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R H Roth

Publications and source records attributed to R H Roth.

At least 145 records · Page 8Linked to original sources
PubMed1990

Improvements in MPTP-induced object retrieval deficits and behavioral deficits after fetal nigral grafting in monkeys.

Improvements in MPTP-induced deficits were only found in subjects that received fetal substantia nigra transplants into the caudate nucleus. The MPTP-induced deficits were assessed using an object retrieval task that examined cognitive and subtle motor performance and by behavioral observation to determine the overall status of the subjects. Subjects that were also moderately or severely impaired by MPTP administration but that received inappropriate donor cells or implant sites (cerebellum to CN or SN to cortex) did not show any evidence of behavioral recovery. These subjects could not respond on the task in the months after grafting and were sacrificed, showing no improvements in parkinsonian signs or healthy behavior signs, up to 5-6 months after surgery. Grafting of SN cells into the striatum of non-MPTP lesioned subjects failed to modify normal behavior or induce abnormal behavior determined by our 2 behavioral assessment methods. In those monkeys that received the appropriate transplants, TH immunohistochemistry revealed that cells of the fetal substantia nigra grafted into the caudate nucleus survived and extended neurites into the host striatum. Indeed, grafted dopamine neurons were often associated with appreciable innervation of the caudate nucleus and appeared to be well incorporated into the host brain. In contrast, examination of the striatum of subjects in the inappropriate-graft group (e.g., cerebellar cells grafted into the caudate) showed no evidence of TH staining within the graft or host caudate nucleus. This indicated that there was no evidence of dopamine neurons present in the grafted tissue and that the mere presence of a fetal graft did not appear to induce sprouting in these MPTP-treated subjects. Although behavioral recovery occurred in only those monkeys that received appropriate transplants (fetal SN to host CN) and not in those that received inappropriate grafts (fetal cerebellum to CN or fetal SN to cortex), the CSF HVA levels did not distinguish those monkeys with improved parkinsonism from those that remained severely parkinsonian. The finding that in some SN-CN grafted subjects reported here, there was evidence of increased dopamine and lowered HVA/dopamine ratio in the vicinity of the SN grafts (cf. Elsworth et al., 1990b) is consistent with the hypothesis that graft-derived or graft-induced dopamine production is responsible for behavioral recovery. In addition, the finding that CSF HVA levels in non-MPTP lesioned subjects were unchanged by fetal SN grafts further indicates that CSF HVA levels may not be sufficiently sensitive to changes in central dopamine production to reflect release of dopamine from relatively small grafts that may, in lesioned subjects, modify behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Cognitive and motor deficits in the performance of an object retrieval task with a barrier-detour in monkeys (Cercopithecus aethiops sabaeus) treated with MPTP: long-term performance and effect of transparency of the barrier.

To assess the stability of neural deficits produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the performance of monkeys on an object retrieval (detour) task was studied. The task required retrieval of a banana slice from a transparent box open on one side and fastened to a tray in front of the cage. The orientation of the open side, position on the tray, and position of the banana in the box were manipulated to vary the difficulty of the trials. Six African green monkeys (Cercopithecus aethiops sabaeus) were treated with MPTP (1.5-1.6 mg/kg cumulative doses over 4-5 days) and compared with 5 saline-treated control monkeys. The MPTP-treated monkeys had no gross neurological deficits but did have motor and cognitive deficits during acquisition of the object retrieval task 8-12 months after treatment (J. R. Taylor, Elsworth, Roth, Sladek, & Redmond, in press). Performance on the task was examined for 3 months after it had been learned. The MPTP-treated subjects reached at the barrier (transparent side) significantly more than controls and were less successful at retrieving the reward on the 1st reach than controls. Although they took longer to initiate the reach and had more motor problems than controls, they were as likely as controls to retrieve the reward in the end. These deficits remained stable throughout testing. An opaque but otherwise identical box was used randomly on some trials. MPTP-treated subjects decreased barrier reaches to control levels on trials in which the opaque box was used, whereas motor problems increased compared with trials in which the transparent box was used. The task can detect subtle performance deficits similar to those found in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Cognitive and motor deficits in the acquisition of an object retrieval/detour task in MPTP-treated monkeys.

