bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoarchitecture of serotonin‐synthesizing neurons in the pontine tegmentum of the human brain
Authors: Baker K. G. , Halliday G. M. , Halasz P. , Hornung J‐P. , Geffen L. B. , Cotton R. G. H. , Törk I.
Published: December 2004

We have employed immunohistochemical and morphometric procedures to study serotonin‐synthesizing (PH8‐immunoreactive) neurons in the pontine reticular formation of the adult human. PH8‐immunoreactive neurons were found in three cytoarchitectural regions: the median rahpe nucleus (MnR), oral pontine reticular nucleus (PnO), and supralemniscal region (group B9). On the basis of cell size, morphology, and position, it was possible to distinguish distinct subgroups within the MnR (dorsal, midline, and paramedian cell clusters) and within the PnO (dorsal and central cell clusters), whereas within the B9 there were no distinct cell clusters. We have estimated that there are approximately 125,000 PH8‐immunoreactive neurons in the human pontine tegmentum; 64,400 in the MnR, 30,700 in PnO and 29,000 in B9. The large numbers of serotonin‐synthesizing neurons in the human pontine tegmentum contrasts with their relative paucity in nonprimate species such as rats and cats. Nonhuman primates also have large numbers of pontine serotonergic neurons but the morphology of these neurons and their spatial arrangement is significantly different in humans. These results are discussed with respect to the possible projections and functions of these neurons in humans.
Two dynamic modes of striatal function under dopaminergic‐cholinergic control: Simulation and analysis of a model
Authors: Wickens J. R. , Alexander M. E. , Miller R.
Published: December 2004

A neural network model based on the anatomy and physiology of the matrix compartment of the striatum is described. The model consists of a network of neurons which are mutually inhibitory within a defined domain. A membrane potassium conductance (GK) under dopaminergic‐cholinergic control is included in the model. Computer simulation results show that changes in GmaxK, can modulate the behaviour of the network to produce either competition or coactivation among striatal output neurons. An analysis of a two‐neuron system based on the model shows that the maximum steepness of the threshold function plays a decisive role in the dynamics, in particular with regard to the competition that exists between the neurons. Competitive interations predominate at low GmaxK, while coactivation predominates at high GmaxK. We suggest that the former dynamic governs reciprocal inhibition of antagonistic muscles, while the latter governs cocontraction and rigidity. The model offers insights into the control of striatal neurodynamics by GmaxK which establish closer links between dopaminergic actions in the striatum and the mechanism of Parkinsonian rigidity. A prediction of the model is that acetylcholine should increase GmaxK in striatal output neurons.
GABAA receptors containing α1 and β2 subunits are mainly localized on neurons in the ventral pallidum
Authors: Churchill Lynn , Bourdelais Andrea , Austin Mark C. , Lolait Stephen J. , Mahan Lawrence C. , O'Carroll Anne‐Marie , Kalivas Peter W.
Published: December 2004

The γ‐aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is important in the regulation of locomotion. Thus, stimulation and inhibition of GABAA receptors in the VP can alter locomotor activity. To determine whether the GABAA receptors are located presynaptically on accumbens efferents to the VP or postysnaptically on neurons intrinsic to the VP two experiments were performed. In the first, quinolinic acid lesions of the nucleus accumbens did not alter [3H]muscimol binding in the VP, while lesions in the VP significantly reduced (60–80%) binding as measured by light microscopic receptor autoradiography. In the second experiment, in situ hybridization with oligonucleotide probes for mRNAs of the α1 and β2 subunits of the GABAA receptor was examined in the nucleus accumbens and VP. No mRNA for either subunit was observed in the nucleus accumbens, although many positively labeled neurons were present within the VP. By contrast, a moderate to high density of cells in both the nucleus accumbens and VP contained mRNA for glutamic acid decarboxylase. These data argue that the majority of GABAA receptors in the VP are not located presynaptically on axonal terminals originating from neurons in the nucleus accumbens.
ACTH and enkephalin axonal input to paraventricular neurons containing c‐fos‐like immunoreactivity
Authors: Pretel S. , Piekut D. T.
Published: December 2004

The presence of c‐fos like protein in neuronal nuclei has been observed in several areas of the central nervous system. It is associated with activation of these neurons by specific stimuli, in particular stressful stimuli. The present study investigated the expression of c‐fos‐like immunoreactivity in the paraventicular nucleus (PVN) of the hypothalamus following stimulation of small diameter, nociceptive afferents in the hindfoot of the rat. The afferent innervation to these c‐fos containing PVN neurons was examined in order to identify putative neurotransmitters which might modulate the activity of stress responsive, i.e. c‐fos containing neurons in the PVN. Adrenocorticotropic releasing hormone (ACTH), enkephalin (ENK) and corticotropin releasing factor (CRF), peptides whose functions have been related to the regulation of stress behavior, were selected to investigate their potential innervation of c‐fos immunolabeled neurons. Analysis of immunocytochemically double‐labeled vibratome and semi‐thin plastic embedded sections revealed that ACTH and ENK immunoreactive axonal varicosities were present in close anatomical proximity to a substantial number of parvocellular PVN neurons that contained c‐fos in response to noxious stimulation. Few c‐fos containing PVN neurons were apposed by CRF axonal varicosities. The resulting data show that a large number of c‐fos immunoreactive PVN neurons, though not the majority, is innervted by ACTH and ENK. This suggests that the activity of stress responsive, c‐fos expressing neurons can substantially be modulated and regulated by ACTH and ENK and to a lesser degree by CRF.
Subsurface cisterns in α‐motoneurons of the rat and cat: Immunohistochemical detection with antibodies against connexin32
Authors: Yamamoto T. , Hertzberg E. L. , Nagy J. I.
Published: December 2004

