scholarly journals Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine

2018 ◽  
Vol 21 ◽  
pp. 135-142
Author(s):  
Toshiro Niwa ◽  
Mayumi Yanai ◽  
Maya Matsumoto ◽  
Marina Shizuku
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Action ◽  
Maximal Velocity ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Cyp2d6 Polymorphism ◽  
Amine Metabolism ◽  
The Brain ◽  
Cyp 2D6 ◽  
Stimulation Of

PURPOSE: The inhibitory effects of antidepressants, such as imipramine, desipramine, and fluvoxamine, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with those on dopamine formation catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: Inhibition constants (Ki) of the antidepressants toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10, which were expressed in recombinant Escherichia coli, were compared. RESULTS: Imipramine and desipramine competitively or non-competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 3.9–4.9, 5.9–9.6, and 26.7–37.5 µM, respectively. The maximal velocity (Vmax) values for dopamine formation by all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations up to 40–100 µM, indicating that fluvoxamine stimulated dopamine formation. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6-mediated dopamine formation by these antidepressants would be affected by CYP2D6 polymorphism in the brain. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Inhibitory and Stimulatory Effects of Selective Serotonin Reuptake Inhibitors on Cytochrome P450 2D6-mediated Dopamine Formation from p-Tyramine

2019 ◽  
Vol 22 ◽  
pp. 585-592
Author(s):  
Toshiro Niwa ◽  
Shizuya Sugimoto
Keyword(s):  
Cytochrome P450 ◽  
Serotonin Reuptake ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Serotonin Reuptake Inhibitors ◽  
Selective Serotonin ◽  
Maximal Velocity ◽  
Cyp2d6 Polymorphism ◽  
Amine Metabolism ◽  
Michaelis Constants ◽  
The Brain

PURPOSE: The effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine on dopamine formation from p-tyramine, mediated by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with their effects on CYP2D6.1 (wild type)-mediated dopamine formation, to investigate the influence of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: The Michaelis constants (Km) and maximal velocity (Vmax) values of dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 (expressed in recombinant Escherichia coli), and inhibition constants (Ki) of the SSRIs toward dopamine formation catalyzed by the CYP2D6 variants were estimated. RESULTS: The Km values for CYP2D6.2 and CYP2D6.10 decreased at lower fluoxetine concentrations, while the Vmax values for all CYP2D6 variants increased, indicating that fluoxetine stimulated dopamine formation. Conversely, paroxetine competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 0.47, 1.33, and 31.3 µM, respectively. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6

scholarly journals Effects of urinary bladder afferents on respiration

1980 ◽  
Vol 48 (5) ◽  
pp. 826-832 ◽  
Author(s):  
R. Schondorf ◽  
C. Polosa
Keyword(s):  
Urinary Bladder ◽  
Low Frequency ◽  
Burst Activity ◽  
High Frequency Stimulation ◽  
Inhibitory Effects ◽  
Pelvic Nerve ◽  
Bladder Afferents ◽  
Frequency Stimulation ◽  
The Brain ◽  
Stimulation Of

The electrical activity of phrenic and recurrent laryngeal motoneurons was recorded during activation of urinary bladder afferents in pentobarbital-anesthetized, paralyzed, artificially ventilated cats. Distension or spontaneous neurogenic contraction of the bladder decreased the amplitude and frequency (bursts/min) of the burst activity in these two nerves. The decrease in frequency was due mainly to a prolongation of the interburst interval (duration of expiration). Similar effects were observed during low-frequency electrical stimulation of pelvic nerve afferents with conduction velocities in the A gamma-A delta range. High-frequency stimulation of pelvic nerve afferents increased the amplitude of the burst activity in these two nerves. These results suggest an action of bladder afferents on the brain stem oscillator controlling respiratory frequency and drive. Some of the excitatory and inhibitory effects of bladder afferents on phrenic motoneurons may be mediated through spinal circuits.

Orthodromically and antidromically evoked local field potentials in the crayfish olfactory lobe

1998 ◽  
Vol 201 (9) ◽  
pp. 1331-1344 ◽  
Author(s):  
D Sandeman ◽  
R Sandeman
Keyword(s):  
Electrical Stimulation ◽  
Local Field ◽  
Olfactory Receptor ◽  
Field Potential ◽  
Olfactory Lobe ◽  
Field Potentials ◽  
Inhibitory Effects ◽  
Olfactory Receptor Neurones ◽  
The Brain ◽  
Stimulation Of

A local field potential, consistent in form and duration, can be recorded from the olfactory lobe of crayfish following electrical stimulation of the outer flagellum of the antennule. The field potential is reversibly blocked by perfusion of the brain with low-[Ca2+] saline or <IMG src="/images/symbols/gamma.gif" WIDTH="9" HEIGHT="12" ALIGN="BOTTOM" NATURALSIZEFLAG="3">-aminobutyric acid and, to a lesser extent, histamine. Paired shocks to the antennule and antidromic electrical stimulation of olfactory lobe output neurones also partially block the field potential. Comparing the field potential with simultaneously recorded intracellular responses of olfactory interneurones reveals a coincidence between excitatory and inhibitory effects in the interneurones and the appearance of identifiable components of the field potential. We interpret the field potential to reflect the response of neural elements in the olfactory lobe to orthodromic activity in the axons of the olfactory receptor neurones on the antennule. We conclude from the blocking experiments that the greater part of the field potential stems from neurones in the olfactory lobe that are postsynaptic to olfactory receptor neurones. As such, it provides a robust indication of olfactory neurone activity.

scholarly journals Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

2015 ◽  
Vol 59 (7) ◽  
pp. 3864-3869 ◽  
Author(s):  
Chau Vuong ◽  
Lisa H. Xie ◽  
Brittney M. J. Potter ◽  
Jing Zhang ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Mouse Strains ◽  
Human Populations ◽  
Radical Cure ◽  
Wild Type ◽  
Poor Metabolizer ◽  
Liver Stage ◽  
Content Type ◽  
Body Weight Dose ◽  
Cyp 2D6

ABSTRACTCytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic forPlasmodium vivaxradical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.