To assess functional changes following treatment with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) in monkeys, we studied a task that reveals sensitivity to dopamine deficits under various conditions. The task required retrieval of a banana slice from a transparent box that is open on one side and fastened to a tray. Successful performance required the subject to suppress a tendency to reach directly at the reward while (1) orientation of the open side, (2) position on the tray, and (3) position of the banana in the box were manipulated in order to vary the cognitive and motor difficulty of the trial. African green monkeys (Cercopithecus aethiops sabaeus) were treated with MPTP (1.5-1.6 mg/kg cumulative dose over 4-5 days). A control group was sham treated (n = 12). MPTP-treated subjects either became severely symptomatic, showing motor impairments that prevented them from performing, or showed no gross motor impairment (n = 6) in spite of major depletions in dopamine concentrations. MPTP-treated subjects showed impaired acquisition of the task when tested 8-12 months later. They made more errors during the sessions, specifically on the trials that were related to cognitive complexity, such as attempting to reach directly towards the reward through the transparent side of the box (a barrier reach), instead of reaching around it (detour) into the open side, as well as other awkward, perseverative or delayed reaches. MPTP appears to cause both cognitive and motor deficits in the acquisition of this task 8-12 months after treatment, even in the group of monkeys which never showed gross motor deficits.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Modulation of mesoprefrontal dopamine neurons by central benzodiazepine receptors. I. Pharmacological characterization.

The benzodiazepine (BZ) recognition sites on the gamma-aminobutyric acid receptor/chloride ionophore complex have been suggested to be involved in the modulation of mesoprefrontal dopamine (DA) neurons. We have examined further the effects of different classes of BZ receptor ligands on DA metabolism in the prefrontal cortex. The anxiogenic inverse agonist FG 7142 elevated selectively 3,4-dihydroxyphenylacetic acid (DOPAC) levels and DO-PAC/DA ratio in the prefrontal cortex in a dose- and time-dependent manner. The activating effect was not, however, observed in any other mesocortical, mesolimbic or nigrostriatal DA terminal fields examined. Pretreatments with BZ agonists such as diazepam, flurazepam, lorazepam and CGS 9896 and BZ antagonists such as Ro15-1788 and CGS 8216 and barbiturates such as pentobarbital, significantly antagonized the beta-carboline-induced elevation of prefrontal DOPAC levels. Furthermore, a significant correlation was found between the pharmacological profile of different BZ receptor ligands on prefrontal DA metabolism and their profiles in behavioral, electrophysiological and receptor binding studies. Agonists increased DA levels and consequently decreased DOPAC/DA ratio in the prefrontal cortex. Inverse agonists, on the other hand, significantly elevated prefrontal DOPAC levels and DOPAC/DA ratio in a dose-dependent manner. Antagonists such as Ro15-1788 and CGS 8216, at low doses, did not alter mesoprefrontal DA metabolism, but at higher doses did elevate DOPAC/DA ratio in the prefrontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin.

The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examine the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental-cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.

Animals↗
PubMed1989

Morphological, neurochemical, and behavioral characterizations associated with the combined treatment of diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

Changes in striatal dopamine (DA) neurochemistry, tyrosine hydroxylase immunocytochemistry of DA fibers, and behavior following the combined administration of diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice were assessed. The combined treatment of DDC and MPTP produced a dose-dependent decrease in striatal DA levels and a dose-related increase in the striatal DOPAC:DA ratio. Cumulative doses of MPTP equal to or exceeding 53.0 (26.5 mg/kg x 2. i.p.), given in combination with DDC, were effective in reducing striatal DA levels to less than 25% of control levels 2 weeks after treatment. Tyrosine hydroxylase immunocytochemistry revealed large deafferentation of DA terminal regions in striatum, moderate reductions in nucleus accumbens and dendritic regions of substantia nigra, and slight reductions in the number of DA cell bodies in substantia nigra. Mice treated with DDC and MPTP became hyperactive during the light phase of their diurnal cycle: psychopharmacological data suggest that postsynaptic DA receptors were supersensitized following this treatment. These data provide evidence that the combined treatment of DDC and MPTP produces severe and enduring depletion of mesostriatal DA, and also concomitant behavioral changes in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

MDMA (3,4-methylenedioxymethamphetamine) inhibits the firing of dorsal raphe neurons in brain slices via release of serotonin.