A monoclonal antibody against amino acids 224–234 of the gap junction protein connexin32 was found by immunohistochemistry to label subsurface cisterns (SSCs) in alpha‐motoneurons of the rat (Yamamoto et al., 1990) and was used here to document by light (LM) and electron microscopy (EM) the appearance of immunoreactive SSCs in motoneurons of the rat and cat. This antibody and a polyclonal antibody against connexin32 labelled gap junctions in rat liver as well as SSCs in facial motoneurons. By LM, SSCs were seen as labelled puncta on motoneuronal perikarya and proximal dendrites. In the rat, they appeared to be present on all motoneurons at cranial and spinal levels, but varied considerably in size and number among motor nuclei. Labelled SSCs were the smallest and most sparse in motoneurons of the dorsal vagal motor nucleus, moderate in size and most numerous in the trochlear, oculomotor, and trigeminal motor nuclei, and largest though less densely distributed in spinal motoneurons. Dendrites were seen to contain SSCs for distances of up to 230 μm from their somal origin. Labelling within individual SSCs seen en face consisted of either numerous small puncta or linear arrays of immunoreactivity. By EM, labelled SSCs in the rat facial nucleus were always seen beneath a cluster of C‐terminals. Immunolabelling was most dense in the space between the plasma membrane and SSC, which we define as the subsurface cisternal cleft. The SSCs were usually intermittently labelled along their length and exhibited a narrow luminal space ranging from 2 to 5 nm. On the basis of structural analogies between SSCs in neurons and the sacroplasmic reticulum terminal cistern/T‐tubule complex in muscle, SSCs have previously been suggested to be important sites of calcium mobilization. The constant association of C‐terminal with SSCs in motoneurons may represent a useful model in which to study SSC function as well as to investigate the possible presence of a connexinlike protein at regions of SSCs that form a narrow lumen similar to that at gap junctions.
Differential agonist profile of the enantiomers of 3‐PPP at striatal dopamine autoreceptors: Dependence on extracellular dopamine
Authors: Clark David , Salah Raymond S. , Galloway Matthew P.
Published: December 2004

The effects of the enantiomers of 3‐hydroxyphenol‐N‐n‐propylpiperidine (3‐PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)‐3‐PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (−)‐3‐PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)‐ and (−)‐3‐PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 μm, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 μM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine‐pretreated rats and was blocked by the selective D2 DA antagonist (−)‐sulpiride. This suggests that 3‐PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)‐3‐PPP. However, the stimulation of DA autoreceptors by (−)‐3‐PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (−)‐3‐PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (−)‐3‐PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors. The change in profile of (−)‐3‐PPP and TDHL is discussed in relation to their low intrinsic efficacy at synthesis modulating DA autoreceptors and to the variations in extracellular DA levels under different experimental conditions.
Differential effects of mu‐ and delta‐receptor selective opioid agonists on feedforward and feedback GABAergic inhibition in hippocampal brain slices
Authors: Lupica Carl R. , Dunwiddie Thomas V.
Published: December 2004

Previous studies have suggested that opioid receptor activation in the hippocampus increases pyramidal neuron excitability by reducing GABAergic inhibition. This hypothesis has received support with regard to μreceptor agonists but has not been adequately tested with selective δ‐receptor agonists. In the present investigation we compared the effects of the selective μ‐opioid receptor agonist [Tyr‐(D‐Ala)‐Gly‐(N‐Me‐Phe)‐Gly‐ol]‐enkephalin (DAGO) and the δ‐receptor agonist [D‐Pen2, D‐Pen5]‐enkephalin (DEDPE) to those of bicuculline methiodide (BMI) on extracellularly recorded feedforward (FFW) and recurrent (feedback; FB) inhibition. It was discovered that the control population spike response, evoked by Schaffer collateral/commissural axon stimulation, increased in response to DAGO, DPDPE, and BMI, while the secondary or test response incrased only in the presence of DAGO and BMI. The resulting hypothesis that δ‐opioid receptor activation facilitates synaptically evoked responses independently of a reduction of inhibition was investigated by examining the effect of DPDPE on the field EPSP response recorded in stratum radiatum of CA1, or postsynaptically on a burst response activated through antidromic stimulation of pyramidal neurons in low calcium medium. δ‐Opioid receptor activation had no effect on either the field EPSP response or the burst response, suggesting that neither synaptic transmission nor postsynaptic excitability were augmented. Finally, the possibility that DPDPE acts to enhance pyramidal cell excitability independently of GABAergic transmission was further investigated by examining responses to both μ‐and δ‐opioid agonists following treatment with BMI (30 μM). Responses to DPDPE and DAGO were completely blocked by this treatment, supporting the involvement of a GABAergic circuit in the actions of these enkephalins. These results suggest that the δ‐opioid receptor agonists DPDPE may mediate a reduction in GABAergic inhibition which is not detectable using paired stimulation techniques designed to examine FFW and FB inhibition in the hippocampal slice.
Dopaminergic modulation of excitotoxicity in rat striatum: Evidence from nigrostriatal lesions
Authors: Filloux F. , Wamsley James K.
Published: December 2004

