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1.
Adv Pharmacol ; 82: 21-34, 2018.
Article in English | MEDLINE | ID: mdl-29413522

ABSTRACT

Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was hoped the receptor binding technique could also be used as a primary screen to speed and simplify the identification of novel drug candidates, experience has taught that ligand binding is most useful for drug discovery when it is used in conjunction with functional, phenotypic assays. The incorporation of ligand binding assays into the drug discovery process played a significant role in altering the search for new therapeutics from solely an empirical undertaking to a mechanistic and hypothesis-driven enterprise. This illustrates the impact of Dr. Snyder's work, not only on neuroscience research but on the discovery, development, and characterization of drugs for treating a variety of medical conditions.


Subject(s)
Biological Assay/methods , Drug Discovery , Receptors, Cell Surface/metabolism , Animals , Drug Evaluation, Preclinical , Humans , Phenotype , Protein Binding
2.
Biochem Pharmacol ; 87(1): 25-39, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-23933389

ABSTRACT

The application of detailed quantitative analyses of the concentration dependence of the biological responses mediated by endogenous hormones and other mediators, drugs, and related compounds has been the foundation of pharmacology for the past century or more. This approach has been remarkably successful in identifying the specific molecular targets for these mediators and drugs, in establishing the mechanisms for those effects at both the cellular and whole organismal levels, and in the development of new chemical entities (NCEs) with great selectivity for individual molecular targets. The availability of such compounds has unfortunately led to a mindset that detailed quantitative analyses are no longer necessary to use such compounds in understanding biological system function and to draw valid conclusions in regard to the utility of NCEs selective for putative drug targets in the potential treatment of human disease states. This lack of appreciation for quantitative approaches has contributed significantly to the all-too-frequent failures of new drug candidates in early-stage clinical trials. The present article reviews basic drug/receptor concepts together with the mathematical relationships that underlie the quantitative analysis of dose-response and concentration-effect relationships for individual compounds and for more complex systems, such as the comparative analysis of multiple compounds at a single receptor. A thorough understanding of these concepts and their associated analyses, along with their proper and rigorous application in all pre-clinical drug development studies, is an essential component of an integrated approach toward improving drug development.


Subject(s)
Models, Chemical , Pharmaceutical Preparations/metabolism , Receptors, Cell Surface/metabolism , Animals , Dose-Response Relationship, Drug , Humans , Pharmaceutical Preparations/chemistry , Quantitative Structure-Activity Relationship , Receptors, Cell Surface/chemistry
3.
Biochem Pharmacol ; 87(1): 64-77, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24269285

ABSTRACT

A pharmacological experiment is typically conducted to: i) test or expand a hypothesis regarding the potential role of a target in the mechanism(s) underlying a disease state using an existing drug or tool compound in normal and/or diseased tissue or animals; or ii) characterize and optimize a new chemical entity (NCE) targeted to modulate a specific disease-associated target to restore homeostasis as a potential drug candidate. Hypothesis testing necessitates an intellectually rigorous, null hypothesis approach that is distinct from a high throughput fishing expedition in search of a hypothesis. In conducting an experiment, the protocol should be transparently defined along with its powering, design, appropriate statistical analysis and consideration of the anticipated outcome (s) before it is initiated. Compound-target interactions often involve the direct study of phenotype(s) unique to the target at the cell, tissue or animal/human level. However, in vivo studies are often compromised by a lack of sufficient information on the compound pharmacokinetics necessary to ensure target engagement and also by the context-free analysis of ubiquitous cellular signaling pathways downstream from the target. The use of single tool compounds/drugs at one concentration in engineered cell lines frequently results in reductionistic data that have no physiologically relevance. This overview, focused on trends in the peer-reviewed literature, discusses the execution and reporting of experiments and the criteria recommended for the physiologically-relevant assessment of target engagement to identify viable new drug targets and facilitate the advancement of translational studies.