The effects of MDMA (3,4-methylenedioxymethamphetamine) on the activity of serotonin (5-HT)-containing dorsal raphe neurons were characterized using extracellular single-unit recording and microdialysis techniques in the in vitro midbrain slice preparation. Addition of (+)-MDMA, (-)-MDMA or p-chloroamphetamine (PCA) to the superfusate (final concentration 3-100 microM) produced a concentration-dependent inhibition of 5-HT cell firing which was reversible and reproducible. Based upon IC50 values, (+)-MDMA was 2- to 3-fold more potent than (-)-MDMA. Pretreatment with the selective 5-HT uptake inhibitor fluoxetine, at a concentration which had no effect on baseline firing (20 microM), blocked the inhibitory effect of (+)-MDMA and PCA on dorsal raphe neurons. The selective norepinephrine uptake inhibitor desipramine (20 microM) was ineffective. In a parallel series of experiments, microdialysis probes resting on the brain slice surface provided a means to estimate 5-HT release from the dorsal raphe nucleus. (+)-MDMA (100 microM) caused the release of measureable quantities of 5-HT with a time course which corresponded to the change in dorsal raphe cell firing rate. Taken together, these data suggest that MDMA acts indirectly to inhibit dorsal raphe neurons through release of endogenous 5-HT.

3,4-Methylenedioxyamphetamine↗
PubMed1989

The anxiogenic beta-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex.

Systemic administration of the anxiogenic beta-carboline FG-7142, a benzodiazepine inverse agonist, results in a regionally selective increase in dopamine (DA) utilization in the anteromedial prefrontal cortex (PFC). We have examined both in vivo and in vitro tyrosine hydroxylation in the PFC and other mesotelencephalic DA system terminal fields in order to determine if FG-7142 effects changes in DA synthesis, and to determine if the beta-carboline biochemically activates certain DA neurons through an action occurring at the cell body level (impulse-dependent regulation) or at the terminal field level (presynaptic regulation). FG-7142 increased in vivo tyrosine hydroxylation in the PFC and in the ventral tegmental area, midbrain source of the DA innervation of the PFC; no changes were observed in mesolimbic or nigrostriatal regions. The beta-carboline also increased in vitro tyrosine hydroxylation in the PFC, but decreased tyrosine hydroxylation in striatal slices. The effects of FG-7142 were blocked by the benzodiazepine antagonist RO 15-1788. Another beta-carboline inverse agonist, methyl-beta-carboline-3-carboline-3-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the beta-carbolines, decreasing in vitro tyrosine hydroxylation in the PFC and increasing DA synthesis in the CP. These data indicate that the benzodiazepine inverse agonists increase both in vivo and in vitro tyrosine hydroxylation in the PFC, and that the beta-carboline may act to increase DA synthesis at both the terminal field and the cell body level.

Animals↗
PubMed1989

Cocaine increases extracellular dopamine in rat nucleus accumbens and ventral tegmental area as shown by in vivo microdialysis.

In vivo microdialysis measurements of extracellular dopamine (DA) were made simultaneously in nucleus accumbens (NAS) and ventral tegmental area (VTA) in anesthetized rats. Intravenous cocaine (1 mg/kg) resulted in rapid increases in DA in both NAS and VTA. The DA increase in NAS was greater in magnitude and persisted longer than that in VTA. The relevance of the observed effects to reported effects of cocaine on firing rate of mesoaccumbens DA neurons is discussed.

Animals↗
PubMed1989

Neuroactive metabolites of L-tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid. Effect of tryptophan loading.

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 microM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

Animals↗
PubMed1989

Quinolinic acid concentrations in striatal extracellular fluid reach potentially neurotoxic levels following systemic L-tryptophan loading.

