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J N Johannessen

Publications and source records attributed to J N Johannessen.

At least 19 recordsLinked to original sources
PubMed1992

MPTP lesions of the nigrostriatal dopaminergic projection decrease [3H]1-[1-(2-thienyl)cyclohexyl]piperidine binding to PCP site 2: further evidence that PCP site 2 is associated with the biogenic amine reuptake complex.

Our previous studies have demonstrated that, using membranes of guinea pig brain, [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) labels not only the phencyclidine binding site associated with the NMDA receptor (PCP site 1), but also a second high affinity binding site which is associated with the biogenic amine reuptake carrier (termed PCP site 2). To test this hypothesis, the binding of [3H]GBR12935 to the dopamine transporter, and [3H]TCP binding to PCP sites 1 and 2 were measured in caudates harvested from control, MPTP-treated and reserpine-treated dogs. MPTP treatment decreased dopamine levels by over 99%, decreased [3H]GBR12935 binding by over 90%, decreased [3H]TCP binding to PCP site 2 by about 50%, and had no significant effect on [3H]TCP binding to PCP site 1. These data are consistent with the hypothesis that a portion of PCP site 2 is associated with dopaminergic nerve terminals in dog caudate.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Selective decrease in extracellular DOPAC concentrations in rat striatum following in vivo dialysis with low concentrations of MPP+.

Using the technique of in vivo dialysis, 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was applied to the rat striatum and the effects of this treatment on the efflux of striatal dopamine (DA) and metabolites were monitored. The inclusion of low concentrations of MPP+ (1 and 10 microM) in the dialysis solution caused a progressive decrease in the efflux of dihydroxyphenylacetic acid (DOPAC), the major deamination product of DA, while homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) remained unchanged. Unlike the effects of dialysis with millimolar concentrations of MPP+, a large increase in the efflux of striatal DA was not observed. The effect of dialysis with 1 microM MPP+ was blocked if 1 microM GBR 12909, a specific DA reuptake blocker, was included in the dialysis fluid, suggesting uptake of MPP+ into striatal DA terminals mediated this effect.

1-Methyl-4-phenylpyridinium↗
PubMed1991

Selective retention of MPP+ within the monoaminergic systems of the primate brain following MPTP administration: an in vivo autoradiographic study.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons of the substantia nigra pars compacta in humans and other primates, producing a parkinsonian condition. MPTP is metabolized to the toxin 1-methyl-4-phenylpyridine (MPP+) which is taken up by dopamine terminals. The subsequent events culminating in cell death in the substantia nigra pars compacta are not understood. To examine these events we first produced a chronic hemiparkinsonian condition in monkeys by administering a toxic dose of MPTP via the right carotid artery. One year later, these monkeys were given a trace dose of [14C]MPTP intravenously and allowed to survive 1, 3, or 10 days. In two acute conditions, monkeys were either given the radiolabeled trace dose intravenously immediately following the toxic intracarotid dose, or were given a single toxic intracarotid radiolabeled dose, and allowed to survive 1, 3, or 10 days. We show by histology and autoradiography that the chronic hemiparkinsonian condition is characterized by selective unilateral loss of nigrostriatal dopamine neurons and absence of MPP+ retention in the caudate-putamen. In the acute conditions, MPP+ is accumulated and selectively retained in high concentrations in the caudate-putamen bilaterally and throughout the nigrostriatal pathway only on the side receiving the toxic dose. In the substantia nigra pars compacta. MPP+ is accumulated in very low concentrations in the dopamine cell bodies and is not selectively retained there. At 10 days survival, the caudate-putamen on the side receiving the toxic dose loses its ability to retain MPP+. The apparent degeneration of the dopamine axon terminals in the caudate-putamen and the development of Parkinson-like behavioral signs seen at 10 days survival were observed to precede the loss of cell bodies in the substantia nigra, which appeared normal by the criteria of Nissl staining and neuromelanin content at all time points in the acute conditions. Other areas of dense MPP+ retention in all cases include noradrenergic and serotonergic cell groups and noradrenergic pathways. MPP+ in the locus coeruleus and other caudal catecholaminergic cell groups is apparently retrogradely transported there after uptake in terminal regions, and although it is retained in high concentrations, no cell loss occurs. These findings suggest that experimentally induced Parkinsonism results from molecular events initiated in the neostriatum and selectively elaborated in the nigrostriatal pathway, ultimately resulting in the death of substantia nigra pars compacta dopamine neurons. They do not support a significant role for neuromelanin binding in the toxicity of MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Effects of MPTP on the cerebrovasculature.

The neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been shown to cause pooling of blood in the brain microvasculature and decrease the permeability of the blood-brain barrier. All areas of the brain examined in this study were affected. This study points out the possibility that reduced nutrient uptake, hypoxia and ensuring free radical damage are involved in the mechanism of toxicity of this neurotoxin.

