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J N Johannessen

Publications and source records attributed to J N Johannessen.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1986

High affinity binding sites for 1-methyl-4-phenyl-pyridinium ion (MPP+) are present in mouse brain.

The possible involvement of 1-methyl-4-phenyl-pyridinium ion (MPP+) in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prompted us to search for and characterize [3H]MPP+ binding sites in the mouse. Our data show that [3H]MPP+ binds saturably and with high affinity to mouse brain membranes. Scatchard analysis resulted in one straight line. The apparent KD was 15 +/- 1 nM and the Bmax 245 +/- 30 fmol/mg protein. The distribution of [3H]MPP+ binding sites shows a regional variation: the hypothalamus having highest binding and the cerebellum the lowest. Several compounds failed to inhibit [3H]MPP+ binding whereas only analogues of MPP+, MPTP and paraquat were able to antagonize this binding to brain. Specific binding with analogous characteristics also occurs in peripheral tissues. Considering the postulated role of MPP+ in MPTP neurotoxicity, further studies on [3H]MPP+ binding sites might be relevant to elucidate the mechanisms of this toxicity.

1-Methyl-4-phenylpyridinium↗
PubMed1986

Increase in hypothalamic cholecystokinin following acute and chronic morphine.

Recent evidence supports an antagonistic interaction between cholecystokinin (CCK) and opiate peptides. The present study determined the effects of various levels of morphine treatment on hypothalamic levels of CCK as determined by radioimmunoassay. Acute treatment with morphine sulfate (10 mg/kg) or implantation of one morphine pellet (75 mg free base) increased levels of CCK in whole hypothalamus. Increased exposure to morphine by either chronic injections or implantation of two pellets did not result in a further change in whole hypothalamic CCK levels. In samples dissected into hypothalamic subregions, the effect of morphine on CCK levels was localized to medial but not lateral or posterior regions. These experiments extend earlier in vitro findings and suggest that some of the physiological and behavioral effects of opiate peptides may result from modulation of endogenous CCK.

Animals↗
PubMed1986

1-Methyl-4-phenylpyridine (MPP+) induces oxidative stress in the rodent.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces an irreversible parkinsonism in primates. Recent evidence suggests metabolism of MPTP to 1-methyl-4-phenylpyridine (MPP+) is required for toxicity. We have proposed that MPP+ may play a central role in the toxicity of MPTP, but direct assessment of the effects of MPP+ in brain is difficult. Therefore, we have sought to define the mechanism of peripheral MPP+ toxicity in the rat and mouse. Systemically administered MPP+ produced its major pathology in the lung and was typified by perivascular edema. An increase in plasma glutathione disulfide concentrations also resulted, suggesting that MPP+ in analogy to paraquat produces oxidative stress. In addition, the lethality of MPP+ in the mouse was increased by dietary selenium deficiency. These results define in both pathological and chemical terms the potent systemic toxicity of MPP+ and suggest that MPP+, because of its high concentration in primate brain, has the potential to play an important role in the CNS toxicity of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Differences in the metabolism of MPTP in the rodent and primate parallel differences in sensitivity to its neurotoxic effects.

Primates and rodents show marked differences in sensitivity to the neurotoxic effects of MPTP. We and others have previously shown that the toxic effects of MPTP on nigrostriatal cells are dependent on the oxidative metabolism of MPTP to the quaternary species MPP+. We have therefore compared the distribution and metabolism of MPTP in the monkey and several rodent species. Three major differences have been identified: 1) the primate, but not the rodents, showed a persistently high concentration of MPTP metabolites in the caudate nucleus compared to other brain regions; 2) the rodent brains cleared MPTP and its metabolites much more rapidly than did the monkey, and; 3) the predominant metabolite retained by the monkey brain was MPP+, while MPP+ cannot be detected in rodent brains for more than a few hours after injection. The persistence of MPP+ in the primate brain may explain the heightened toxicity of MPTP in this species.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat.