Subject(s)
Drug Delivery Systems/methods , Drug Delivery Systems/trends , Drug Discovery/methods , Drug Discovery/trends , Pharmaceutical Preparations/administration & dosage , Animals , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/trends , High-Throughput Screening Assays , Humans , Pharmaceutical Preparations/metabolism , Protein Binding/genetics , Protein Binding/physiology
4.
Methods Mol Biol ; 746: 135-64, 2011.
Article in English | MEDLINE | ID: mdl-21607856

ABSTRACT

The radioligand binding assay is a relatively simple but powerful tool for studying G protein-coupled receptors. There are three basic types of radioligand binding experiments: (1) saturation experiments from which the affinity of the radioligand for the receptor and the binding site density can be determined; (2) inhibition experiments from which the affinity of a competing, unlabeled compound for the receptor can be determined; and (3) kinetic experiments from which the forward and reverse rate constants for radioligand binding can be determined. Detailed methods for typical radioligand binding assays for G protein-coupled receptors in membranes and intact cells are presented for these types of experiments. Detailed procedures for analysis of the data obtained from these experiments are also given.


Subject(s)
Cell Membrane/metabolism , Radioligand Assay , Animals , Binding Sites , CHO Cells , Cricetinae , Cricetulus , HT29 Cells , Humans , Kinetics , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism
5.
Behav Brain Res ; 221(1): 25-33, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21333691

ABSTRACT

Exposure of rats to unpredictable, inescapable stress results in two distinct behaviors during subsequent escape testing. One behavior, suggestive of lack of stress resilience, is prolonged escape latency compared to non-stressed rats and is labeled learned helplessness (LH). The other behavior suggestive of stress resilience is normal escape latency and is labeled non-helpless (NH). This study examines the effects of unpredictable, inescapable tail-shock stress (TSS) on alpha(2)-adrenoceptor (α(2A)-AR) and corticotropin-releasing factor 1 receptor (CRF(1)-R) regulation as well as protein levels of G protein-coupled receptor kinase 3 (GRK3), GRK2, tyrosine hydroxylase (TH) plus carbonylated protein levels in locus coeruleus (LC), amygdala (AMG), cortex (COR) and striatum (STR). In NH rats, α(2A)-AR and CRF(1)-R were significantly down-regulated in LC after TSS. No changes in these receptor levels were observed in the LC of LH rats. GRK3, which phosphorylates receptors and thereby contributes to α(2A)-AR and CRF(1)-R down-regulation, was reduced in the LC of LH but not NH rats. GRK2 levels were unchanged. In AMG, GRK3 but not GRK2 levels were reduced in LH but not NH rats, and receptor regulation was impaired in LH rats. In STR, no changes in GRK3 or GRK2 levels were observed. Finally, protein carbonylation, an index of oxidative stress, was increased in the LC and AMG of LH but not NH rats. We suggest that reduced stress resilience after TSS may be related to oxidative stress, depletion of GRK3 and impaired regulation of α(2A)-AR and CRF(1)-R in LC.


Subject(s)
Helplessness, Learned , Locus Coeruleus/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Resilience, Psychological , Stress, Psychological/metabolism , Animals , Brain/metabolism , Cluster Analysis , Down-Regulation , Electric Stimulation/methods , G-Protein-Coupled Receptor Kinase 2/metabolism , G-Protein-Coupled Receptor Kinase 3/metabolism , Male , Protein Carbonylation , Rats , Rats, Sprague-Dawley , Tyrosine 3-Monooxygenase/metabolism
6.
Neurochem Int ; 55(6): 355-61, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19447153

