Treatment with antidepressants and histamine receptor mediated 3H-cyclic AMP formation in guinea pig cortex

It has been recently reported that most of the antidepressant drugs block histamine H1 and H2 receptors in the brain under in vitro conditions and it has been suggested that this may be related in part to their therapeutic effect. Since the in vitro and in vivo effects of these drugs may differ, we studied the effect of treatment with antidepressant drugs on histamine receptor sensitivity in the guinea pig brain and observed that chronic treatment with tricyclic antidepressants or phenelzine (an MAO inhibitor) causes a reduction in histamine receptor sensitivity. This reduction is probably mediated through two different mechanisms, since only tricyclic antidepressants cause a reduction after acute treatment. Although some of the side effects of antidepressant treatment may be related to the blockade of histamine receptors, these results do not support the assumption that this effect of antidepressant treatment contributes to their clinical effects.     

Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants

The effects of tricyclic antidepressants drugs (TCA) amitriptyline, imipramine and nortriptyline, on purified Electrophorus electricus (L.) acetylcholinesterase (AChE; acetylcholine hydrolase, EC 3.1.1.7) were studied using kinetic methods and specific fluorescent probe propidium. The antidepressants inhibited AChE activity by a non-competitive mechanism. Inhibition constants range from 200 to 400 microM. Dimethylated amitriptyline and imipramine were more potent inhibitors than the monomethylated nortriptyline. Fluorescence measurements using bis-quaternary ligand propidium were used to monitor ligand-binding properties of these cationic antidepressants to the AChE peripheral anionic site (PAS). This ligand exhibited an eight-fold fluorescence enhancement upon binding to the peripheral anionic site of AChE from E. electricus (L.) with K(D)=7 x 10(-7)M. It was observed that TCA drugs displaced propidium from the enzyme. On the basis of the displacement experiments antidepressant dissociation constants were determined. Similar values for the inhibition constants suggest that these drugs have similar affinity to the peripheral anionic site. The results also indicate that the catalytic active center of AChE does not participate in the interaction of enzyme with tricyclic antidepressants. These studies suggest that the binding site for tricyclic antidepressants is located at the peripheral anionic site of E. electricus (L.) acetylcholinesterase.     

Antidepressant drugs: imipramine, mianserin and trazodone

The advent of newer antidepressant drugs (second generation) during the past two decades has provided an alternative to the use of tricyclic antidepressants in the alleviation of depression. These antidepressants have not been proven to be superior in the therapy of depression to the tricyclic antidepressants but they have been reported to cause fewer cardiac effects. Most of the reported adverse cardiac reactions elicited by antidepressant drugs are based on observations from clinical studies. The possible underlying mechanisms by which these adverse reactions arise have for the large part been proposed on the basis of clinical findings which have been extrapolated back to the known pharmacological actions of such drugs. There is a paucity of hard experimental data in this respect.     

Effects of antidepressant drugs on histamine-H1 receptors in the brain

The histamine-H1 receptor blocking properties of a number of structurally different antidepressant drugs have been evaluated using a 3H-mepyramine binding assay and a guinea-pig ileum preparation. The tricyclic antidepressants all inhibited the histamine-H1 receptor. Some newer antidepressant drugs, such as zimelidine and nomifensine were devoid of activity while others, such as iprindole and mianserin were very potent. It is concluded that antagonistic effects on the histamine-H1 receptor is not associated with the therapeutic efficacy in depression, but may contribute to the sedative effects of the antidepressant drugs.     

Tricyclic antidepressants induce sphingomyelinase deficiency in fibroblast and neuroblastoma cell cultures

Tricyclic antidepressants (imipramine and desipramine) gave rise to an important decrease of sphingomyelinase activity in murine neuroblastoma and human fibroblast cell cultures. It occurred within 1 to 2 hours at a final concentration of 1 or 2 X 10(-5) M in cell culture medium. Other lysosomal enzymes such as acid lipase, arylsulfatases A and B and hexosaminidases were not modified. Low level of sphingomyelinase activity may be related to the amphiphilic characteristics of the drugs: iminodibenzyle which has the same tricyclic core but is devoid of the side chain necessary for amphiphilic properties had no effect. As iminodibenzyle has no therapeutic action, amphiphilic may be requisite to antidepressant properties of tricyclic drugs.     

General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants.