Considerable evidence indicates that dopamine may, under certain circumstances, play a role in the mediation of central nervous system tissue damage. Furthermore, recent studies suggest a synergistic role between the neurotoxic effects of excitatory amino acids and dopamine. To address this issue, rats received a unilateral injection of 6‐hydroxydopamine or vehicle into the medial forebrain bundle. After recovery (18 days), both groups of animals received an ibotenic acid injection of the ipsilateral striatum. Seven days later the brains were removed and the size of the striatal lesion was assessed histologically and by means of receptor autoradiography. Regional analysis of profound D1 receptor loss was determined using [3H]SCH 23390, and extent of astrocytic proliferation was examined using autoradiography with the peripheral benzodiazepine receptor ligand [3H]R05‐4864. Prior interruption of the nigrostriatal pathway (resulting in dopaminergic denervation of the ipsilateral striatum) partially protected this latter structure from subsequent injection of ibotenic acid (the extent of the lesion was reduced by 28%, P < .05). The findings indicate that endogenous dopamine release may modulate (and intensify) the excitotoxic effects of ibotenic acid.
An arthropod NMDA receptor
Authors: Pfeiffer‐Linn Cindy , Glantz Raymon M.
Published: December 2004

Identified crayfish visual interneurons respond to illumination with a compound EPSP of up to 40 mV. L‐gultamate, quisqualate, and kainate mimic the depolarizing action of the natural transmitter. In reduced Mg2+, N‐methyl‐D‐aspartate (NMDA) elicits a depolarization with a reversal potential (Erev) = −60 mV. Erev is independent of extracellular calcium but shifts to +4 mV if potassium conductances are blocked by intracellular CS+. The results suggest that NMDA may gate more than one class of ionic channel. The NMDA‐elicited response is enhanced and prolonged by glycine, and kynurenate competitively blocks the action of glycine. The NMDA antagonist, D‐AP7, selectively blocks the NMDA response while enhancing the EPSP. The actions of NMDA are consistent with a role in the neural mechanisms of visual adaptation. This is the first description of an NMDA receptor in an invertebrate.
Aminooxyacetic acid produces excitotoxic lesions in the rat striatum
Authors: Urbańska Ewa , Ikonomidou Chrysanthy , Sieklucka Maria , Turski Waldemar A.
Published: December 2004

The neuropathological, biochemical, and behavioral effects of intrastriatal injection of aminooxyacetic acid (AOAA), a non‐specific transaminase inhibitor, were examined in rats. AOAA, 0.1–1 μmol, produced neuronal damage when injected into the striatum of adult rats but failed to damage the striatum of 6‐d‐old or decorticated rats. AOAA‐induced (0.25 μmol‐1 μmol) striatal lesions in adult rats displayed excitotoxic characteristics and could be prevented by the N‐methyl‐D‐aspartate (NMDA) receptor antagonists (–)‐2‐amino‐7‐phosphono‐heptanoate (AP7; 0.25 μmol) or kynurenate (KYNA; 0.5 μmol), but not by the non‐NMDA antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo(F)quinoxaline (NBQX; 0.25 μmol). AOAA produced a dose‐dependent reduction in striatal L‐glutamate decarboxylase activity, as measured 14 d following intrastriatal injection, which could also be prevented by AP7 or KYNA, but not by NBQX. These findings suggest that AOAA‐induced lesions are preferentially mediated by activation of the NMDA subtype of excitatory amino acid receptors. Behavioral studies revealed that the cataleptic response to haloperidol, 2 mg/kg, was decreased whereas the cataleptic response to arecoline, 15 mg/kg, and morphine, 15 mg/kg, was potentiated in AOAA lesioned animals 14 d following bilateral intrastriatal injections of AOAA, 0.25 and 1 μmol. In rats which received unilateral intrastriatal injection of AOAA, 0.1–1 μmol, apomorphine, 0.5 mg/kg, induced circling towards the lesioned side. Rats which received AP7, 0.25 μmol, or KYNA, 0.5 μmol, coadministered with AOAA, 0.25 μmol, behaved as vehicle‐treated controls, while those which received NBQX, 0.25 μmol, and AOAA, 0.25 μmol, had behavioral patterns similar to those subjected to AOAA alone. γ‐Vinyl‐GABA (4‐amino‐5‐hexenoate; 1 μmol), an inhibitor of the γ‐aminobutyrate (GABA) transaminase, and 3‐mercaptoproprionate (1 μmol), a preferential inhibitor of L‐aspartate transaminase, caused no damage when injected into the striatum of adult rats. Therefore we propose that inhibition of endogenous KYNA synthesis might be responsible for the neurotoxic properties of AOAA. Our findings are consistent with the hypothesis on the existence of a sensitive balance between endogenous excitotoxins and endogenous antagonists in the adult rat brain and suggest that blockede of the synthesis of the latter may result in excitotoxic cell death.
Partial dopamine depletions result in an enhanced sensitivity of residual dopamine neurons to apomorphine
Authors: Pucak M. L. , Grace A. A.
Published: December 2004

