The nonspecific binding ranged from 15% of the total binding in the anterior hypothalamus to 20% in the mediobasal and posterior hypothalamic levels. Taken together, these results provide evidence for a large distribution of VIP binding sites in neonate/infant and adult human hypothalamus suggesting the implication of VIP in the development of this brain structure and the maintenance of its various functions. © 1994 Wiley‐Liss, Inc.
Effects of chronic ethanol ingestion on long‐term potentiation remain even after a prolonged recovery from ethanol exposure
Authors: Tremwel Margaret F. , Hunter Bruce E.
Published: December 2004

Previous work in our laboratory has demonstrated that memory formation, a behavioral process thought to be at least in part attributed to hippocampal functioning, is severely attenuated following 5 months of chronic ethanol treatment (CET) and 2 months of recovery from CET. Additionally, 48 h following CET, a well‐recognized physiological correlate of memory formation, long‐term potentiation (LTP), is reduced in the hippocanipus. We hypothesized that the reduction in LTP may in part contribute to the behavioral deficit in memory formation, which is a permanent consequence of CET. In order for the reduction of LTP to be involved with the permanent deficit in memory acquisition, it too must be present following a prolonged period of ethanol abstinence. The present study examined the permanent effect of CET on LTP. Animals were fed a nutritionally complete, ethanol containing diet for 28 weeks and then allowed a 5‐7 month abstinence period. A control group was fed the same diet except sucrose was isocalorically substituted for ethanol. Neurophysiological methods measured the capacity of synaptic connections onto CA1 pyramidal cells to support LTP in response to a variety of conditioning trains. The magnitude of LTP was reduced in CET animals as compared with pair‐fed controls. LTP induction is mediated by activation of the N‐methyl‐D‐aspartate (NMDA) receptor complex and is modulated by activation of β‐amino‐butyric acid (GABA)ergic synaptic transmission. The effect of CET on LTP magnitude may be due to effects on the NMDA‐induced induction itself or on the GABAergic modulation of induction. To distinguish between these possibilities, the induction of LTP was tested in the presence of bicuculline methiodide (a specific antagonist to the GABAA receptor). Under these conditions, the ethanol‐induced deficit in LTP was abolished. On the basis of these results we hypothesized that the CET reduction in LTP magnitude observed in the absence of bicuculline was due to a permanent alteration of GABAergic modulation of LTP induction. Portions of this paper have been presented previously in abstract form [Tremwel and Hunter (1990), Soc. Neurosci Abstr., 980]. © 1994 Wiley‐Liss, Inc.
Attenuation of the locomotor‐sensitizing effects of the D2 dopamine agonist bromocriptine by either the D1 antagonist SCH 23390 or the D2 antagonist raclopride
Authors: Wise Roy A. , Carlezon William A.
Published: December 2004

Injections of the selective D2 dopamine agonist bromocriptine (5.0 mg/kg, IP) produced progressively stronger locomotion over 10 days of repeated testing. Concurrent treatment with either the D1 antagonist SCH 23390 (0.01 or 0.1 mg/kg, IP) or the D2 antagonist raclopride (0.1 or 1.0 mg/kg, IP) suppressed bromocriptine‐induced locomotion on treatment days and attenuated or blocked the progressive increases in locomotion that accompanied repeated injections of bromocriptine alone. The fact that D1 and D2 antagonists each block the acute actions of bromocriptine and attenuate the development of bromocriptine sensitization is suggested to imply a striatal rather than a ventral tegmental mechanism for the sensitization produced by repeated treatments with direct dopamine agonists. © 1994 Wiley‐Liss, Inc.
Electrophysiological verification of the presence of D1 and D2 dopamine receptors within the ventral pallidum
Authors: Napier T. Celeste , Maslowski‐Cobuzzi Renata J.
Published: December 2004