OBJECTIVE: To examine inceptions and discontinuations of antidepressants in general practice. DESIGN: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative sample of 250 doctors recorded prescribing activity for four weeks. This provided 4000 general practitioner weeks of recording per year. SETTING: A representative panel of general practitioners in England, Wales, and Scotland. SUBJECTS: Patients who began a new course of an antidepressant or had their treatment stopped or changed by the general practitioner between 1 July 1990 and 30 June 1995. MAIN OUTCOME MEASURES: Numbers of patients prescribed a new course of antidepressant; numbers discontinuing treatment; the ratio of antidepressant discontinuations to antidepressant inceptions; reasons for discontinuation; proportion of switches to another antidepressant. RESULTS: There were 13,619 inceptions and 3934 discontinuations of selective serotonin reuptake inhibitors and tricyclic antidepressants during the study. The number of newly prescribed courses of antidepressants increased by 116%, mostly due to an increase in prescribing of serotonin reuptake inhibitors. The ratio of total discontinuations to inceptions was significantly lower for serotonin reuptake inhibitors (22%) than for tricyclic antidepressants (33%). Differences persisted when controlled for age and sex of patients and severity of depression. However, there was more switching away from selective serotonin reuptake inhibitors when they failed (72%) than from tricyclic antidepressants (58%). CONCLUSIONS: Selective serotonin reuptake inhibitors are less likely than tricyclic antidepressants to be discontinued. A prospective study is needed in general practice to assess the implications of differences in discontinuation rates and switches on clinical and economic outcomes.     

Relationship between Plasma Level and Therapeutic Effect of Nortriptyline

The relationship between plasma concentration of nortriptyline and therapeutic effect after two weeks'' treatment with the drug was investigated in 29 psychiatric inpatients. Endogenous depression was diagnosed in all patients. Amelioration of depressive symptoms was estimated as reduction in score on a rating scale, based on a psychiatric interview. Amelioration was not correlated to the patient''s sex or age. There was a curved relationship between plasma level of nortriptyline and therapeutic effect. Amelioration was most pronounced in the intermediate plasma level range (50-139 ng nortriptyline/ml plasma) and was slight both at lower and at higher plasma levels. This type of relationship may be due to the dual action of tricyclic antidepressants which has been found in animal experiments. On larger dosages a phenothiazine-like blockade of the monoaminergic receptor is added to the blockade of monoamine reuptake thought to be related to the antidepressant action of the drugs.This study thus suggests two possible reasons for a therapeutic failure with nortriptyline: a too low or a too high plasma level. The large individual variation in the pharmacokinetics of the tricyclic antidepressants makes prediction of plasma level from dosage in a given individual virtually impossible without knowledge of rate of elimination and apparent volume of distribution. Hence monitoring plasma levels may be a way to increase the efficacy of treatment with these drugs.     

Controlled trial of trimipramine,monoamine oxidase inhibitors,and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks'' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.     

What is an antidepressant binding site doing in a bacterial transporter?

LeuT is a bacterial amino acid transporter belonging to a large family of membrane proteins, including the neurotransmitter transporters that are targets for antidepressant drugs. The high-resolution structure of LeuT has provided an important model for understanding structure and function in this family. Two recent papers found that LeuT can bind tricyclic antidepressants, raising the possibility that it may also serve as a model for the pharmacological properties of neurotransmitter transporters.     

Direct interaction of tricyclic antidepressants with opiate binding sites in the bovine adrenal medulla

This note reports the interaction of three currently used tricyclic antidepressant drugs (clomipramine, imipramine and amitriptyline) with delta, mu and kappa opioid binding sites in the bovine adrenal medulla. Clomipramine was the only drug interacting with delta and mu sites. On the contrary, all three drugs showed a significant interactions with subtypes of the kappa binding site. Clomipramine was the most active on the kappa 2 and kappa 3 subtypes while amitriptyline showed the highest interaction with the kappa 1 subtype. On the contrary the tricyclic cyproheptadine did not present any interaction with opioid binding sites in our system. This interaction between tricyclic antidepressants and opioid binding sites might be the origin of their analgesic action.     

Drugs That Cause Weight Gain

Among drugs which cause weight gain, the tricyclic antidepressant medications are a drug class producing persistent and problematic body weight gain in many treated patients. Major depressive illness is often associated with reductions in appetite and body weight, and treatment with antidepressants effectively restores mood, appetite and weight. However, a frequent complaint of patients treated with tricyclic drugs is of excessive and unwanted weight gain, oftentimes resulting in medication noncompliance. The incidence of weight gain during acute and chronic treatment with different, frequently prescribed antidepressant drugs will be reviewed, as will the possible mechanisms by which such drugs alter caloric intake and expenditure, contributing to drug-induced weight gain.     

HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4

The clinical use of several first generation HIV protease inhibitors (PIs) is associated with the development of insulin resistance. Indinavir has been shown to act as a potent reversible noncompetitive inhibitor of zero-trans glucose influx via direct interaction with the insulin responsive facilitative glucose transporter GLUT4. Newer drugs within this class have differing effects on insulin sensitivity in treated patients. GLUTs are known to contain two distinct glucose-binding sites that are located on opposite sides of the lipid bilayer. To determine whether interference with the cytoplasmic glucose binding site is responsible for differential effects of PIs on glucose transport, intact intracellular membrane vesicles containing GLUT1 and GLUT4, which have an inverted transporter orientation relative to the plasma membrane, were isolated from 3T3-L1 adipocytes. The binding of biotinylated ATB-BMPA, a membrane impermeable bis-mannose containing photolabel, was determined in the presence of indinavir, ritonavir, atazanavir, tipranavir, and cytochalasin b. Zero-trans 2-deoxyglucose transport was measured in both 3T3-L1 fibroblasts and primary rat adipocytes acutely exposed to these compounds. PI inhibition of glucose transport correlated strongly with the PI inhibition of ATB-BMPA/transporter binding. At therapeutically relevant concentrations, ritonavir was not selective for GLUT4 over GLUT1. Indinavir was found to act as a competitive inhibitor of the cytoplasmic glucose binding site of GLUT4 with a K(I) of 8.2 μM. These data establish biotinylated ATB-BMPA as an effective probe to quantify accessibility of the endofacial glucose-binding site in GLUTs and reveal that the ability of PIs to block this site differs among drugs within this class. This provides mechanistic insight into the basis for the clinical variation in drug-related metabolic toxicity.     

Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex: Structure activity study

The effects of 20 tricyclic and 12 chemically unrelated ‘atypical’ antidepressant drugs on the noradrenaline (NA) receptor coupled adenylate cyclase system were investigated in slices of the rat cerebral cortex. While no changes occurred after a single dose, 14 tricyclic compounds down-regulated the receptor system when administered for 9 days. Six tricyclic antidepressants (trimipramine, butriptyline, noxiptyline, doxepine, dosulepine, propizepine) failed to desensitize the NA sensitive adenylate cyclase although some were potent inhibitors of the neuronal uptake of NA. Using the two optically active enantiomers of oxaprotiline inhibition of NA uptake was observed with the (+)-enantiomer while the (?)-enantiomer had only weak inhibitory potency. However, in contrast to published data, both enantiomers and the racemate administered at 30 mg/kg for 9 days did down-regulate the NA receptor coupled adenylate cyclase. Therefore, the experiments were repeated with Sprague-Dawley rats from a different supplier. Now, data published earlier were reproducible, only the racemate and the (+)-enantiomer of oxaprotiline being significantly active on the desensitization of the NA sensitive adenylate cyclase. Using F-344, Long Evans and Wistar rats significant differences were found in the response of the adrenoceptor coupled adenylate cyclase to a 9 day treatment with 30 mg/kg imipramine. Although some of the atypical antidepressants are potent inhibitors of the biogenic amine uptake systems none of these compounds lead to statistically significant changes of the NA stimulated cAMP formation after a 9-day treatment period. Only with the NA uptake inhibitor tandamine and with the serotonin uptake inhibitors zimelidine and fluoxetine a trend toward adrenergic down-regulation was recognized. Using enantiomers of mianserin only the (?)-isomer which is a poor NA uptake inhibitor, was slightly active. It thus appears that the therapeutic action of antidepressant drugs cannot generally be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system. Variabilities in pharmacokinetics and in NA sensitivity of the cAMP generating system in various rat strains and possibly in different animal species may be important factors determining whether β-receptor down-regulation will occur during chronic treatment with antidepressant drugs.     

Expression and distribution of facilitative glucose (GLUTs) and monocarboxylate/H+ (MCTs) transporters in rat olfactory epithelia

Cell-to-cell metabolic interactions are crucial for the functioning of the nervous system and depend on the differential expression of glucose transporters (GLUTs) and monocarboxylate transporters (MCTs). The olfactory receptor neurons (ORNs) and supporting cells (SCs) of the olfactory epithelium exhibit a marked polarization and a tight morphological interrelationship, suggesting an active metabolic interaction. We examined the expression and localization of MCTs and GLUTs in the olfactory mucosa and found a stereotyped pattern of expression. ORNs exhibited GLUT1 labeling in soma, dendrites, and axon. SCs displayed GLUT1 labeling throughout their cell length, whereas MCT1 and GLUT3 localize to their apical portion, possibly including the microvilli. Additionally, GLUT1 and MCT1 were detected in endothelial cells and GLUT1, GLUT3, and MCT2 in the cells of the Bowman's gland. Our observations suggest an energetic coupling between SCs and Bowman's gland cells, where glucose crossing the blood-mucosa barrier through GLUT1 is incorporated by these epithelial cells. Once in the SCs, glucose can be metabolized to lactate, which could be transported by MCTs into the Bowman's gland duct, where it can be used as metabolic fuel. Furthermore, SCs may export glucose and lactate to the mucous layer, where they may serve as possible energy supply to the cilia.     

