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R H Roth

Publications and source records attributed to R H Roth.

At least 181 records · Page 10Linked to original sources
PubMed1987

The activation of mesoprefrontal dopamine neurons by FG 7142 is absent in rats treated chronically with diazepam.

Administration of methyl-beta-carboline-3-carboxamide (FG 7142, 15 mg/kg i.p.) to rats has previously been shown to cause a selective increase in the levels of 3,4-dihydroxy-phenylacetic acid (DOPAC) in the prefrontal cortex and ventral tegmental area (VTA) via an interaction with benzodiazepine receptors. On withdrawal 3 days following chronic treatment with diazepam for 21 days, FG 7142 no longer increased DOPAC levels in either the prefrontal cortex or the VTA. Chronic diazepam treatment alone was ineffective in altering dopamine metabolism in the eight brain regions examined. The present findings indicate that chronic diazepam treatment may cause changes at the level of GABA/benzodiazepine receptor macromolecular complex, which is normally functionally integrated with the mesoprefrontal dopaminergic neurons, so that FG 7142 can no longer exert its intrinsic actions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response.

The effects of acute administration of phencyclidine, an indirect dopamine agonist, on biochemical indices of dopaminergic activation were examined in mesocortical, mesolimbic and nigrostriatal regions of the rat. High doses (10 mg/kg) of phencyclidine resulted in a marked increase in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in all mesolimbic and mesocortical sites examined, as well as in the ventral tegmental area, source of the dopaminergic innervation of mesolimbic/cortical sites. In contrast, levels of both metabolites decreased in the striatum and tended to decrease in the substantia nigra, source of the striatal dopaminergic innervation. The metabolite response to phencyclidine was dose-related. These data indicate that the mesolimbic and mesocortical dopaminergic neurons are activated by phencyclidine. Since the firing rate of both A10 (ventral tegmental area) and A9 (substantia nigra) dopamine neurons has previously been shown to be increased by phencyclidine, these data suggest that phencyclidine results in a differential regulation of presynaptic release of dopamine in mesolimbic/cortical as opposed to nigrostriatal dopaminergic regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Calcitonin gene-related peptide in the ventral tegmental area: selective modulation of prefrontal cortical dopamine metabolism.

The distribution of calcitonin gene-related peptide (CGRP) in the A10 dopamine (DA) cell group region of the ventral tegmental area (VTA) of the rat was examined using immunohistochemical techniques. CGRP-like immunoreactivity was localized to axons innervating the rostral and dorsal VTA. Direct administration of CGRP to the VTA of the rat resulted in a dose-related increase in DA utilization in the medial prefrontal cortex, but not other mesocortical, mesolimbic, or striatal DA terminal field regions. These data suggest that CGRP may function to selectively modulate the activity of VTA dopaminergic neurons which innervate the prefrontal cortex.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Differential responsiveness to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in sub-regions of the primate substantia nigra and striatum.

After treatment with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), there was a severe loss of dopamine (DA) at all examined sites in the striatum, both in those monkeys which remained asymptomatic (77-99%) and in one monkey which developed severe parkinsonian disability (94-99%). However, the asymptomatic animals had normal DA concentration in the substantia nigra (SN); yet in the symptomatic animal DA was largely depleted in the central (86%) and medial (94%), but not lateral (8%) regions of the SN. The HVA/DA ratio was raised in the striatum of all MPTP-treated animals. In the SN though, this ratio was elevated only in the symptomatic animal, in the central and medial, but not lateral regions. The contralateral half of these brains were examined for DA histofluorescence. The SN of asymptomatic animals had a slight increase in lipofuscin fluorescence within dopaminergic neurons and a small reduction in the number of dopaminergic cells, while fluorescent intensity of individual neurons was unchanged. The SN of the symptomatic animal displayed a sharp decline in the number of DA neurons along with an increase in autofluorescent pigment granules; these changes were most pronounced in the central and medial regions of the SN. These data suggest that after MPTP the terminals of the nigrostriatal pathway are affected before the cell bodies. In the one symptomatic animal emergence of parkinsonian disability corresponded with a marked loss of DA neurons and DA concentration in the central and medial regions of the SN. In the control monkeys a gradient in the concentration of amines and metabolites was observed within the SN; the lateral region contained the highest and the medial region the lowest concentration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Homovanillic acid concentrations in brain, CSF and plasma as indicators of central dopamine function in primates.

