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The Journal of Biological Chemistry Sep 2011The most common cause for adverse cardiac events by antidepressants is acquired long QT syndrome (acLQTS), which produces electrocardiographic abnormalities that have...
The most common cause for adverse cardiac events by antidepressants is acquired long QT syndrome (acLQTS), which produces electrocardiographic abnormalities that have been associated with syncope, torsade de pointes arrhythmias, and sudden cardiac death. acLQTS is often caused by direct block of the cardiac potassium current I(Kr)/hERG, which is crucial for terminal repolarization in human heart. Importantly, desipramine belongs to a group of tricyclic antidepressant compounds that can simultaneously block hERG and inhibit its surface expression. Although up to 40% of all hERG blockers exert combined hERG block and trafficking inhibition, few of these compounds have been fully characterized at the cellular level. Here, we have studied in detail how desipramine inhibits hERG surface expression. We find a previously unrecognized combination of two entirely different mechanisms; desipramine increases hERG endocytosis and degradation as a consequence of drug-induced channel ubiquitination and simultaneously inhibits hERG forward trafficking from the endoplasmic reticulum. This unique combination of cellular effects in conjunction with acute channel block may explain why tricyclic antidepressants as a compound class are notorious for their association with arrhythmias and sudden cardiac death. Taken together, we describe the first example of drug-induced channel ubiquitination and degradation. Our data are directly relevant to the cardiac safety of not only tricyclic antidepressants but also other therapeutic compounds that exert multiple effects on hERG, as hERG trafficking and degradation phenotypes may go undetected in most preclinical safety assays designed to screen for acLQTS.
Topics: Animals; Antidepressive Agents, Tricyclic; Desipramine; ERG1 Potassium Channel; Endocytosis; Endoplasmic Reticulum; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Long QT Syndrome; Protein Transport; Rats; Ubiquitination
PubMed: 21832094
DOI: 10.1074/jbc.M111.254367 -
Science (New York, N.Y.) Sep 2007Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter...
Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
Topics: Amino Acid Sequence; Animals; Antidepressive Agents, Tricyclic; Bacterial Proteins; Binding Sites; Caenorhabditis elegans Proteins; Cell Line; Conserved Sequence; Crystallography, X-Ray; Desipramine; Dopamine; Dopamine Uptake Inhibitors; Drosophila Proteins; Humans; Leucine; Models, Molecular; Molecular Sequence Data; Neurotransmitter Uptake Inhibitors; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Plasma Membrane Neurotransmitter Transport Proteins; Protein Binding; Protein Conformation; Sequence Homology, Amino Acid; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 17690258
DOI: 10.1126/science.1147614 -
Translational Psychiatry Sep 2019BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a...
BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Compulsive Behavior; Desipramine; Disease Models, Animal; Exploratory Behavior; Fluoxetine; Mice; Mice, Knockout; Motor Activity; Nerve Net; Nerve Tissue Proteins; Obsessive-Compulsive Disorder
PubMed: 31501410
DOI: 10.1038/s41398-019-0558-7 -
British Journal of Pharmacology Nov 19741 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat,...
1 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat, anaesthetized with halothane.2 Imipramine and desipramine, when applied for a brief period, did not affect the firing rate of the vast majority of the neurones tested.3 Both potentiation and antagonism of excitatory responses to noradrenaline could be observed after a brief application of either of the antidepressants. Four drug-interaction patterns could be distinguished: potentiation of immediate onset; potentiation reaching its maximum after a delay; antagonism followed by potentiation; antagonism followed by recovery.4 When different doses of the same antidepressant were applied, it was found that the drug-interaction patterns were related to the dose of antidepressant applied, a lower dose causing potentiation, and a higher dose antagonism of the response.5 Both potentiation and antagonism of depressant responses to noradrenaline could be observed.6 Both excitatory and depressant responses to 5-hydroxytryptamine were modified by imipramine and desipramine: a smaller dose of the antidepressant potentiated, and a higher dose antagonized the responses.7 Excitatory responses to glutamate were not affected by imipramine and desipramine.
Topics: Action Potentials; Animals; Cats; Cerebral Cortex; Desipramine; Drug Interactions; Female; Glutamates; Imipramine; Male; Neurons; Norepinephrine; Serotonin; Serotonin Antagonists
PubMed: 4458844
DOI: 10.1111/j.1476-5381.1974.tb08602.x -
British Journal of Clinical Pharmacology Oct 2010To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional...
AIMS
To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates.
RESULTS
The mean population estimates of the first order absorption rate constant (k(a) ), apparent clearance (CL/F) and apparent volume of distribution at steady state (V(ss) /F) were 0.15h(-1) , 111 lh(-1) and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 lh(-1) with between-subject variability of 84%. d-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second d-optimal sample was earlier at 14 and 19h, respectively, compared with 24h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates.
CONCLUSIONS
A two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.
Topics: Administration, Oral; Adult; Bayes Theorem; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine; Enzyme Inhibitors; Female; Genotype; Humans; Male; Middle Aged; Models, Biological; Phenotype
PubMed: 20840444
DOI: 10.1111/j.1365-2125.2010.03731.x -
Pharmacological Research Dec 2016Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct...
Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems.
Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval; neuropathic pain did not return. The opioid receptor antagonist naloxone blocked the antinociceptive effects of both prophylactic and therapeutic desipramine treatments throughout the entire timecourse of desipramine-induced antinociception. By contrast, cannabinoid CB and CB receptor antagonists partially attenuated the antinociceptive actions of desipramine in a manner that was restricted to the development phase of paclitaxel-induced neuropathic pain only. Paclitaxel decreased cell viability in TMD231 tumor cells in an MTT assay in vitro. Notably, desipramine (1nM-1μM) alone did not alter tumor cell viability and did not prevent the cytotoxic effects of paclitaxel under identical conditions. The highest concentration of desipramine (10μM) reduced tumor cell viability alone and enhanced the cytotoxic effects of paclitaxel. Our study identifies a previously unrecognized preemptive analgesic strategy that prevents development of paclitaxel-induced neuropathic pain, and also dissects receptor mechanisms underlying desipramine-induced antinociceptive effects. This information may be applied to improve current therapeutic strategies with the goal of preventing and managing neuropathic pain induced by chemotherapeutic treatment.
Topics: Animals; Antidepressive Agents, Tricyclic; Antineoplastic Agents, Phytogenic; Desipramine; Hyperalgesia; Male; Neuralgia; Paclitaxel; Rats, Sprague-Dawley; Receptors, Cannabinoid; Signal Transduction
PubMed: 27773824
DOI: 10.1016/j.phrs.2016.10.007 -
British Journal of Pharmacology Jul 19731. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200...
1. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 mug/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2-3 h of incubation unless concentrations of desipramine higher than 1 mug/ml were used.2. The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.3. The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria.4. The inhibition of (-)-noradrenaline uptake and the potentiation of the chronotropic response to (-)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 0.01 to 1 mug/g. Higher tissue levels show less potentiation of the effect of (-)-noradrenaline or even inhibition of the maximal response to (-)-noradrenaline. These concentrations of desipramine (> 7 mug/g) markedly depressed the atrial rate.5. The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.
Topics: Animals; Binding Sites; Carbon Radioisotopes; Desipramine; Drug Synergism; Heart Atria; Heart Rate; In Vitro Techniques; Male; Myocardium; Norepinephrine; Perfusion; Rats; Time Factors
PubMed: 4764292
DOI: 10.1111/j.1476-5381.1973.tb08354.x -
The European Respiratory Journal Nov 2016We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans... (Randomized Controlled Trial)
Randomized Controlled Trial
We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea-hypopnea index (AHI) in OSA patients.A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway (P)) and ventilation under both passive (V') and active (V') upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP.Desipramine reduced active P (median (interquartile range) -5.2 (4.3) cmHO on desipramine versus -1.9 (2.7) cmHO on placebo; p=0.049) but not passive P (-2.2 (3.4) versus -0.7 (2.1) cmHO; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined as V'-V') on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009).In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation.
Topics: Adrenergic Neurons; Adrenergic Uptake Inhibitors; Adult; Aged; Anthropometry; Continuous Positive Airway Pressure; Cross-Over Studies; Desipramine; Double-Blind Method; Electromyography; Female; Humans; Male; Middle Aged; Muscles; Patient Compliance; Sleep; Sleep Apnea, Obstructive; Supine Position
PubMed: 27799387
DOI: 10.1183/13993003.00823-2016 -
International Journal of Molecular... May 2021Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of...
Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1‑adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D‑ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D‑AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.
Topics: Animals; Antidepressive Agents; Citalopram; Depression; Desipramine; Fluoxetine; Gene Expression Regulation; Humans; Imipramine; Mianserin; Mice; PC12 Cells; Rats; Reboxetine; Receptors, Adrenergic, alpha-1; Signal Transduction
PubMed: 34062902
DOI: 10.3390/ijms22094817 -
European Journal of Pharmacology Dec 2007Although major metabolites of some antidepressant drugs are known to be active, their pharmacological effects are poorly characterized. Two of the most selective...
Although major metabolites of some antidepressant drugs are known to be active, their pharmacological effects are poorly characterized. Two of the most selective antidepressants, desipramine (selectively inhibits norepinephrine reuptake) and citalopram (selectively inhibits serotonin reuptake) are frequently used in animal studies of antidepressant action, as well as being useful therapeutically. The primary aim of this study was to determine the affinity of desmethyldesipramine, an active metabolite of desipramine, for the rat norepinephrine and serotonin transporters, as well as for the rat alpha(2)-adrenoceptor. The pharmacological characteristics of desmethyldesipramine and desmethylcitalopram, an active metabolite of citalopram, were also determined for various human transporters and neurotransmitter receptors. Competition binding studies using [(3)H]nisoxetine and [(3)H]citalopram showed desipramine to be 25 times more selective for the rat norepinephrine as compared to serotonin transporter (6.2 nM vs. 158 nM) whereas desmethyldesipramine is 12 times more selective for the serotonin over the norepinephrine transporter (12.8 nM vs. 153 nM). Interestingly, the affinity of desmethyldesipramine for the serotonin transporter is similar to the affinity of desipramine for the norepinephrine transporter. Desipramine and desmethyldesipramine were found to have a lower affinity for the rat alpha(2A(D))-adrenoceptor than the transporters, suggesting that this receptor is not a major site of action for either compound. Thus, the pharmacological effects of desipramine in rats may be attributed not only to the inhibition of the norepinephrine transporter by desipramine but also to the inhibition of serotonin transporter by the active metabolite desmethyldesipramine.
Topics: Animals; Antidepressive Agents; Citalopram; Desipramine; Imipramine; Male; Norepinephrine Plasma Membrane Transport Proteins; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Serotonin Plasma Membrane Transport Proteins
PubMed: 17850785
DOI: 10.1016/j.ejphar.2007.08.017