Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied six patients with MPTP-induced parkinsonism to assess intellectual function, attention, reaction time, and depression. Eight controls with a similar history of drug abuse also participated. General intellectual function, construction, category naming, and frontal lobe function were worse in the patients; other aspects of performance were comparable. All affected women but none of the men were depressed, usually before onset of parkinsonism. The pattern of intellectual deficit in the MPTP patients was similar to that of idiopathic Parkinson's disease. Since MPTP-induced parkinsonism probably represents a purely dopaminergic deficiency, these findings suggest that changes in the dopamine system are responsible for at least some of the intellectual changes of idiopathic Parkinson's disease.
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PMID:Intellectual changes in patients with MPTP-induced parkinsonism. 387 7

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.
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PMID:Assessment of the opiate properties of two constituents of a toxic illicit drug mixture. 614 25

Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, is an inhibitor of the serotonin and norepinephrine neuronal transporters (Wong et al., 1993). In mice, duloxetine antagonized the depletion of brain serotonin by p-chloroamphetamine (ED50 = 2.5 mg/kg, i.p.) and the depletion of heart norepinephrine by 6-hydroxydopamine (ED50 = 1.1 mg/kg, i.p.). Brain concentrations of 5-hydroxyindoleacetic acid were decreased by duloxetine at 2 hr after doses of 1, 3 and 10 mg/kg and at 1 to 8 hr (but not 24 hr) after a 10 mg/kg i.p. dose of duloxetine. Duloxetine antagonized norepinephrine depletion in frontal cortex, but not dopamine depletion in striatum, after treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In rats, duloxetine decreased brain 5-hydroxyindoleacetic acid dose-dependently for up to 8 hr and decreased serotonin turnover measured by the accumulation of 5-hydroxytryptophan in rat hypothalamus after decarboxylase inhibition. In rats, duloxetine antagonized the depletion of brain serotonin by p-chloramphetamine and the depletion of norepinephrine and epinephrine in hypothalamus after i.c.v. injection of 6-hydroxydopamine. In vitro, duloxetine had little effect on either type A (serotonin as substrate) or type B (phenylethylamine as substrate) monoamine oxidase, IC50 concentrations being above 10(-5) M. These data extend evidence that duloxetine inhibits serotonin and norepinephrine transporters in vivo, actions that may lead to therapeutic efficacy in mental depression.
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PMID:Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice. 751 56

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on nicotinic acetylcholine (ACh) receptor channels were studied in cultured myocytes of 1-day-old Xenopus embryos. The amplitude and decay time of iontophoretic ACh-induced currents were reduced by MPTP in a concentration-dependent manner. The inhibitory action of MPTP was frequency-dependent, being enhanced by higher frequencies of stimulation at 7 and 30 Hz. Neither pargyline nor tranylcypromine affected the inhibitory effects of MPTP on ACh-induced currents. Single channel recordings showed that MPTP decreased the opening frequency, mean open time as well as the conductance of both low- and high-conductance ACh channels. These results suggest that the inhibitory actions of MPTP on ACh receptor channels in skeletal muscle may contribute to the depression of the nerve-evoked contraction of the mouse diaphragm as previously reported.
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PMID:Blockade by MPTP of the nicotinic acetylcholine receptor channels in embryonic Xenopus muscle cells. 751 80

Dynamics of appearance and maintenance of emotional-behavioural disorders in male Wistar rats was studied on and after repeated neurotoxin MPTP injection at a dose of 15 mg/kg intraperitoneally daily for 18 days MPTP caused suppression of locomotion and rearing in open field test, decrease of daily liquid consumption and lowering of preference for the sucrose over water, increase of immobility time and depression index simultaneously with disadaptation in forced swimming test. Behavioural alterations were maintained for not less than a week after abolition of MPTP injection. Data improved the appearance and development of the state of decreased motivation simultaneously with anhedonia and behavioural despair in rats in response to MPTP injection. The state can be considered as a new model of DA-depended depression-like syndrome in rats.
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PMID:[A new model of an experimental depressive syndrome in rats induced by the systemic administration to the animals of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. 759 34

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.
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PMID:Neuroleptic medications inhibit complex I of the electron transport chain. 790 2

In order to elucidate the effects of MPTP on enkephalinergic neurons, dopamine (DA), norepinephrine (NE), proenkephalin (PE) mRNA and met-enkephalin (ME) were measured in striatum, olfactory tubercle, and prefrontal cortex of C57/B16 mice 1 day-2 weeks following treatment with 96 mg/kg MPTP HCl (24 mg/kg i.p., twice/day for 2 days). DA and its metabolites were depleted 70% in striatum and 40% in olfactory tubercle within 1 day. In cortex, DA was unchanged, whereas homovanillic acid and NE were depleted 50 and 40% respectively by 3 days. ME increased in all three brain regions at different times whereas PE mRNA showed a different pattern in each region, with an increase in olfactory tubercle, a decrease in cortex, and in striatum, a decrease at 1 day followed by an increase at 3 days. Thus enkephalinergic neurons in each region respond differently to MPTP treatment. In striatum and olfactory tubercle. DA is depleted sufficiently to release its tonic inhibition on the enkephalinergic neurons, thereby leading to increased enkephalin synthesis. In cortex, the change in NE metabolism appears to cause a decrease of ME release and thereby a depression of PE synthesis. The possible relationship between these results and the changes observed in Parkinson's disease are discussed.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effects on enkephalinergic neurons in various regions of mouse brain. 843 70

Induction of autoantibodies to serotonin and dopamine in blood serum was demonstrated in a new rat model of experimental depression-like syndrome induced by intraperitoneal injection of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg daily for 12 days). The level and frequency of detection of antibodies to serotonin within 2 and 3 weeks after MPTP withdrawal did not differ, and the level and frequency of detection of antibodies to dopamine were significantly reduced within 3 weeks as compared with 2 weeks after the MPTP withdrawal. In is suggested that disturbances in neuroimmune interactions play an important part in development of depressive states.
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PMID:[A model of the depressive syndrome in rats induced by the neurotoxin MPTP and autoantibodies to serotonin and dopamine]. 938 10

In rats injected with neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) the development of experimental depressive syndrome was accompanied by local epileptiform activity in the caudate-putamen complex and by reorganization of electrical processes in the brain. The spectral power density in the caudate-putamen in the delta range was increased in the formative stage of depressive syndrome (day 3-4 from the beginning of MPTP administration) and in the stage of behaviour recovery (a week after the withdrawal) as compared to control rats. On the contrary, the spectral power in the alpha range was decreased at the peak of depression (day 11-12 from the beginning of neurotoxin administration) and a week after the withdrawal as compared to the initial value. In the formative stage of depressive syndrome the spectral power in the delta range was increased in hippocampus whereas in sensorimotor cortex it was decreased at the frequency 6 Hz compared to control. It is suggested that a new pathodynamical organization is formed in the CNS of animals in response to MPTP administration, which is thought to be a neuropathophysiological basis of depressive syndrome.
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PMID:[The electrical activity of the brain structures in an experimental depressive syndrome induced by the systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to rats]. 964 12

We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D2-like dopamine receptors with N-[11C]methylspiperone (NMSP). The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease.
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PMID:NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy. 1041 11


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