Tricyclic antidepressant drugs affect histamine receptors in human leukocytes

Tricyclic antidepressant drugs bind to histamine receptors in rodent and other mammalian tissues. However, a readily accessible, normal human tissue for studies of these drugs has not been available. We showed that freshly isolated human leukocytes can be used for this purpose. Following isolation by dextran sedimentation, leukocytes were incubated for 30 sec. in histamine concentrations from 1.0 nM to 1.0 mM. A dose-related increase in intracellular cyclic AMP was observed. When the cells were preincubated for 10 min. in the tricyclic, nortriptyline, and then challenged with histamine, the concentration of histamine needed for a comparable cyclic AMP increase was elevated 100-fold over non-preincubated cells. These results indicate that the tricyclic drug interacts with histamine receptors on leukocytes, and that these cells may be used for biochemical and clinical studies of these drugs.     

Modifications of sphingomyelin and phosphatidylcholine metabolism by tricyclic antidepressants and phenothiazines

Phenothiazines and tricyclic antidepressants, when added to culture medium, gave rise in several types of cells (C6 rat glioma cells and human fibroblasts), to a decrease in lysosomal sphingomyelinase activity. The effect of chlorpromazine and desipramine was dose dependent, and was observed after 3 hours of incubation with the drugs at concentrations ranging between 1 and 10 microM. In C6 glioma cell cultures, the decrease in sphingomyelinase activity was related to the clinical effectiveness of phenothiazines, tricyclic antidepressants and derivatives. Incorporation of (choline-14C) sphingomyelin showed that the metabolic pathway implying the synthesis of phosphatidylcholine from the hydrolysis of sphingomyelin and/or transfer of phosphorylcholine to phosphatidylcholine was also partially reduced.     

High- and Low-Affinity Binding of [3H]Imipramine in Rat Hypothalamus

In the rat hypothalamus [3H]imipramine binding is inhibited by tricyclic and nontricyclic antidepressant drugs in a complex manner, with biphasic curves and Hill coefficients less than 1.0. 5-Hydroxytryptamine (serotonin) inhibited with high affinity a decreasing proportion of the [3H]imipramine binding sites as the [3H]imipramine concentration was raised. In the absence of sodium ions, IC50 values for the inhibition by tricyclic and nontricyclic antidepressants were increased by approximately 1,000-fold, and the inhibition curves became classically monophasic with Hill coefficients close to 1.0. These data are interpreted as suggesting that [3H]imipramine binds to two independent sites in the rat hypothalamus. One site is sodium-dependent with a high affinity for the drugs tested; the other is sodium-independent and has a low affinity for these drugs.     

Antidepressants Cause Bradycardia and Heart Block in GD 13 Rat Embryos In Vitro

This study investigated the effects of a range of antidepressant drugs on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the drugs would adversely affect the function of the embryonic heart since they all have some cardiac ion channel blocking activity in addition to their main pharmacological effect on neurotransmitters. The results showed that all the tested drugs caused bradycardia in a generally concentration‐dependent manner. At higher concentrations most of the drugs caused some degree of heart block consistent with sodium channel blockade and some drugs also showed negative inotropy associated with blockade of the L‐type calcium channel. One drug, trazodone, caused arrhythmia consistent with blockade of the hERG (human ether‐a‐go‐go related gene) potassium channel. In general the effects on the embryonic rat heart were only seen at “free drug” concentrations much greater than those likely to occur in pregnant women taking antidepressant medication. The least margin of safety was seen with the tricyclic antidepressants and the serotonin antagonist and reuptake inhibitor trazodone.     

Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs

Depression has been treated pharmacologically for over three decades, but the views regarding the mechanism of action of antidepressant drugs have registered recently a major change. It was increasingly appreciated that adaptive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are connected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphorylation, which represents an obligate step for most pathways, is markedly affected by long-term treatment. Changes were reported to be induced in the function of protein kinase C, cyclic AMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase. For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolated neuronal compartments (microtubules and presynaptic terminals). Antidepressant treatment activates the two kinases and increases the endogenous phosphorylation of selected substrates (microtubule-associated protein 2 and synaptotagmin). These modifications may be partly responsible for the changes induced by antidepressants in neurotransmission. The changes in protein phosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.