Extracellular recordings from identified dopamine neurons were used to assess the effect of 6‐hydroxydopamine‐induced partial lesions of the nigrostriatal dopamine system on the sensitivity of the residual dopamine neurons to the dopamine agonist apomorphine. This was done by testing the response of identified nigral dopamine neurons in control and lesioned rats to systemic apomorphine administration at two time points: (1) 6–10 days post‐lesion, when the loss of dopamine cells is nearly complete, and (2) 4–8 weeks post‐lesion, which should be sufficient time for changes in dopamine receptor density to occur. As reported previously, dopamine neurons in control rats were inhibited by systemic administration of apomorphine, with their sensitivity being inversely related to their initial firing rate. The sensitivity of the residual dopamine neurons to apomorphine was unaltered in rats tested 6–10 days after depletions of at least 60% of striatal dopamine. However, by 4–8 weeks post‐lesion, there was a significant increase in the sensitivity to apomorphine; furthermore, sensitivity was no longer related to baseline firing rate, but instead was uniformly high in all dopamine neurons tested at this time. This enhanced sensitivity was not altered by hemisection of the striatonigral projection, suggesting that the increased sensitivity to apomorphine was most likely a result of a time‐dependent up‐regulation of somatodendritic autoreceptors on the residual dopamine neurons.
Effects of CI‐943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations
Authors: Levant Beth , Bissette Garth , Davis M. Duff , Heffner Thomas G. , Nemeroff Charles B.
Published: December 2004

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI‐943, a novel compound without appreciable affinity for dopamine‐binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI‐943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI‐943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI‐943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI‐943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.
Immunocytochemical evidence for methamphetamine‐induced serotonergic axon loss in the rat brain
Authors: Axt Karen J. , Molliver Mark E.
Published: December 2004

Central serotonin (5‐HT) axons were visualized by immunocytochemistry to assess both acute and long‐lasting changes in innervation density following methamphetamine administration to rats. Two morphologically distinct subtypes of 5‐HT axons (fine and beaded) were differentially affected by d‐methamphetamine (d‐MA); the density of fine serotonergic axons was selectively decreased both 4 hours and 2 weeks after administration of d‐MA. Acute depletion of 5‐HT from fine axons, but not from beaded axons, was observed in the brains of all rats treated 4 hours previously with either a 100 mg/kg or 15 mg/kg dose of d‐MA. Persistent loss of 5‐HT axons was observed in 30% of rats treated 1 or 2 weeks previously with doses of d‐MA which produce long‐term deficits in biochemical markers for 5‐HT. In the fraction of animals that exhibited denervation, fine serotonergic fibers were selectively ablated by d‐MA, but beaded serotonergic fibers were spared. Thus, d‐MA is similar to other amphetamine derivatives (e.g., p‐chloroamphetamine, 3,4‐methylenedioxyamphetamine) in that it acts selectively upon a morphologically distinct class of 5‐HT axons but differs in that it produces long‐lasting axon loss in only a fraction of animals.

These data provide morphologic evidence of 5‐HT axon loss following methamphetamine administration and further confirm the differential vulnerability of a particular morphological subtype of serotonergic axons to the neurotoxic effects of substituted amphetamines.
Electrophysiological profile of the new atypical neuroleptic, sertindole, on midbrain dopamine neurones in rats: Acute and repeated treatment
Authors: Skarsfeldt Torben
Published: December 2004

Sertindole (Lundbeck code No. Lu 23‐174) (1‐[2‐[4‐[5‐chloro‐1‐(4‐fluorophenyl)‐1H‐indol‐3‐yl]‐1‐piperidinyl]ethyl]‐2‐ imidazolidinone) is a new potential neuroleptic compound.

After 3 weeks of treatment sertindole shows an extreme selectivity to inhibit the number of spontaneously active dopaminergic (DA) neurones in ventral tegmental area (VTA) while leaving the number of active DA neurones in substantia nigra pars compacta (SNC) unaffected. Acute injection of apomorphine or baclofen reverse the inhibition of activity seen after repeated treatment with sertindole. This suggests that sertindole induces a depolarization inactivation of the DA neurones. The depolarization inactivation is reversible since normal activity of DA neurones is found in both SNC and VTA after two weeks withdrawal from repeated treatment with a low dose with sertindole. One or two weeks administration of a high dose of sertindole induced only minor effects on the DA neurones in VTA; i.e., in order to obtain the depolarization inactivation sertindole requires 3 weeks of treatment as has also been reported for other neuroleptics.