ABSTRACT

The therapeutic usefulness of current agents that activate the three alpha(2)-adrenoceptors, alpha(2A), alpha(2B) and alpha(2C) is limited by their lack of subtype selectivity. One approach to the development of subtype-selective agents is the in silico docking of potential ligands to the receptors in quantitative molecular modeling studies. Because the crystal structure of the alpha(2)-adrenoceptors is not known, we used homology modeling based on the published structure of bovine rhodopsin. We developed individual models for each of the three receptors, which were found to accurately represent published data from both radioligand binding mutagenesis experiments. Using 18 non-subtype-selective agents to validate the models, the calculated transformed and the experimental binding free energies were satisfactory correlated (r(2)(A)=0.888, r(2)(B)=0.887, r(2)(C)=0.790). The binding pockets differed in size (482-619A(3)) with the alpha(2B) receptor subtype having the largest and the alpha(2c) the smallest cavity. The binding sites for all three subtypes were found to be essentially identical with the exception of two subtype-specific residues, and thus we were unable to identify any significant differences in the interactions of ligands with the three receptor subtypes. Although, the binding properties of all three receptors are very similar, the differences in pocket volume and two subtype-specific residues in the binding pocket might play an as yet undocumented role in subtype selectivity.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Models, Molecular , Receptors, Adrenergic, alpha-2/chemistry , Animals , Binding Sites/physiology , Binding, Competitive/drug effects , Binding, Competitive/physiology , Biophysics/methods , Cattle , Computer Simulation , Crystallography, X-Ray , Ligands , Protein Isoforms/chemistry , Protein Structure, Tertiary/physiology , Receptors, Adrenergic, alpha-2/metabolism , Software
7.
Psychopharmacology (Berl) ; 205(2): 249-59, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19387616

ABSTRACT

RATIONALE: The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. OBJECTIVES: To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. MATERIALS AND METHODS: Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. RESULTS: Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. CONCLUSIONS: The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Citalopram/pharmacology , Escape Reaction/drug effects , Helplessness, Learned , Reaction Time/drug effects , Age Factors , Analysis of Variance , Animals , Antidepressive Agents, Tricyclic/pharmacology , Biophysics , Desipramine/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Electroshock , Male , Rats , Rats, Sprague-Dawley
8.
BMC Pharmacol ; 8: 17, 2008 Oct 02.
Article in English | MEDLINE | ID: mdl-18831759

ABSTRACT

BACKGROUND: The effects of acute and repeated treatment with desipramine on the functional response of alpha2-adrenoceptors were tested in adult and 13-day old rats. The functional response measured was hypothermia that was induced by brimonidine, an alpha2-adrenoceptor agonist. The change in the extent of the brimonidine-induced hypothermia following pretreatment with either single or 4 twice-daily injections of desipramine was compared in 13-day old and adult (65-75 days old) male rats. RESULTS: Brimonidine, alone, lowered rectal temperature to a greater extent in juvenile than in adult rats, and this response was dose-dependently blocked by the selective alpha2-adrenoceptor antagonist, RX821002, in both groups of rats. Single desipramine administration lowered rectal temperature in the absence of brimonidine in adult but not in juvenile rats. The adult rats developed tolerance to this hypothermic effect after 4 days of desipramine treatment (10 mg/kg twice daily). Repeated desipramine treatment of adult rats also resulted in an enhancement in the brimonidine-induced hypothermic effect 24 h after the last dose, a time when above 90% of desipramine and its metabolite, desmethyldesipramine, had cleared the brain, but not at 14, 48 or 96 h after the last dose. In juvenile rats repeated injections of desipramine (3 mg/kg twice daily for 4 days) had no effect on the alpha2-agonist-induced hypothermia when brimonidine was given 14, 24, 63 and 96 h after the last dose of desipramine. CONCLUSION: The results suggest that juvenile rats response differently than adult rats to agonist stimulation of alpha2-adrenoceptors with and without pretreatment with the antidepressant desipramine. In the absence of desipramine pretreatment, the alpha2-adrenoceptor-induced hypothermic effect in juvenile rats is greater than in adult rats. Acute injections of desipramine, in the absence of agonist produced a hypothermic effect in adult but not juvenile rats. In addition, the increased alpha2-agonist-induced hypothermic effect following repeated injections of desipramine that is seen in adult rats is not seen in juvenile rats.


Subject(s)
Body Temperature/drug effects , Desipramine/administration & dosage , Receptors, Adrenergic, alpha-2/physiology , Age Factors , Animals , Body Temperature/physiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Rats , Rats, Sprague-Dawley
9.
Psychopharmacology (Berl) ; 197(3): 433-41, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18180907