Convergence of olfactory inputs from both antennae in the brain of the honeybee

1975 ◽  
Vol 62 (1) ◽  
pp. 11-26
Author(s):  
H Suzuki
Keyword(s):  
Bilateral Stimulation ◽  
Inhibitory Effects ◽  
Neural Models ◽  
Impulse Frequency ◽  
Electrical Activities ◽  
The Brain ◽  
Antenna Input ◽  
Stimulation Of

Electrical activities of the olfactory neurones in the brain of the honeybee were investigated. Odorous stimuli were given to each antenna separately or to both simultaneously. The inputs from the antennae affected both the impulse frequency and the latency of the olfactory interneurones in the protocerebrum. The predominant response was to the stimulation of the ipsilateral antenna. Input from the contralateral antenna produced mainly excitatory effects, although a few inputs gave inhibitory effects. No particular relationships between the loci of the units in the brain and the types of responses produced were found. Most of the units were located in the protocerebral lobe and in the central commissure. The units in the deutocerebrum responded only to the stimulation of the ipsilateral antenna, and the magnitude of response and the latency were not different with respect to unilateral or bilateral stimulation of the antennae. Differences in latency between unilateral and bilateral stimulation were observed in some of the units in the protocerebrum. Neural models which explain these phenomena are postulated.

Inhibition of dorsal-horn cell responses by stimulation of the Kölliker-Fuse nucleus

1986 ◽  
Vol 65 (6) ◽  
pp. 825-833 ◽  
Author(s):  
Charles J. Hodge ◽  
A. Vania Apkarian ◽  
Richard T. Stevens
Keyword(s):  
Brain Stem ◽  
Biogenic Amines ◽  
Dorsal Horn ◽  
Inhibitory Effect ◽  
Control Mechanisms ◽  
Inhibitory Effects ◽  
Content Type ◽  
Cell Responses ◽  
The Brain ◽  
Stimulation Of

✓ The Kölliker-Fuse nucleus (KF) in the dorsolateral pons has been shown to be the major source of catecholamine innervation of the spinal cord. This has important implications in terms of pain control mechanisms, since catecholamine-mediated mechanisms are essential for the expression of opiate and other varieties of antinociception. This study examines the effects of KF stimulation on responses of dorsal-horn cells to innocuous and noxious cutaneous stimuli in anesthetized cats. Stimulation of the KF potently inhibits the responses of dorsal-horn cells to both noxious and innocuous stimuli. The threshold for the inhibitory effect is significantly lower for responses to noxious stimuli as opposed to innocuous stimuli. The inhibitory effect is specific to the stimulus site, as evidenced by a marked decrease in the effect following small changes in the position of the stimulating electrode in the brain stem. The latency of the effects indicates a bulbospinal conduction velocity of 4 to 5 m/sec, which is much slower than usual reticulospinal effects and is consistent with a catecholamine-mediated system. The dependence of KF-spinal inhibition on intact biogenic amines was tested by depleting the animals of these amines with reserpine pretreatment. Depletion of biogenic amines resulted in a significant decrease in the KF spinal inhibitory effects, suggesting their dependence on intact noradrenergic stores. The results of these studies are consistent with the idea that the KF-spinal system plays an important noradrenergic-dependent role in the brain-stem modulation of spinal processing of noxious, potentially painful stimuli.

Chemical Stimulation of the Brain Makes Stimulating Reading

1975 ◽  
Vol 20 (12) ◽  
pp. 923-924
Author(s):  
MADGE E. SCHEIBEL ◽  
ARNOLD B. SCHEIBEL
Keyword(s):  
Chemical Stimulation ◽  
The Brain ◽  
Stimulation Of

Inhibition of ADP-Induced Responses in Human Platelets by Agents Elevating the Cyclic AMP Level: Comparison of Aggregation and Shape Change

1984 ◽  
Vol 52 (03) ◽  
pp. 333-335 ◽  
Author(s):  
Vider M Steen ◽  
Holm Holmsen
Keyword(s):  
Inhibitory Action ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Early Step ◽  
Stimulus Response ◽  
Sequential Relationship

SummaryThe inhibitory effect of cAMP-elevating agents on shape change and aggregation in human platelets was studied to improve the understanding of the sequential relationship between these two responses.Human platelet-rich plasma was preincubated for 2 min at 37° C with prostaglandin E1 or adenosine, agents known to elevate the intracellular level of cAMP. Their inhibitory effects on ADP-induced shape change and aggregation were determined both separately and simultaneously. The dose-inhibition patterns for shape change and aggregation were similar for both PGE1 and adenosine. There was no distinct difference between the inhibitory action of these two inhibitors.These observations suggest that elevation of the intracellular concentration of cAMP interferes with an early step in the stimulus-response coupling that is common for aggregation and shape change.

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