Three weeks of treatment with clozapine induces a selective inhibition of the active DA neurones in VTA but at much higher doses than seen with sertindole, while haloperidol induces a non‐selective decrease of spontaneously active DA neurones in both areas.

In acute electrophysiological experiments intraveneous (i.v.) administration of sertindole—in contrast to both clozapine and haloperidol—neither reverse d‐amphetamine‐ nor apomorphine‐induced inhibition of the firing frequencies of DA neurones in SNC or in VTA. In addition, sertindole does not—even in high doses—increase the firing frequency of DA neurones in SNC or VTA.

In conclusion the study indicates that sertindole is a potential antipsychotic compound which should induce fewer extrapyramidal side‐effects than seen after classical neuroleptics.
Differential effects of amfonelic acid on the haloperidol‐ and clozapine‐induced increase in extracellular dopac in the nucleus accumbens and the striatum
Authors: Rivest Robert , Marsden Charles A.
Published: December 2004

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4‐dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5‐HT‐2), was co‐administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic‐induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions. Furthermore, the interaction between amfonelic acid and clozapine suggests that the increase in dopamine metabolism induced by the atypical neuroleptic results from the blockade of both dopaminergic and nondopaminergic receptors and may include the sertonergic (5‐HT‐2) receptors.
Autoradiographic localization of 5HT1 binding sites in autonomic areas of the rat dorsomedial medulla oblongata
Authors: Thor Karl B. , Blitz‐Siebert Alisa , Helke Cinda J.
Published: December 2004

Serotonin (5HT) binding sites in autonomic portions of the dorsomedial medulla oblongata of the rat were localized using autoradiographic techniques with radioactive ligands that express high affinity for the 5HT1 (3H‐5HT), 5HT1A (3H‐8OH‐DPAT), or 5HT1B (125I‐CYP with isoproterenol) receptor subtypes. 5HT1A sites were densely distributed in the nucleus tractus solitarius (NTS), with the highest densities localized to the interstitial subnucleus and the central subnucleus. 5HT1B sites were also found in the NTS, with the highest densities localized to the substantia gelatinosa subnucleus. The dorsal motor nucleus of the vagus nerve and nucleus ambiguus exhibited low densities of 5HT1B sites. However, the nucleus intercalatus, a cerebellar relay nucleus that also contains dendrites of vagal parasympathetic preganglionic neurons and receives autonomic forebrain afferent input, showed very dense 5HT1B sites. The promontorium, paratrigeminal islands, and the dorsomedial portion of the trigeminal nucleus (DM5), which are areas of viscerosomatic integration, exhibited high densities of both 5HT1A and 5HT1B sites. The area postrema contained low levels of both 5HT1A and 5HT1B sites.

Visceral deafferentation via cervical vagotomy or nodose ganglionectomy caused a significant decrease in 5HT1A sites in the interstitial subnucleus of the NTS ipsilateral to the lesion. No changes were seen in 5HT1B sites.

These studies suggest that 5HT1A and 5HT1B sites are involved in the processing of visceral sensory information in the NTS and associated areas. Based upon viscerotopic organization of the NTS, 5HT1A sites appear preferentially distributed in portions of the NTS that are associated with the coordination of swallowing, respiration, and cardiovascular function, while 5HT1B sites appear preferentially distributed in areas of the NTS associated with gastrointestinal, hepatic, pancreatic, and cardiovascular function. However, since these associations were not absolute and there was a great deal of overlap between the two sites, speculation regarding their specific functions in autonomic control must await pharmacological examination.
Regional distribution and kinetics of haloperidol binding in human brain: A pet study with [18F]haloperidol
Authors: Schlyer David J. , Volkow Nora D. , Fowler Joanna S. , Wolf Alfred P. , Shiue Chyng‐Yann , Dewey Stephen L. , Bendriem Bernard , Logan Jean , Raulli Robert , Hitzemann Robert , Brodie Jonathan , Alavi Abass A. , MacGregor Robert R.
Published: December 2004

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N‐methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10‐hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors. © 1992 Wiley‐Liss, Inc.
Within‐subject sensitization of striatal dopamine release after a single injection of cocaine: An in vivo microdialysis study
Authors: Keller Richard W. , Maisonneuve Isabelle M. , Carlson Jeffrey N. , Glick Stanley D.
Published: December 2004