Following a systemic tryptophan load, striatal extracellular fluid levels of quinolinic acid in the rat were quantified using intracerebral microdialysis. After an intraperitoneal dose of L-tryptophan (250 mg/kg), quinolinic acid levels in striatal perfusates increased by 230 fold. Peak concentrations of quinolinic acid exceeded 10(-5)M, a concentration previously shown to be neurotoxic in vitro. These results indicate that quinolinic acid is markedly precursor responsive and that its concentration in striatal extracellular fluid may reach neurotoxic levels following an acute tryptophan load.

Animals↗
PubMed1989

Controlled release of dopamine from a polymeric brain implant: in vivo characterization.

Intracerebral microdialysis was used to evaluate the long-term in vivo release of dopamine from ethylene-vinyl acetate (EVAc)-dopamine copolymer matrix discs for up to 65 days following striatal implantation. Dopamine release occurred through a single cavity present on one side of the disc, which was otherwise fully coated with an additional, impermeable layer of EVAc. At 20 days following implantation of the device, extracellular concentrations of dopamine within the striatum reached micromolar levels, over 200-fold greater than control values. Release of dopamine was shown to be stable and maintained for the 2-month duration of the experiment. Histological examination confirmed the biocompatible nature of the implant. There are potential applications of this technology to the treatment of Parkinson's disease and other neurological and psychiatric disorders.

Animals↗
PubMed1989

Regionally-specific alterations in mesotelencephalic dopamine synthesis in diabetic rats: association with precursor tyrosine.

The effect of diabetes-induced chronic tyrosine (Tyr) deficiency on dopamine (DA) synthesis in different areas of the mesotelencephalic DA system was examined. Diabetes was induced using streptozotocin. In vivo Tyr hydroxylation was used as an index of DA synthesis. The brain areas examined were prefrontal cortex (PFC), pyriform cortex (PYR), olfactory tubercle (OT), caudate-putamen (CP), substantia nigra (SN), and ventral tegmental area (VTA). Significant decreases in Tyr hydroxylation were observed in PFC, CP, and PYR. The largest decrease was seen in the PFC. Variations in tissue Tyr levels were shown to account for 62% of the variability in Tyr hydroxylation in the PFC, and 23% of the variability in the CP; a significant correlation between Tyr levels and Tyr hydroxylation was not seen in the other brain areas. The mechanisms underlying this regionally selective effect, and possible clinical relevance are discussed.

Animals↗
PubMed1989

3-Acetylpyridine-induced degeneration of the nigrostriatal dopamine system: an animal model of olivopontocerebellar atrophy-associated parkinsonism.

The effects of 3-acetylpyridine (3-AP) administration to rats on the mesotelencephalic dopamine system were assessed. A single 3-AP injection resulted in biochemical and immunohistochemical evidence of degeneration of the nigrostriatal dopamine system. Six weeks after 3-AP treatment decreases in both striatal dopamine content and the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase were observed. Immunohistochemical examination suggested a decreased density of striatal tyrosine hydroxylase-immunoreactive fibers and revealed the emergence of a distinctly patchy organization of the dopamine innervation to the dorsolateral striatum. While 3-AP administration resulted in biochemical and anatomical data consistent with the degeneration of nigrostriatal dopamine fibers, no significant changes in dopamine content or the density or pattern of tyrosine hydroxylase-immunoreactive fibers in the anteromedial prefrontal cortex or nucleus accumbens were seen. These data suggest that 3-AP administration may result in a relatively specific degeneration of the nigrostriatal dopamine system. Since 3-AP causes both a profound loss of the climbing fiber input to the cerebellum derived from the inferior olivary nucleus, and the degeneration of nigrostriatal dopamine neurons, 3-AP administration may provide a useful model of olivopontocerebellar atrophy-associated parkinsonism. Moreover, the differences in the neurotoxicity caused by 3-AP and that elicited by another pyridine which causes striatal dopamine depletion (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) may offer important insights into the mechanisms of both species- and site-specific pyridine neurotoxins.

Animals↗