Animals↗
PubMed1991

Prolonged alterations in canine striatal dopamine metabolism following subtoxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 4'-amino-MPTP are linked to the persistence of pyridinium metabolites.

Single toxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).HCl (2.5 mg/kg i.v.) and 4'-amino-MPTP.2HCl (22.5 mg/kg) induce loss of striatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'-amino-MPTP, dose-response studies of these compounds were carried out in the dog, using 6- and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1.0, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (15, 7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in a dose-related fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measurement of striatal 1-methyl-4-phenylpyridinium (MPP+) and 4'-amino-MPP+ levels revealed that high concentrations (up to 150 microM) persist in the striatum for weeks following administration of a single nontoxic dose of MPTP or 4'-amino-MPTP. A causal relationship between the striatal concentration of MPP+ or 4'-amino-MPP+ and the change in DA metabolism as reflected in the DA/DOPAC ratio is suggested by a significant correlation between these measures. It is suggested that presynaptic sequestration and retention of MPP+ and 4'-amino-MPP+ by striatal DA terminals result in the inhibition of the monoamine oxidase contained within these terminals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

A model of chronic neurotoxicity: long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons.

The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces lesions in the nigrostriatal dopamine system has been extensively studied. MPTP, a lipophilic molecule, enters the brain rapidly where it is converted to the pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP+), by a two-step reaction that requires the enzyme monoamine oxidase. Following this conversion, which occurs primarily in astrocytes, MPP+ is sequestered within monoaminergic neurons by the energy-requiring monoaminergic transporters. Inside the neuron, MPP+ is thought to act as a mitochondrial toxin, slowly sapping the neuron of its energy-producing potential by blocking the action of NADH dehydrogenase. Much attention has been focused on cell death after MPTP administration, but little attention has been paid to the effects of small subtoxic doses of MPTP (i.e., doses that do not produce overt neuropathologic changes), which might occur during environmental exposure to a nigrostriatal toxin. Low doses of MPTP (as little as 1/25th of a toxic dose) produce long-term (greater than 6 weeks) but reversible changes in catecholamine metabolism. These changes are characterized by a decrease in the products of enzymatic oxidative deamination without a concomitant decrease in the amine concentrations (apparent MAO inhibition). Striatal concentrations of MPP+, which is retained in catecholaminergic terminals for similarly long periods, parallel the metabolic changes. Thus, the long-term storage of the MPTP metabolite, MPP+, correlates with altered catecholamine metabolism. The data on the effects of MPTP have been combined into a working model of how MPP+ exerts its effects following subtoxic or toxic doses. The site of this long-term neuronal storage of MPP+ after exposure to subtoxic doses of MPTP is as yet undetermined, but several studies suggest that monoaminergic vesicles may be the primary site, with mitochondria contributing some storage capacity. This vesicular site could represent a potential brain site for the accumulation of toxins during continual or repeated exposure to low levels of MPTP. Induced release from this site might accelerate the toxic interactions with cellular components such as mitochondria.

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

Differential uptake of HRP by intact axon terminals versus transected axons: a study on bulbospinal fibers in the dorsolateral funiculus.

A comparison was made of the amount of HRP uptake from transected versus intact axonal endings of rostral ventromedial medulla (RVMM) and locus coeruleus cells projecting via the dorsolateral funiculus in the rat. We found that retrograde labelling in the RVMM was reliably different between treatments, while locus coeruleus retrograde labelling was highly variable and not reliably different. HRP applied to intact endings retrogradely labelled approximately twice as many RVMM cells, including 25 times as many 5-hydroxytryptamine (B3) cells, as HRP applied to transected axons. In this first quantitative assessment of HRP uptake from transected versus intact endings, reliable differences have been found. These results have implications for the neural circuitry involved in pain modulatory systems.

Animals↗
PubMed1990

Prolonged changes in plasma concentrations of catecholamine metabolites following a single infusion of an MPTP analog.

The magnitude and duration of effects of a single intravenous injection of 4'-amino MPTP, an analogue of the dopamine neurotoxin, MPTP, on plasma levels of catechols and normetanephrine were examined in conscious dogs. Plasma samples were collected prior to treatment with intravenous saline or 4'-amino MPTP.2HCl (22.5 mg/kg) and at weekly intervals for six weeks following treatment. Saline treatment had no effect on plasma levels of any of the measured compounds. Following 4'-amino MPTP, plasma DHPG fell to 14% of the pre-injection value and remained decreased for the full 6-week test period, with partial recovery by week 6 to 42% of the pre-injection value. Plasma DOPAC levels fell to 28% of pre-injection values 1 week after treatment with 4'-amino MPTP and showed no evidence of recovery during the 6-week test period. Plasma DOPA fell to 58% of the pre-injection level, while concentrations of the catecholamines NE, EPI, and DA were generally unaffected. The plasma concentration of the O-methylated NE metabolite, normetanephrine, was also unchanged by 4'-amino MPTP treatment. There were no differences in the concentrations of DA, NE or EPI within the adrenal medulla between saline and 4'-amino MPTP treated groups. This pattern of changes in plasma levels of catechols, which is consistent with presynaptic inhibition of MAO within sympathetic terminals, may be a useful indicator of exposure to MPTP-like neurotoxins.