Repeated microdialysis measurements, conducted 1 week apart at the same tissue site, were used to investigate the changes in basal and cocaine‐stimulated extracellular dopamine (DA) levels after a single prior exposure to either saline or cocaine. Dialysis probes were placed into rats previously implanted with guide cannulas and basal levels of dopamine (DA), and its metabolites (DOPAC and HVA) were estimated in 20‐min fractions of the dialysate. Basal levels in the extracellular fluid (ECF), estimated from pre‐implantation calibration of the probes, were 7.9 ± 0.7 nM DA, 4.9 ± 0.8 μM DOPAC, and 3.6 ± 0.6 μM HVA. After a stable baseline was obtained saline (1 ml/kg, i. p.) or cocaine (20 mg/kg, i. p.) was injected. Saline produced no significant changes in any of the neurochemical markers. A cocaine injection produced a sixfold increase in DA, while DOPAC and HVA were unchanged. One week later the same procedure was repeated except this time both groups received cocaine. In rats that had received cocaine 1 week earlier, basal DA levels in the ECF were doubled, whereas they were unchanged in rats that received saline a week earlier. Furthermore, the dopamine release in response to acute cocaine during the second week was elevated in animals which had been previously exposed to cocaine. Rotation was also measured during both weeks and, while a tendency toward behavioral sensetization was observed, it did not reach significance. Thus, a single exposure to cocaine, while not sufficient to induce behavioral sensitization in these rats, was sufficient to produce an elevated basal DA level and a sensitization of cocaine‐stimulated DA release when in vivo microdialysis measurements were repeated within the same rat. © Wiley‐Liss, Inc.
Distribution of enkephalin and its relation to serotonin in cat and monkey spinal cord and brain stem
Authors: Arvidsson Ulf , Cullheim Staffan , Ulfhake Brun , Ramírez Vania , Dagerlind Å;ke , Luppi Pierre‐Hervé , Kitahama Kunio , Jouvet Michel , Terenius Lars , Åman Katarina , Hökfelt Tomas
Published: December 2004

The distribution of enkephalin (ENK)‐like immunoreactivity (LI) in spinal cord and medulla oblongata of cat and gray monkey (Macaca fascicularis) was studied by use of immunofluorescence and peroxidase antiperoxidase (PAP)techniques. Possible coexistence between ENK‐ and 5‐hydroxytryptamine (5‐HT)‐LI was also analyzed with double labeling immunofluorescence. Furthermore, in situ hybridization was used to demonstrate cell bodies in the brain stem expressing mRNA encoding for ENK.

ENK‐immunoreactive (IR) axonal varicosities and fibers were demonstrated throughout the spinal cord gray matter, with the highest density in the superficial dorsal horn, the area around the central canal, the intermediolateral cell column, the sacral parasympathetic nucleus, and in Onuf's nucleus. In the monkey ventral horn, ENK‐IR varicose fibers could in some cases be demonstrated in very close apposition to cell bodies. A low degree of co‐localization between ENK‐ and 5‐HT‐LI was seen in the spinal cord of both species. Still, fibers containing both compounds could as a rule be demonstrated in every section studied. The highest degree of coexistence was encountered in the motor nucleus of the ventral horn. Six weeks after a low thoracic spinal cord transection a decreased staining for ENK‐LI was demonstrated in the ventral horn motor nucleus, whereas other parts of the spinal cord appeared unaffected.

In the brain stem of cats after colchicine treatment, ENK‐LI was found in a majority of the 5‐HT‐IR cell bodies in the raphe nuclei (nucleus raphe magnus, pallidus and obscurus) and in the lateral reticular nucleus (rostroventrolateral reticular nucleus). In cat not pretreated with colchicine, a few weakly stained ENK‐IR cell bodies could be found in the midline raphe nuclei and in the lateral reticular nucleus with the PAP technique. In the monkey brain stem without colchicine treatment, using the PAP technique, heavily stained ENK‐IR cell bodies could be seen in the lateral reticular nucleus while no convincing mRNA signal could be found over cell bodies in the raphe nuclei.

It is concluded that part of the ENKergic innervation of the cord in both species derives from supraspinal or suprasegmental levels. In the cat there is a discrepancy between the low degree of coexistence with 5‐HT observed in terminals in the spinal cord and the extensive coexistence in presumed cell bodies of origin in the medulla of colchicine treated animals. One possible explanation for this is that the expression of ENK in raphe neurons under normal circumstances is very low but that colchicine induces an upregulation of the synthesis of this peptide. © Wiley‐Liss, Inc.
Muscarinic M2‐selective ligands also recognize M4 receptors in the rat brain: Evidence from combined in situ hybridization and receptor autoradiography
Authors: Vilaró M. Teresa , Wiederhold Karl‐Heinz , Palacios José M. , Mengod Guadalupe
Published: December 2004

We have used autoradiographic techniques to examine the characteristics and distribution of the binding of reported selective M2 muscarinic ligands and compared them with the distribution of cells expressing mRNAs for the different subtypes of muscarinic receptors. Our results suggest that the M2 ligands used in the present study ([3H]OXO‐M, [3H]AF‐DX 384, AF‐DX 116, methoctramine) also recognize M4 receptors present in regions such as the striatum and olfactory tubercle. This is supported by (1) relative abundances of the different transcripts, with m2 mRNA being very scarce and m4 mRNA very abundant in these regions; (2) comparison of the pharmacological characteristics of M2‐ligand binding sites in brain areas selected by their exclusive expression of M2 receptors versus areas enriched in M4 receptors. An important conclusion of these studies is that none of the muscarinic radioligands available at the present time appears to label specifically a single muscarinic receptor subtype population. Areas are suggested where autoradiographic techniques can be helpful in elucidating the subtype selectivity of existing and new ligands. © Wiley‐Liss, Inc.
Acute stress impairs (or induces) synaptic long‐term potentiation (LTP) but does not affect paired‐pulse facilitation in the stratum radiatum of rat hippocampus
Authors: Shors Tracey J. , Thompson Richard F.
Published: December 2004