At doses of 5-10 mg kg-1, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) produces in rats acute immobility, retropulsion, straub tail, piloerection, exophthalmos, salivation and clonic movements of the forepaws. It does not produce analgesia as measured by the tail test, nor does it produce permanent motor impairment after chronic or intranigral administration. The acute retropulsion and immobilizing effects can be blocked by methysergide. Administered acutely, NMPTP doubles levels of serotonin in the raphe nucleus and substantia nigra. At the same time, levels of dopamine increase in the caudate nucleus and decrease in the substantia nigra. The NMPTP-induced decrease in dopamine content of the substantia nigra persists in chronically treated rats, but there is no significant decrease in striatal dopamine. After chronic administration of NMPTP, striatal levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased by about 50%. Intranigral administrations of NMPTP (10 micrograms daily for 5 days) failed to produce a 6-hydroxydopamine-like lesion in the nigrostriatal system. These results indicate that NMPTP in the rat does not cause selective destruction of dopaminergic neurons, but it does produce acute tryptamine-like effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

The neurochemical basis of footshock analgesia: the role of spinal cord serotonin and norepinephrine.

Previous studies have demonstrated that brief front paw and brief hind paw shock produce potent opiate and non-opiate analgesia, respectively. Additionally, opiate analgesia can be classically conditioned by using either front paw shock or hind paw shock as the unconditioned stimulus. Front paw footshock-induced analgesia (FSIA), hind paw FSIA, and classically conditioned analgesia are similar in that each is mediated by a medullospinal pathway. However, the neurochemistry of these medullospinal connections has never been investigated. One question which arises is whether any of these phenomena are mediated by monoaminergic neurotransmitters at the level of the spinal cord. The present series of experiments examined the effect of depleting spinal serotonin (5-HT) and combined depletion of spinal 5-HT and norepinephrine (NE) on front paw FSIA, hind paw FSIA, and classically conditioned analgesia. Hind paw FSIA and classically conditioned analgesia were not attenuated by either of these neurochemical manipulations. Front paw FSIA was significantly reduced by both 5-HT depletion and combined 5-HT and NE depletion. To assess the relative importance of spinal 5 HT and NE in front paw FSIA, NE and 5-HT antagonists were injected onto the lumbosacral cord prior to shock exposure. Attenuation of front paw FSIA by equimolar doses of the monoamine blockers was much greater following injection of the 5-HT blocker than after the NE blocker. These data indicate that spinal 5-HT and, apparently to a lesser extent, spinal NE mediate front paw (opiate) FSIA whereas neither 5-HT nor NE appears to mediate hind paw FSIA or classically conditioned analgesia.

Afferent Pathways↗
PubMed1984

Assessment of the opiate properties of two constituents of a toxic illicit drug mixture.

The intravenous use of an illicit synthetic drug preparation has caused permanent parkinsonism in a number of addicts. Chemical analysis has revealed the ingredients to be two related compounds 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP). The opiate properties of these two compounds have been assessed using in vitro receptor binding techniques as well as behavioral tests indicative of opiate action, including analgesia, catatonia, respiratory depression and the loss of righting and corneal reflexes. All opiate activity was found to reside with MPPP, which proved to be a potent mu-type agonist. It is concluded that the opiate properties of MPPP alone explain repeated abuse of MPTP/MPPP mixtures by heroin addicts.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Non-serotonergic origins of the dorsolateral funiculus in the rat ventral medulla.

Cells within the ventral medulla whose axons descend to the spinal dorsal horn via the dorsolateral funiculus (DLF) play an important role in pain modulation. Previous evidence suggests that this pathway is primarily serotonergic. We have examined this hypothesis directly using combined retrograde horseradish peroxidase/serotonin immunohistochemical staining. Cells of the ventral medulla contributing to the DLF were found to be largely non-serotonergic. This result was confirmed by two approaches: by the absence of a significant number of double-labeled cells following discrete horseradish peroxidase labeling of the DLF and by the persistence of double-labeled cells in animals with DLF lesions made rostral to intraspinal injections of horseradish peroxidase solutions. The conclusion is made that the previously described nucleus raphe magnus-DLF-dorsal horn pathway is predominantly non-serotonergic.

3,3'-Diaminobenzidine↗
PubMed1982

Failure of spinal cord serotonin depletion to alter analgesia elicited from the periaqueductal gray.

The effects of spinal cord serotonin depletion or combined serotonin/norepinephrine depletion on analgesia elicited by electrical stimulation of, or morphine microinjection into, the periaqueductal gray, were tested. Spinal cord serotonin was depleted by intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT), preceded by systemic desipramine, while 5,7-DHT alone was used to deplete both norepinephrine and serotonin. Selective serotonin depletion had no effect on analgesia induced by either method at 24 h, 1 week, or 2 weeks after treatment. Depletion of both monoamines had no effect on stimulation produced analgesia 24 h and one week after treatment, but produced a slight attenuation 2 and 3 weeks after treatment. In contrast, depletion of both monoamines drastically attenuated morphine analgesia 24 h after treatment. The results are discussed in relation to multiple pain inhibitory pathways.