ABSTRACT

RATIONALE: Currently, there are limited treatment options for major depressive disorder in children and adolescents compared to the options available for adults. Many effective treatments used for adult depression, such as the tricyclic antidepressants, lack efficacy when given to children and adolescents. OBJECTIVE: To more quickly identify compounds that could be effective for treating childhood and adolescent depression, a reliable preclinical animal behavioral test of antidepressant efficacy for pediatric depression is needed. The forced-swim test (FST) with juvenile rats was assessed to determine its reliability as a predictive model for pediatric depression. MATERIALS AND METHODS: We adapted procedures from the adult FST to test 21-day-old juvenile rats. The 21-day-old animals were treated with three classes of antidepressant drugs before being assessed in the FST: the selective serotonin reuptake inhibitors escitalopram or fluoxetine; the tricyclic antidepressants desipramine or imipramine; and the monoamine oxidase inhibitor tranylcypromine. RESULTS: The 21-day-old rats showed dose-dependent changes in behaviors similar to those seen in adults when treated with escitalopram or fluoxetine. Tranylcypromine also decreased immobility in 21-day-old rats. Treatment with desipramine or imipramine, however, was not effective at reducing immobility in the 21-day-old rats. CONCLUSIONS: The juvenile FST accurately predicts the efficacy of selective serotonin reuptake inhibitors and the lack of efficacy of tricyclic antidepressants in the treatment of depression in children and adolescents. This suggests that the FST using 21-day-old rats may help to develop better treatments for childhood and adolescent depression.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder/drug therapy , Disease Models, Animal , Helplessness, Learned , Motivation , Adolescent , Age Factors , Animals , Child , Citalopram/therapeutic use , Depressive Disorder/psychology , Desipramine/therapeutic use , Escape Reaction/drug effects , Fluoxetine/therapeutic use , Humans , Imipramine/therapeutic use , Injections, Intraperitoneal , Male , Rats , Rats, Sprague-Dawley , Swimming , Tranylcypromine/therapeutic use
10.
Pharmacol Ther ; 117(1): 30-51, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17949819

ABSTRACT

The focus of this review is to critically examine and review the literature on the role of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin-related kinase B (TrkB), in the actions of pharmacologically diverse antidepressant treatments for depression. This will include a review of the studies on the regulation of BDNF and TrkB by different types of antidepressant drug treatments and animal in models of depression, as well as altered levels of BDNF and TrkB in the blood and postmortem brain of patients with depression. Results from clinical and basic studies have demonstrated that stress and depression decrease BDNF expression and neurogenesis and antidepressant treatment reverses or blocks these effects, leading to the neurotrophic hypothesis of depression. Clinical studies demonstrate an association between BDNF levels and several disorders, including depression, epilepsy, bipolar disorder, Parkinson's and Alzheimer's diseases. Physical activity and diet exert neurotrophic effects and positively modulate BDNF levels. A common single nucleotide polymorphism (SNP) in the BDNF gene, a methionine substitution for valine, is associated with alterations in brain anatomy and memory, but what role it has in clinical disorders is unclear. Findings suggest that early childhood events and adult stress produce neurodegenerative alterations in the brain that can eventually cause breakdown of information processing in the neuronal networks regulating mood. Antidepressant treatments elevate activity-dependent neuronal plasticity by activating BDNF, thereby gradually restoring network function and ultimately mood.


Subject(s)
Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Receptor, trkB/metabolism , Adult , Animals , Brain-Derived Neurotrophic Factor/drug effects , Child , Clinical Trials as Topic , Depressive Disorder/drug therapy , Disease Models, Animal , Drug Delivery Systems , Humans , Mood Disorders/drug therapy , Receptor, trkB/drug effects
11.
Neuropharmacology ; 54(2): 251-7, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18048068