Rats were exposed to restraint coupled with 60, 1‐sec, 1‐mA, 60‐Hz tail shocks. One hippocampus was immediately dissected for in vitro measurement of pairedpulse facilitation and LTP of the excitatory postsynaptic potential (EPSP) recording from the stratum radiatum of field CA1. There was no change in paired‐pulse facilitation, suggesting that acute exposure to the stressor does not result in a decrease in presynaptic neurotransmitter release. There was, however, a significant decrease in the percent LTP produced by theta burst stimulation relative to naïve controls. These results are consistent with the hypothesis that the stress‐induced impairment of LTP is a result of changes in the postsynaptic glutamate receptors, specifically the AMPA type. © Wiley‐Liss, Inc.
Acute effects of Sigma ligands on the electrophysiological activity of rat nigrostriatal and mesoaccumbal dopaminergic neurons
Authors: Zhang Jing , Chiodo Louis A. , Wettstein Joseph G. , Junien Jean‐Louis , Freeman Arthur S.
Published: December 2004

The effects of acute i. v. administration of several sigma ligands on the single‐unit activity of nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate‐anesthetized rats. DTG (1, 3‐di(o‐tolyl)guanidine) did not alter DA neuronal activity at nontoxic doses and JO 1784 [(+)‐N‐cyclopropylmethyl‐N‐methyl‐1, 4‐diphenyl‐1‐ethylbut‐3‐en‐1‐ylamine] was inactive. (+)‐Pentazocine was more effective in increasing mesoaccumbal vs. nigrostriatal DA cell firing rates. BMY 14802(α‐(4‐fluorophenyl)‐4‐(5‐fluoro‐2‐pyrimidinyl)‐1‐piperazine‐butanol) dose‐dependently increased DA cell firing rate in both populations. The inhibition of nigrostriatal DA cell firing rate by (+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine [(+)‐3‐PPP] was reversed by(−)‐eticlopride and (+)‐but not (−)‐butaclamol, which supports previous evidence that (+)‐3‐PPP‐induced inhibition is due to the DA agonist properties of the drug. From what is known of the pharmacological properties of these compounds, it is concluded that acute sigma receptor occupation does not markedly alter the firing rate of DA neurons. The dose‐response curve for inhibition of nigrostriatal DA neuronal activity by the D2 DA agonist, quinpirole, was shifted to the right tenfold by BMY 14802 pretreatment (8mg/kg, i. v.) and twofold by (+)‐pentazocine (8 mg/kg, i. v.), but was not changed by DTG (2 mg/kg, i. v.). It is concluded that the marked effects of certain sigma ligands on DA cell electrophysiology are likely due to their non‐sigma properties. © Wiley‐Liss, Inc.
Perforated synapses are present during synaptogenesis in rat neocortex
Authors: Itarat W. , Jones D. G.
Published: December 2004

It has been known for some time that perforated synapses increase in number and size with increasing age. Initially, these trends were used to support the concept that nonperforated synapses anlarge until an optimal size is reached, at which point they perforate and may subsequently split. More recent stereological and threedimensional reconstruction investigations, however, suggest that this may not be the case and that perforated and nonperforated synapses constitute separate synaptic populations. In order to test the separate population hypothesis, synapses have been studied ultrastructurally in the parietal cortex of rats aged 19 and 20 days gestation, and 1 and 4 days postnatal. By examining synapses serially, and also by studying three‐dimensional reconstructions, it has been demonstrated that perforated synapses are present at each of these ages. Some are relatively simple in organization, resembling previously described perforated synapses at 14 days of age, although others appear to consist of two or more separate PSD components. These findings demonstrate that perforated synapses are present from early on in synaptogenesis and that developing perforated synapses are present from early on in synaptogenesis and that developing perforated synapses may have distinct characteristics that cast light on their developmental course. © Wiley‐Liss, Inc.
Effects of high‐dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography
Authors: Brunswick David J. , Benmansour Saloua , Tejani‐Butt Shanaz M. , Hauptmann Miroslawa
Published: December 2004

The neurotoxicity of methamphetamine to monoaminergic neurons was examined. Neurotoxicity was assessed by quantitative autoradiography using radioligands specific for binding to norepinephrine, dopamine, and serotonin uptake sites. High‐dose administration of methamphetamine led to decreases in binding to uptake sites for the three monoamines. Norepinephrine binding sites were decreased in certain amygdaloid nuclei and in the dorsomedial hypothalamic nucleus. Serotonin binding sites were reduced in widespread brain areas, while dopamine binding sites were reduced in the caudate putamen, olfactory tubercle, and nucleus accumbens. The decreases in binding site density for the three monoamines are limited to terminal field areas; cell body areas are not affected. Our results indicate that methamphetamine is neurotoxic to serotonin, dopamine, and norepinephrine neurons. The neurotoxicity to norepinephrine neurons is in selected brain areas. © Wiley‐Liss, Inc.
Enhanced hydroxyl radical generation by 2′‐methyl analog of MPTP: Suppression by clorgyline and deprenyl
Authors: Chiueh C. C. , Huang S.‐J. , Murphy D. L.
Published: December 2004