In a large number (91) of vervet monkeys, correlation coefficients were determined between homovanillic acid (HVA) concentrations in four brain areas. Significant correlations existed between dorsal frontal cortex and orbital frontal cortex and between putamen and caudate nucleus. However, no significant correlations existed between either cortical area and the basal ganglia areas. Correlations were tested between CSF and plasma HVA and between these fluids and brain regions. The only significant relationship found was between CSF and dorsal frontal cortex, after possible treatment effects were statistically removed. The assumption that primate CSF HVA concentration necessarily reflects basal ganglia HVA concentration is questioned and furthermore, the results suggest that HVA from cortex contributes significantly to that in cisternal CSF. Raw plasma HVA measurements (even when uninfluenced by diet or anesthetic) appear to be of limited value in gauging central dopamine metabolism and turnover.

Animals↗
PubMed1987

Nigrostriatal dopamine neurons: modulation of impulse-induced activation of tyrosine hydroxylation by dopamine autoreceptors.

The role of dopamine autoreceptors on nerve terminals in controlling the activity of tyrosine hydroxylase in the striatum was examined using a model involving supramaximal electrical stimulation of the nigro-neostriatal fibers and accumulation of 3,4-dihydroxyphenylalanine (DOPA) as a measure of the activity of tyrosine hydroxylase in vivo. In this way effects of drugs on impulse flow in these neurons could be negated and the effects on dopamine autoreceptors evaluated. Electrical stimulation, haloperidol, pimozide and clozapine increased the activity of tyrosine hydroxylase in vivo while trivastal, a dopamine agonist, had no significant effect. Combination of electrical stimulation with haloperidol or pimozide produced an additive effect on the activity of tyrosine hydroxylase, consistent with blockade of autoreceptors on nerve terminals. The combination of stimulation with clozapine (a drug shown to have minimal blocking action on autoreceptors in this model) produced an effect equivalent to stimulation alone, consistent with a lack of effect on autoreceptors. Trivastal reduced the effect of electrical stimulation, indicating a stimulatory action on dopamine autoreceptors on nerve terminals. These data are consistent with the theory of regulation of the activity of tyrosine hydroxylase in dopaminergic nerve terminals of the striatum by means of dopamine autoreceptors.

Animals↗
PubMed1987

Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors.

The ability of dopamine (DA) agonists and antagonists to modulate the K+-evoked overflow of radioactivity from superfused slices of prefrontal cortex of the rat, preincubated with [3H]DA in the presence of 1 microM desipramine, was examined. Apomorphine and the putative autoreceptor-selective DA agonist EMD 23 448 inhibited the K+-evoked overflow of radioactivity, while the DA antagonist sulpiride enhanced the evoked overflow in a dose-dependent and stereoselective manner. The latter effect was partially reversed by EMD 23 448. More than 95% of the radioactivity retained by the slices chromatographed with DA, while deaminated metabolites represented the majority of both the basal efflux (84% metabolites, 4-5% DA) and evoked overflow (84% metabolites, 14% DA) of radioactivity. These findings indicate that mesoprefrontal DA neurons possess release-modulating nerve terminal autoreceptors. Previous studies have shown that these neurons lack synthesis-modulating autoreceptors. Thus, autoreceptors on prefrontal DA terminals appear to be coupled to regulation of the release but not the synthesis of DA.

Animals↗
PubMed1987

Immunohistochemical localization of a neuronal nicotinic acetylcholine receptor in mammalian brain.