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

Spinal paralysis and catalepsy induced by intrathecal injection of opioid agonists.

The intrathecal administration of high (1.05 mumol) doses of D-Ala2-Met5-enkephalinamide (DAMA), D-Ala2-Leu5-enkephalinamide (DADLE), Try-D-Thr-Gly-Phe-Leu-Thr, MR2034-TA, dextrorphan tartrate, U50,488H, levorphanol tartrate, methadone hydrochloride, and 1-methyl-4-phenyl-4-propionoxypiperidine induced spinal hypokinesia. The first 5 of these compounds caused spinal paralysis, whereas the other compounds and lower doses of the first 4 induced waxy catalepsy that was restricted to the hindquarters of rats. The paralysis induced by DAMA was not reversible by IT injections of 50 micrograms naltrexone, indicating, together with the paralytic effects of dextrorphan, that traditional opiate receptors are not involved in this behavioral effect. The spinal catalepsy induced by 0.26 mumol of DAMA was prevented by IT pretreatment with 10 micrograms of naltrexone. In view of this finding and the observation that spinal catalepsy can be induced by agonists of all opiate receptor classes, it seems likely that spinal catalepsy is produced by activation of specific opiate receptors, although the subtype remains to be established.

Animals↗
PubMed1989

MPTP treatment combined with ethanol or acetaldehyde selectively destroys dopaminergic neurons in mouse substantia nigra.

We have previously reported that ethanol and acetaldehyde potentiate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, enhancing dopamine (DA) depletion in the striatum. The present study was designed to determine whether such enhancement of neurotoxicity was specific for the nigro-striatal DA pathway. In 5-week-old mice acetaldehyde treatment did not enhance DA depletion seen 7 days after MPTP treatment. In 8-week-old animals, however, acetaldehyde or ethanol given with MPTP decreased striatal DA content to about 10% of controls, whereas the depletion was to 43% of controls when MPTP was given alone. In acetaldehyde or ethanol and MPTP-treated mice, changes in DA levels were observed only in the striatum. DA contents in the hypothalamus, olfactory bulb and frontal cortex were similar to that in controls. Contents of norepinephrine and serotonin in striatum, hypothalamus, olfactory bulb and cerebral cortex were not affected by any of the treatments. Three months after MPTP alone, striatal DA recovered to 74% of controls in 8-week-old mice, whereas no recovery occurred in acetaldehyde and MPTP-treated mice. Moreover, both tyrosine hydroxylase (TH) immunocytochemistry and Cresyl violet staining showed an extensive and selective cell loss in the pars compacta of the substantia nigra (SNc) of the mice treated with acetaldehyde or ethanol and MPTP, whereas MPTP alone caused only a limited cell degeneration.

Acetaldehyde↗
PubMed1989

Blockade of morphine-induced increases in brain tryptophan hydroxylase activity by systemic pretreatment with CCK-8: no reversal by vagotomy.

The treatment of rats with CCK-8 suppresses the behavioral responses to subsequent injection of opiates. We have investigated the possibility that peripherally administered CCK-8 can also suppress a neurochemical response to opiates, namely the increase in brain tryptophan hydroxylase (TrpH) activity and tissue 5-hydroxyindole acetic acid (5-HIAA) which results from morphine administration. While morphine sulfate (4 mg/kg s.c.) roughly doubled brain TrpH activity and tissue 5-HIAA 40 min after injection, pretreatment with CCK-8 (5 micrograms/kg i.p., 10 min prior to morphine) completely abolished this neurochemical change induced by morphine. Doses of CCK-8 as low as 1 microgram/kg were effective in blunting the morphine-induced increase in cortical TrpH activity, but the desulfated form was ineffective at doses of 5 and 100 micrograms/kg. Subdiaphragmatic vagotomy did not prevent the effect of CCK-8.

Animals↗
PubMed1989

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the dog: effect of pargyline pretreatment.