Sodium salicylate was infused through a microdialysis probe placed in the striatum of anesthetized rats in order to assay the formation of hydroxyl radical (.OH) in the extracellular fluid in vivo. In addition to causing sustained dopamine relese, intrastriatal infusion of the 2′‐methyl analog of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropridine (2′CH3‐MPTP) increased the formation of 2,3‐dihydroxybenzoic acid (2,3‐DHBA), the nonenzymatic. OH adduct of salicylate in the brain dialysate. Inhibition of monoamine oxidase (MAO) by clorgyline and deprenyl completely blocked the formation of 2,3‐DHBA and the sustained dopamine overflow induced by 2′‐CH3‐MPTP. The results indicate that the enhanced formation of cytotoxic. OH by 2′‐CH3‐MPTP is suppressed by MAO inhibitors. These data support the hypothesis that the protective effect of MAO inhibitors on the neurotoxicity induced by MPTP analogues may be due not only to the inhibition of MPTP metabolism by MAO but also the blockade of the formation of OH free radicals. An enhanced generation of cytotoxic. OH free radicals in the striatum which in turn leads to oxidant damage may be relevant to the development of parkinsonism‐like changes in animals produced by MPTP analogues. © Wiley‐Liss, Inc.
Quantitation of Carbon‐11‐labeled raclopride in rat striatum using positron emission tomography
Authors: Hume Susan P. , Myers Ralph , Bloomfield Peter M. , Opacka‐Juffry Jolanta , Cremer Jill E. , Ahier Randall G. , Luthra Sajinda K. , Brooks David J. , Lammertsma Adriaan A.
Published: December 2004

Using conventional autoradiographic and tissue counting techniques, the experimental quantitation of in vivo kinetics of prospective or established radioligands for PET is animal and labour intensive. The present study tested the feasibility of using PET itself to quantitate the specific binding of [11C] raclopride to rat striatum and to study the effects of experimental manipulation of endogenous dopamine on binding parameters.

Carbon‐11‐labeled raclopride was given i. v. to anaesthetised rats, positioned in a PET camera and dynamic emission scans acquired over 60 min. Time‐activity curves were generated for selected regions of interest, representing striatum and cerebellum and the striatal data fitted to a compartmental model, using cerebellum as the input function, thus circumventing the need for individual metabolite‐corrected plasma curves. In control rats, the binding potential (BP), defined as the ratio of the rate constants for transfer from “free to bound” and “bound to free” compartments, was of the order of 0.6. This was reduced threefold by predosing with nonraioactive raclopride. Increasing extracellular dopamine levels by predosing with d ‐amphetamine resulted in a significant decrease in BP whereas reducing extracellular dopamine by predosing with γ‐butyrolactone caused a significant increase.

Thus, despite the limitation in spatial resolution of PET, specific binding of raclopride could be assessed from regional time‐activity curves from individual rats. The system was sufficiently sensitive that changes in BP could be detected following modulation of endogenous dopamine levels, a finding of potential relevance to the interpretation of clinical PET data.
The paradoxical effect of NMDA receptor stimulation on electrical activity of the sensorimotor cortex in freely behaving rats: Analysis by combined EEG‐intracerebral microdialysis
Authors: Ludvig Nandor , Mishra Pravin K. , Yan Qing‐Shan , Lasley Stephen M. , Burger Robert L. , Jobe Phillip C.
Published: December 2004

This study was designed to determine the effects of N‐methyl‐D‐aspartate (NMDA) receptor stimulation on the electrical activity of neocortex in freely behaving rats. Electroencephalogram (EEG) recording and intracerebral microdialysis were conducted simultaneously in the same site of the sensorimotor cortex, where the basal extracellular concentrations of aspartate and glutamate were 2.1 ± 0.7 m̈M and 11.5 ± 2.4 m̈M, respectively. Microdialysis with NMDA solutions (ranging from 10.0 m̈M to 10.0 mM) reduced the amplitude of the EEG activity and decreased the power of all frequency bands, with a virtual elimination of the high frequency waves, in a dose‐dependent manner. These EEG changes were reversed after washing out the drug from the microdialysis fluid, and could be effectively antagonized with the competitive NMDA receptor antagonist DL‐2‐amino‐5‐phosphonovalerate. Remarkably, the NMDA actions were not associated with epileptiform behavioral or electrographic events. Control studies demonstrated that in the same experimental conditions, cholinergic receptor agonist carbachol caused seizures, and microdialysis with NMDA in the hippocampus readily induced epileptiform spikes. Our study shows that NMDA receptor stimulation in the rat sensorimotor cortex, although excitatory at synaptic level, can depress the local EEG activity. This may indicate that the NMDA receptor‐mediated signals are processed by the neocortical network in a different way than by many other brain circuitries including hippocampus. © 1992 Wiley‐Liss, Inc.