The ventral pallidum is a basal forebrain region recently shown to receive dopaminergic projections from the midbrain. Binding sites for the D1 and D2 dopamine receptor families have been identified within the ventral pallidum, yet the consequences of activating these receptors have not been studied. Thus, to characterize the physiological pharmacology of D1 and D2 receptor subtypes for the ventral pallidum, extracellular single‐neuron recording and microiontophoretic techniques were used in chloral hydrate‐anesthetized rats. Half of the 93 ventral pallidal neurons tested were sensitive to iontophoresis of dopamine (DA), and both rate increases and decreases were observed. Co‐iontophoresis of either the D1 antagonist SCH23390, or the D2 antagonist sulpiride, generally attenuated the DA‐induced rate changes. Like DA, about half of the ventral pallidal neurons tested were sensitive to the D1 agonist, SKF38393. Yet in contrast to DA, rate suppression was observed almost exclusively, and the magnitude of this decrease was greater than that produced by DA. SKF38393‐induced suppressions were antagonized by SCH23390, but not by sulpiride, demonstrating the specificity of the D1 agonist. Most of the neurons tested were not affected by quinpirole, but when responsive to the D2 agonist, rate increases were observed most often. The increases were antagonized by the D2 antagonist sulpiride, but not SCH23390, demonstrating that this response resulted from an activation of D2 receptors. These results support binding studies demonstrating that both D1 and D2 receptors are present in the ventral pallidum, and reveal that the independent activation of each of these is sufficient to alter neuronal activity. © 1994 Wiley‐Liss. Inc.
Effects of haloperidol, quinelorane, and lithium on regional neurotensin/neuromedin N concentrations: Further evidence for neurotensin/neuromedin N‐Dopamine interactions
Authors: Clement Rita , Griff Dan , Banks Beth , Nemeroff Charles , Kitabgi Patrick , Bissette Garth
Published: December 2004

In order to further characterize the pharmacologic mechanisms that mediate the antipsychotic drug‐induced increase in neurotensin (NT) in nucleus accumbens and striatum, the effects of three weeks treatment with psychotherapeutic levels of lithium alone or in conjunction with haloperidol were compared to the ability of haloperidol alone to alter NT and neuromedin N (NMN) regional brain concentrations in rats. A separate experiment examined the ability of a selective dopamine D2 receptor agonist, quinelorane, to alter NT/NMN regional concentrations after three weeks of treatment as compared to haloperidol, a D2 receptor antagonist. Haloperidol (1 mg/kg) increased both NT and NMN concentrations in several brain regions and these parallel peptide increases were highly correlated. Lithium chloride (0.4 mM) had no effect, either alone or with haloperidol, on NT/NMN concentrations. Quinelorane (1 mg/kg), however, effectively increased both NT and NMN concentrations in the caudate nucleus and nucleus accumbens, as did haloperidol (2 mg/kg). These data indicate that the induction of NT and NMN, whose adjacent sequences are contained in a pro‐hormone product of a single gene, occurs in tandem and remains proportional, as well as demonstrating that putative D2 receptor agonists can produce effects on NT/NMN systems that are similar to D2 receptor antagonists. © 1994 Wiley‐Liss, Inc.
Local communication within dendritic spines: Models of second messenger diffusion in granule cell spines of the mammalian olfactory bulb
Authors: Woolf Thomas B. , Greer Charles A.
Published: December 2004

Dendritic spines are generally believed to play a role in modulating synaptically induced electrical events. In addition, they may also confine second messengers and thus topologically limit the distance over which second messenger cascades may be functionally significant. In order to address this possibility, computer simulations of transient second messenger concentration changes were performed. The results show the importance of spine morphology and binding and extrusion mechanisms in controlling second messenger transients. In the presence of intrinsic cytoplasmic binding sites and kinetic rates similar to that expected for calcium, second messengers were confined to the spine head. In the absence of binding/extrusion mechanisms, the size and time course of the input transient to the spine head influenced the second messenger transients that might be seen at the base of the spine neck and in other spines. Large and/or sustained increases in second messenger concentration in the spine head were communicated to the spine base and to other spine heads. The results emphasize the importance of a knowledge of breakdown pathways, concentrations and kinetics of binding sites, and extrusion mechanisms for understanding the dynamics of local chemical changes for dendritic spine function. © 1994 Wiley‐Liss, Inc.
Nitric oxide inhibits 3H‐glutamate transport in synaptosomes
Authors: Pogun Sakire , Dawson Valina , Kuhar Michael J.
Published: December 2004

3H‐glutamate (GLU) uptake was measured in hippocampal synaptosomes from rat brain. Addition of sodium nitroprusside (SNP) (Sodium nitroferricyanide), a generator of nitric oxide (NO), produced a time‐, temperature‐, and dose‐dependent inhibition of 3H‐GLU uptake. The inhibition was due to changes in both Kd and Vmax of GLU uptake, and it was at least partially reversible upon washing. Addition of reduced hemoglobin (Hb), a substance that binds NO, prevented the SNP‐induced depression of uptake. Potassium ferricyanide, a compound similar to SNP, did not cause a reduction in 3H‐GLU uptake. Utilization of another generator of NO, S‐nitroso‐N‐acetylpenicillamine (SNAP), produced similar results as did NO itself. Decreases in uptake were also observed in the striatum and cerebellum. Similar treatments did not consistently affect 3H‐norepinephrine (NE) uptake, suggesting some selectivity in the NO effect. Thus, the observed inhibition of 3H‐GLU uptake appears to be produced by NO, and it may represent a novel type of transynaptic retrograde regulation of transport. If found in vivo, inhibition of uptake activity could also be involved in the toxic effects of NO, the neurotoxicity of glutamate, and other potential neuronal changes associated with NO such as hippocampal long‐term potentiation. © 1994 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Ultrastructural organization of the noradrenergic innervation of the superficial gray layer of the hamster's superior colliculus
Authors: Arce Erick A. , Bennett‐Clarke Carol A. , Rhoades Robert W.
Published: December 2004