5,7-Dihydroxytryptamine↗
PubMed1981

Efficient extraction and mass spectrometric assay of serotonin in biological fluids.

A gas chromatographic mass spectrometric assay for serotonin (5-hydroxytryptamine) has been developed. Serotonin is acylated in homogenized biological media, efficiently extracted into ethyl acetate, and further derivatized with pentafluoropropionic anhydride. Mass spectral characterization of derivatized serotonin using electron and positive or negative chemical ionization indicates that electron ionization mass spectrometry is useful for serotonin assay in most biological fluids and tissues, but that electron capture negative chemical ionization is required for samples containing less than 1-2 ng (cerebrospinal fluid). An assay limit of 10 pg per sample has been established. Examples of applications for the assay of serotonin in human platelets, rat spinal cord, and monkey cerebrospinal fluid are presented.

Animals↗
PubMed1975

Behaviorally evoked hippocampal theta waves: a cholinergic response.

Forced running in a treadmill results in the instantaneous appearance of a synchronous electroencephalographic pattern in the dorsal hippocampus of the rat. A similar bioelectric response in the absence of movement is induced by physostigmine. Both responses are blocked with scopolamine. Lesions of the medial septal nucleus abolish hippocampal theta waves induced by forced running or physostigmine.

Acetylcholine↗
PubMedDate not supplied

Domoic acid: neurobehavioral and neurohistological effects of low-dose exposure in adult rats.

Adult rats treated IP with domoic acid at 0, 0.22, 0.65, or 1.32 mg/kg were tested for passive avoidance (PA), auditory startle (AS), or conditioned avoidance (CAR) behaviors. Clinical signs were observed only at the 1.32 mg/kg dose level. Within 24 h of dosing, rats surviving a dose of 1.32 mg/kg exhibited transient decreased body weight and exaggerated AS responding. Startle latency and habituation, PA, and CAR were not affected. Examination of brains from six rats per group revealed a subset (2/6) of animals receiving 1.32 mg/kg domoic acid with degenerating neurons in the hippocampal CA1/CA3 subregions and gliosis. The decreased body weight and increased startle suggest a hyperreactivity syndrome possibly related to neuronal degeneration in the hippocampus. In a separate experiment, domoic acid at an IP dose of 0.93 mg/kg was found to produce hypomotility in addition to a decrease in body weight. Both effects were reduced by pretreatment with scopolamine (2 mg/kg), but not with caffeine (30 mg/kg), indicating a possible cholinergic involvement in domoate's toxicity.

Acoustic Stimulation↗
PubMedDate not supplied

Metabolism of [14C]MPTP in mouse and monkey implicates MPP+, and not bound metabolites, as the operative neurotoxin.

The distribution, identification, and binding of [phenyl-14C]- or [methyl-14C]MPTP metabolites have been determined in brains of mouse and monkey exposed to toxic doses of MPTP. The distribution of radiolabeled metabolites was heterogeneous, with levels of MPP+ 1-100 mumol/L in dissected and homogenized monkey brain tissues. MPP+ constituted greater than 98% of all tissue radioactivity remaining at 1-3 days in the monkey and was identified in both cortical and striatal tissue. The relevance of the 2% of unextractable ("bound") radiolabeled metabolite was assessed in mouse brain by using pargyline or mazindol pretreatments which block dopamine depletion. The amount of binding increased rather than decreased when [phenyl-14C]MPTP was used along with pargyline or mazindol but was unchanged when [methyl-14C]MPTP was employed. This demonstrates that bound metabolites are inversely correlated to neurotoxicity as well as being N-demethylated. Two extractable metabolites, demethylated MPTP (PTP) and 1-methyl-4-phenyl-2-pyridone, were found at 30-min survival times in mouse brain and probably derive from peripheral metabolism of MPTP. At 4 h, mouse brain profiles of extractable metabolites resembled those from monkey brain, containing MPP+ as the predominant (greater than 90%) constituent. The similarity of MPP+ concentrations in mouse and monkey brain homogenates with those concentrations of MPP+ known to produce biological effects in vitro, along with the inverse relationship between bound metabolites and neurotoxicity, supports the intermediacy of MPP+ as the operative neurotoxin.

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