ABSTRACT

Major depressive disorder is a major health problem in adults and is now recognized as a substantial problem in children as well. Tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in treating adult depression. Several studies have suggested that normal BDNF (brain-derived neurotrophic factor) signaling is necessary for antidepressant drug action. Antidepressant drugs induce several plastic changes in the rodent brain which may be associated with changes in BDNF levels and/or with BDNF function. In the present study we report parallel measurements of BDNF mRNA and protein in the frontal cortex and hippocampus after four days of twice daily treatments with escitalopram, a selective serotonin reuptake inhibitor, and desipramine, a tricyclic antidepressant. Post-natal day 13, 21, 28 and adult rats were used in this study. TrkB (the primary receptor for BDNF) mRNA levels were also examined under the same treatment conditions. BDNF mRNA and protein levels, as well as TrkB mRNA levels, were increased significantly in post-natal day 13 pups after escitalopram treatment as compared to control, but desipramine failed to increase either BDNF or TrkB. The failure of desipramine to increase BDNF and TrkB levels in juvenile rats is consistent with the lack of efficacy of desipramine in children and adolescents. The serotonergic nervous system matures earlier than the noradrenergic system, which may explain why escitalopram, but not desipramine, increases BDNF and TrkB levels.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Brain-Derived Neurotrophic Factor/biosynthesis , Citalopram/pharmacology , Desipramine/pharmacology , Receptor, trkB/biosynthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Aging/metabolism , Animals , Antidepressive Agents, Tricyclic/pharmacokinetics , Chromatography, High Pressure Liquid , Citalopram/pharmacokinetics , Desipramine/pharmacokinetics , Enzyme-Linked Immunosorbent Assay , Hippocampus/metabolism , Injections, Intraperitoneal , Prefrontal Cortex/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/isolation & purification , Rats , Reverse Transcriptase Polymerase Chain Reaction , Selective Serotonin Reuptake Inhibitors/pharmacokinetics
14.
Eur J Pharmacol ; 576(1-3): 55-60, 2007 Dec 08.
Article in English | MEDLINE | ID: mdl-17850785

ABSTRACT

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.


Subject(s)
Citalopram/analogs & derivatives , Imipramine/analogs & derivatives , Animals , Antidepressive Agents/metabolism , Citalopram/metabolism , Desipramine/metabolism , Imipramine/metabolism , Male , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-2/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism
15.
Neurochem Int ; 51(5): 246-53, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17664028

ABSTRACT

Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group, the differences between adults, children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals, therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.


Subject(s)
Aging/psychology , Antidepressive Agents/therapeutic use , Depression/drug therapy , Adolescent , Adult , Animals , Behavior/drug effects , Behavior, Animal/drug effects , Child , Depression/psychology , Disease Models, Animal , Humans , Hypothermia/physiopathology , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/metabolism , Species Specificity
16.
J Neurosci Methods ; 163(1): 83-91, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17400296

ABSTRACT

The tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in adult depression. Animal studies comparing the effects of DMI in juveniles and adults are complicated by age-related variations in elimination rates. Thus, different dosing regiments are needed to achieve similar brain drug levels in juvenile and adult rats. We compared the half-life of DMI as well as the brain and serum concentrations of DMI and its active metabolite desmethyldesipramine in juvenile and adult rats after various drug administration paradigms. After acute i.p. administration DMI is eliminated from the brain more slowly in postnatal day (PND) 21 and 28 rats as compared to adults. After chronic i.p. administration (for 4-5 days between PND 9 and 28), lower doses of DMI are needed with juvenile rats to obtain the same brain DMI concentrations as adults. By contrast, 2 weeks of continuous drug delivery (minipump) to PND 21-35 and adult rats result in similar brain DMI concentrations. Thus, the pharmacokinetic properties of DMI varies with the age of the animal and dosing of DMI and needs to be carefully adjusted in order to have appropriate brain levels of the drug.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacokinetics , Behavior, Animal/drug effects , Brain Chemistry/drug effects , Desipramine/pharmacokinetics , Age Factors , Animals , Animals, Newborn , Antidepressive Agents, Tricyclic/metabolism , Brain/drug effects , Brain/metabolism , Chromatography, High Pressure Liquid/methods , Desipramine/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Half-Life , Imipramine/analogs & derivatives , Imipramine/metabolism , Male , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Swimming , Time Factors
17.
J Pharmacol Exp Ther ; 321(2): 770-6, 2007 May.
Article in English | MEDLINE | ID: mdl-17293562