Immunocytochemistry with an antibody‐directed tyrosine hydroxylase (TH) was combined with electron microscopy and serial‐section analysis to examine the synaptic organization of the catecholaminergic projection to the stratum griseum superfciale (SGS) of the hamster's superior colliculus (SC). A total of 250 TH‐immunoreactive profiles within SGS were examined. Of these, 114 (45.6%) made synaptic contacts; 81 (71.1%) were axodendritic, and the remainder (33, 28.9%) were axo‐axonic. Serial‐section analysis was employed to evaluate the presence or absence of synaptic contacts for 26 profiles. Overall, 19 (73.1%) of the profiles followed through serial sections exhibited synaptic contacts. Double staining of single sections with antibodies directed against TH and dopamine‐ß‐hydroxylase (DßH) and examination in the light microscope indicated that virtually all TH‐positive fibers also contained DßH. This indicated that the fibers examined at the electron microscopic level were noradrenergic rather than dopaminergic. These results suggest that norepinephrine may have both pre‐ and postsynaptic actions in the hamster's SC and that at least some of these effects are mediated by conventional synapses.
Intracellularly recorded response of rat striatal neurons in vitro to fenoldopam and SKF 38393 following lesions of midbrain dopamine cells
Authors: Twery M. J. , Thompson L. A. , Walters J. R.
Published: December 2004

The effect of long‐term (6–19 weeks) 6‐hydroxydopamine‐induced (6‐OHDA) lesions of midbrain dopamine cells on dopamine D1‐like agonist‐induced changes in the excitability of rat striatal neurons was investigated in vitro using tissue slices and intracellular recording techniques. Fenoldopam and (±)‐SKF 38393 predominantly decreased excitability in control preparations including striatal neurons located contralateral to 6‐OHDA injection sites and neurons obtained from rats receiving sham injections or no treatment. Fenoldopam also inhibited neurons ipsilateral to lesions of midbrain dopamine cells. (±)‐SKF 33393, unlike fenoldopam, produced predominantly increases in the excitability of ipsilateral striatal neurons. Superfusion of the D1 receptor antagonist, SCH 23390, blocked fenoldopam‐induced decreases in excitability but not the (±)‐SKF 38393‐induced excitation of neurons ipsilateral to the lesion. Sequential application of fenoldopam and quinpirole, a D2/D3 receptor agonist, produced responses to both drugs in a majority of neurons. The results demonstrate that inhibitory responses to fenoldopam are mediated by D1 receptors, while excitatory effects of (±)‐SKF 38393 in the striatum ipsilateral to the lesion are apparently not dependent on D1 receptor activation. These findings also suggest that dopamine D1 and D2/D3 receptors are able to concurrently influence the excitability of striatal neurons in the dopamine deafferentated striatum. Similar regulation of striatal neurons in vivo may contribute to dopaminergic regulation of basal ganglia output and the ability of dopaminomimetic agents to ameliorate symptoms of dopaminergic deficiency in Parkinson's disease. © 1994 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Transient increase in the in vivo binding of the benzodiazepine antagonist [3H]flumazenil in deafferented visual areas of the adult mouse brain
Authors: Madar Igal , Scheffel Ursula , Frost J. James
Published: December 2004