A monoclonal antibody generated against purified acetylcholine receptor from Torpedo electric organ was used to immunohistochemically localize a neuronal nicotinic acetylcholine receptor. Regions of the rat brain stained with this antibody paralleled those areas of the brain exhibiting [3H]nicotine binding sites and corresponded to areas in which mRNAs encoding for alpha subunits of the neuronal nicotinic acetylcholine receptor are present. Thus, the anteroventral thalamus, cortex, hippocampus, medial habenula, interpeduncular nucleus, and substantia nigra/ventral tegmental area exhibited significant immunoreactivity. Neurons of the medial habenula and substantia nigra were densely stained, and processes were prominently delineated. Furthermore, in the projection areas of the medial habenula (interpeduncular nucleus and median raphe) axons were strongly immunoreactive and were distributed to distinct subdivisions of the target sites. The present data suggest that there are several discrete neuronal systems in which nicotinic acetylcholine receptors have functional importance. These immunohistochemical studies delineate at the single-cell level the localization within the mammalian central nervous system of certain nicotinic acetylcholine receptors.

Animals↗
PubMed1986

The ascending projections of the dopaminergic neurons of the substantia nigra, zona reticulata: a combined retrograde tracer-immunohistochemical study.

The efferent projections of the dopaminergic neurons in the zona reticulata of the substantia nigra were examined using a combined retrograde tracer-immunohistochemical method. These dopamine (DA) neurons were found to project exclusively to striatal targets in a topographically defined fashion. The zona reticulata DA neurons do not innervate mesolimbic or mesocortical dopaminergic terminal fields, nor do they project to the superior colliculus or the ventromedial thalamic nucleus. These data suggest that the dopaminergic neurons of the zona reticulata represent a ventrally placed subset of the nigrostriatal DA cells of the pars compacta.

Animals↗
PubMed1986

Mild footshock stress dissociates substance P from substance K and dynorphin from Met- and Leu-enkephalin.

Mild footshock stress selectively activates ventral tegmental area dopamine neurons innervating the prefrontal cortex. The same stressor rapidly dissociates ventral tegmental substance P from its preprotachykinin-derived co-transmitter substance K, and preproenkephalin B-derived dynorphin B from preproenkephalin A-derived Met-enkephalin-Arg-Gly-Leu and Leu-enkephalin. Mild footshock stress may provide a paradigm for studying both peptidergic modulation of brain dopaminergic neurons and the dynamic regulation of tachykinin and opioid peptide transcription, processing and utilization.

Animals↗
PubMed1986

Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Immunohistochemical examination of the midbrain of vervet monkeys treated with MPTP revealed a marked loss of dopaminergic neurons in the lateral, but not medial, region of the A8 dopamine (DA) cell group. In the same animals, the number of DA neurons in the substantia nigra was only slightly decreased. Biochemical assessment revealed a marked (greater than 85%) depletion of DA in the striatum. However, in the DA cell body regions significant decreases in DA and homovanillic acid were observed only in the lateral A8 region, and not in the medial A8 region or substantia nigra. These data suggest that those A8 DA neurons which project to the striatum are preferentially vulnerable to MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine.

Fetal substantia nigra cells of two different gestational ages were successfully transplanted into the brains of three methylphenyltetrahydropyridine-treated monkeys with severe parkinsonian motor and behavioural deficits. Functional improvement continued for 10 weeks after cell grafts into the striata of two monkeys with substantial numbers of tyrosine-hydroxylase-positive fetal neurons at necropsy. Behavioural improvement was correlated with increases in cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations after the transplants. A control monkey with inappropriately placed transplanted cells of an earlier gestational age remained severely parkinsonian and died during a similar period. CSF HVA fell slightly in this monkey from the low level seen before the transplants. Fetal dopamine neurons of two different gestational ages appear to survive transplantation in primates and have biochemical and functional effects.

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