ABSTRACT

Although the tricyclic antidepressants, such as desipramine (DMI), are among the most efficacious treatments for adult depression, they are not effective in treating childhood and adolescent depression. Because the adrenergic nervous system is not fully developed until late adolescence, we hypothesized that the mechanisms regulating receptor density may not yet be mature in young mammals. To test this hypothesis, the effects of DMI treatment on cortical alpha-1-, alpha-2-, and beta-adrenergic receptors were compared in juvenile and adult rats. DMI was delivered either by 4 days of twice daily injections to postnatal day 9 to 13 (4 and 7 mg/kg/day) and adult (20 mg/kg/day) rats, or by 2 weeks of continual drug infusion (osmotic minipumps) to postnatal day 21-35 (15 mg/kg/day) and adult (10 mg/kg/day) rats. These delivery paradigms gave juvenile brain concentrations of DMI similar to those in adult rats. The beta-adrenergic receptor was down-regulated with both treatment paradigms in both juvenile and adult rats. By contrast, in the postnatal day 9 to 13 rats, there was a dose-dependent up-regulation of the alpha-1 in the cortex and alpha-2-adrenergic receptor in the prefrontal cortex, whereas there was no change in density in adult rats. These differences in the alpha-adrenergic receptor regulation after DMI treatment suggest that the lack of efficacy of tricyclic antidepressants in treating childhood depression may be related to immature regulatory mechanisms for these receptors.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Desipramine/pharmacology , Receptors, Adrenergic/drug effects , Age Factors , Animals , Cerebral Cortex/chemistry , Male , Prefrontal Cortex/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic/analysis , Receptors, Adrenergic, alpha-1/analysis , Receptors, Adrenergic, alpha-2/analysis
18.
Biochem Pharmacol ; 73(8): 1225-36, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17316571

ABSTRACT

Our understanding of the development of neurotransmitter systems in the central nervous system has increased greatly over the past three decades and it has become apparent that drug effects on the developing nervous system may differ considerably from effects on the mature nervous system. Recently it has become clear there are significant differences in the effectiveness of antidepressant drug classes in children and adolescents compared to adults. Whereas the selective serotonin reuptake inhibitors are effective in treating all ages from children to adults, the tricyclic antidepressants, many of which inhibit norepinephrine reuptake, have been shown to be ineffective in treating children and adolescents even though they are effective in adults. We review here the development of the noradrenergic and serotonergic nervous systems, both in terms of neurotransmitter system markers and function. Both of these neurotransmitter systems are primary targets of antidepressant medications as well as of central nervous system stimulants. It is clear from a comparison of their development that the serotonin system reaches maturity much earlier than the norepinephrine system. We suggest this may help explain the differences in response to antidepressants in children and adolescents compared to adults. In addition, these differences suggest that drugs acting preferentially on either neurotransmitter system may impact the normal course of CNS development at different time points. Consideration of such differences in the development of neurotransmitter systems may be of significance in optimizing treatments for a variety of centrally mediated disorders.


Subject(s)
Adrenergic Agents/pharmacology , Neurotransmitter Agents/physiology , Receptors, Adrenergic/physiology , Receptors, Serotonin/physiology , Adolescent , Adult , Animals , Humans
20.
Brain Res ; 1109(1): 45-53, 2006 Sep 13.
Article in English | MEDLINE | ID: mdl-16854392

ABSTRACT

The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-beta-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh-/-) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (alpha1-AR, alpha2-AR and beta-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh-/- mice with those in Dbh heterozygotes (Dbh+/-), which have normal levels of norepinephrine throughout life. The densities of alpha1-AR, alpha2-AR and beta-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The alpha2-AR agonist high affinity state was examined with [125I]-para-iodoclonidine autoradiography and alpha2-AR functionality by alpha2-AR agonist-stimulated [35S]GTPgammaS autoradiography. The density of alpha1-AR in Dbh-/- mice was similar to Dbh+/- mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in alpha2-AR were found in septum, hippocampus and amygdala, but these were not reflected in alpha2-AR functionality. The density of beta-AR was up-regulated to varying degrees in many brain regions of Dbh-/- mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region.


Subject(s)
Brain/metabolism , Dopamine beta-Hydroxylase/deficiency , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Analysis of Variance , Animals , Animals, Newborn , Autoradiography/methods , Brain/drug effects , Brain/growth & development , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/genetics , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Idazoxan/analogs & derivatives , Idazoxan/metabolism , Isotopes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Pindolol/metabolism , Prazosin/metabolism , Receptors, Adrenergic, alpha-1/genetics , Receptors, Adrenergic, alpha-2/genetics
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