Flumazer it is an imidazobenzodiazepine, an antagonist of central benzodiazepine (BDZ) receptors. BDZ binding sites are a modulatory component located on the gamma‐aminobutyric acid (GABA) receptor macromolecule. We studied the effect of monocular enucleation on [3H]flumazenil binding in deprived and intact visual areas and nonvisual areas of the adult mouse brain under in vivo conditions. [3H]flumazenil binding was examined at seven time points up to 56 days postenucleation. In some monocularly deprived mice, changes in local blood flow accompanied with the BDZ receptor response were evaluated by coinjection of [3H]flumazenil and 9mTc‐HMPAO. Monocular enucleation produced a transient increase in [3H]flumazenil binding in the deprived visual cortex and superior colliculus. At 17 days postenucleation, [3H]flumazenil binding in the anterior and posterior portions of the visual cortex and the superior colliculus increased by 28%, 15% and 23%, respectively, and declined to control levels at 45 days postenucleation. The increase in [3H]flumazenil was accompanied with a decrease in blood flow. Alterations in BDZ receptors and blood flow were selective to deprived visual structures. The regional correlation between the metabolic deficit and the BDZ response provides further support that the increase in BDZ receptor binding is confined to regions of reduced neuronal activity. [11C]flumazenil is an excellent radiotracer for in vivo imaging of benzodiazepine receptors in human brain using positron emission tomography (PET). This study suggests the suitability of [11C]flumazenil for in vivo PET study of BDZ receptor response to deafferentation of visual structures in human brain. © 1994 Wiley‐Liss, Inc.
Slow recovery of human brain MAO B after L‐Deprenyl (Selegeline) withdrawal
Authors: Fowler Joanna S. , Volkow Nora D. , Logan Jean , Wang Gene‐Jack , Mac Gregor Robert R. , Schlyer David , Wolf Alfred P. , Pappas Naomi , Alexoff David , Shea Colleen , Dorflinger Ernest , Kruchowy Lesia , Yoo Kisook , Fazzini Enrico , Patlak Clifford
Published: December 2004

L‐Deprenyl (Selegeline) is an enzyme‐activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L‐deprenyl requires the synthesis of new enzyme. We have measured a 40 day half‐time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L‐deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L‐Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L‐deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use. © 1994 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Pharmacokinetics and in vivo specificity of [LLC]dl‐threo‐methylphenidate for the presynaptic dopaminergic neuron
Authors: Ding Yu‐Shin , Fowler Joanna S. , Volkow Nora D. , Gatley S. John , Logan Jean , Dewey Stephen L. , Alexoff David , Fazzini Enrico , Wolf Alfred P.
Published: December 2004

dl‐threo‐Methylphenidate (Ritalin) was labeled with carbon‐11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [llC]dl‐threo‐methylphenidate ([llC]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5‐15 minutes post‐injection. The half‐time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed ≤8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43% The ratios of distribution volumes at the steady‐state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively. In contrast, pretreatment with tomoxetine (1.5 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, respectively, did not produce a significant change in the kinetics of [11C]MP and the ST/CB after pretreatment was similar to that for control. In one patient with Parkinson's disease, the striatum to cerebellum ratio of [11C]MP was markedly lower than that of an elderly normal subject. These results demonstrate the saturable [11C]MP binding to the dopamine transporter in the baboon brain and that [11C]MP is sensitive to dopamine neuron degeneration in Parkinson's disease. © 1994 Wiley‐Liss, Inc

This article is a US Government work and, as such, is in the public domain in the United States of America

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Haloperidol‐induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity
Authors: Meshul Charles K. , Tan Soon‐Eng
Published: December 2004

Administration of haloperidol for 2 weeks causes an increase within the caudate nucleus of asymmetrical synapses associated with a discontinuous or perforated, postsynaptic density (PSD) [Meshul et al. (1992), Psychopharmacology, 106:45–52; Meshul et al. (1992), Neuropsychopharmacology, 7:285–293]. Coadministration of the N‐methyl‐D‐aspartate noncompetitive antagonist, MK‐801, with haloperidol blocked the increase in striatal synapses containing a perforated PSD [Meshul et al. (1994), Brain Res., 648:181–195]. Examination of the caudate using immuno‐gold electron microscopy revealed the vast majority (90%) of asymmetrical synapses were labelled with a glutamate antibody [Meshul et al. (1994), Brain Res., 648:181–195]. The purpose of this study was to determine if there were any changes in the density of glutamate immunoreactivity within presynaptic terminals of asymmetric synapses within the striatum following treatment with haloperidol for 1 month that would correlate with the previously observed increase in synapses with perforated PSDs. We also determined the activity of striatal calcium/ calmodulin kinase II (CaMK II), an enzyme known to be localized within the synaptic region, after administration of haloperidol. We report here that haloperidol causes an increase in the activity of CaMK II and a decrease in the density of immuno‐gold labelling for glutamate within the nerve terminals of asymmetrical synapses containing a perforated or nonperforated PSD. These results are consistent with the hypothesis that the haloperidol‐induced increase in activity of CaMK II and the increase in glutamate release, as suggested by the decrease in presynaptic glutamate immunoreactivity, may ultimately lead to an increase in the number of synapses displaying a perforated PSD. These results support the speculation that the haloperidol‐induced increase in synapses containing a perforated PSD may be associated with enhanced activity at excitatory synapses. © 1994 Wiley‐Liss, Inc.