Adult beagle dogs of either sex were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-HCl (2.5 mg/kg, i.v.) alone or after pretreatment with pargyline (5.0 mg/kg, s.c., twice), with pargyline alone, or were uninjected. Groups were killed 2 h, 3 weeks, or 3 months after injection, and several brain areas were assayed for biogenic amines and their synthetic and degradative enzymes. MPTP caused a massive and permanent loss of striatal dopamine, tyrosine hydroxylase, and 3,4-dihydroxyphenylalanine decarboxylase activities and the loss of cells within the substantia nigra pars compacta. Dopamine and norepinephrine also were depleted to various degrees in cortex, olfactory bulb, and hypothalamus; however, dopamine beta-hydroxylase activity in cortex was normal. There was no cell loss in the ventral tegmental area or locus ceruleus. The activities of monoamine oxidase (MAO)-A and MAO-B in cortex and caudate were not affected by MPTP. Despite a permanent loss of the nigrostriatal system, the dogs exhibited only a transient hypokinesia lasting 1-2 weeks. Pargyline pretreatment prevented the loss of striatal dopamine and cells from the substantia nigra, but did not prevent a prolonged but reversible decrease in the concentration of dopamine metabolites. It is argued that this apparent inhibition of MAO is due not to suicide inactivation of the enzyme by MPTP, but to reversible inhibition by accumulation of the pyridinium metabolite, 1-methyl-4-phenylpyridinium, selectivity in aminergic terminals.

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

3,4-Methylenedioxymethamphetamine ("ecstasy") selectively destroys brain serotonin terminals in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), an amphetamine analog, is a "designer drug" which is being increasingly abused. The potential neurotoxic hazard of MDMA in humans was assessed by examining the effects of repeated systemic administration of MDMA on selected neurochemical and behavioral measures in rhesus monkeys. In the first study, MDMA (2.5 or 10 mg/kg twice daily for 4 days) produced selective and significant neurochemical decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and brain concentrations of serotonin and 5-HIAA. At the high dose of MDMA, a selective decrease in serotonin uptake sites (reflecting destruction of brain serotonin terminals) was observed. To determine if these changes after high dose MDMA were pharmacologic or truly neurotoxic, in a subsequent study monkeys were treated with MDMA (10 mg/kg twice daily for 4 days) and then monitored for 14 weeks. Throughout this period, CSF 5-HIAA was decreased in MDMA-treated animals but not in saline-injected controls. At the end of this period, significant decreases in the concentration of serotonin, 5-HIAA and serotonin uptake sites were observed in cerebral cortex and striatum but not in hypothalamus or spinal cord. In contrast to these widespread alterations in serotonin markers, comparable noradrenergic and dopaminergic measures in CSF and brain appeared generally unaffected. These data demonstrating potent and selective effects of MDMA on various brain serotonin parameters in rhesus monkeys suggest that the drug may produce similar effects in humans.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+.

Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.

1-Methyl-4-phenylpyridinium↗
PubMed1987

Activation of cortical tryptophan hydroxylase by acute morphine treatment: blockade by 6-hydroxydopamine.

Acute morphine produced a dose-dependent, naloxone-sensitive, reversible increase in tryptophan hydroxylase activity in low speed supernatants of midbrain, pons-medulla and cerebral cortex but not spinal cord. The increase in cortical enzyme activity was blocked by 6-hydroxydopamine pretreatment, could be reversed in vitro by incubation with alkaline phosphatase and was non-additive with the increase in enzyme activity induced in the presence of phosphorylating conditions. Morphine administration produced an increase in Vmax but no change in Km of cortical enzyme for substrate, tryptophan, or the artificial reduced pterin cofactor, 6-methyl-5,6,7,8-tetrahydropterin. The failure of morphine to increase spinal tryptophan hydroxylase activity despite enhancement of enzyme activity in medulla indicates regional differences in responsiveness of the enzyme to in vivo activation.

Alkaline Phosphatase↗
PubMed1987

The development of amine substituted analogues of MPTP as unique tools for the study of MPTP toxicity and Parkinson's disease.

We are currently developing amino-substituted MPTP analogues as useful probes for understanding the mechanism of MPTP toxicity and Parkinson's disease. One analogue, 4'-amino MPTP, induces a loss of striatal dopamine and is thus a suitable substitute for MPTP. This probe will be used as a histologically fixable MPTP which can be used to answer detailed anatomical questions concerning the sites of MPTP, MPP+ uptake and storage. In addition, antibodies have been raised against MPTP and MPP+ in rabbits using diazo-linked bovine serum albumin conjugates. The antibodies have been characterized with regard to their recognition of relevant structural analogues using an enzymelinked immunoassay (ELISA) procedure. Antibodies to MPTP detected MPTP in mouse brain extracts derived from as little as 5 micrograms of tissue. The antibodies will be used for immunohistochemical localization of 4'-NH2-MPTP and 4'-NH2-MPP+ in brain, as well as probes for the screening of parkinsonian brain tissue for any MPTP- or MPP+-like materials which might exist.

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