Effect of pH changes and ethanol on the binding of tricyclic antidepressants to cholestyramine in simulated gastric fluid.

Tricyclic antidepressants have previously been shown by this laboratory to bind significantly (greater than 80%) to cholestyramine in 1.2 mol/L HCl, used to simulate gastric fluid. This finding has important implications for individuals using tricyclic and cholestyramine concurrently, and it may also have potential therapeutic implications in the treatment of tricyclic overdose. In the present study the effects of pH changes and ethanol on this binding were evaluated. Percent binding of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline decreased from 75-90% (pH 1.0) to 35-50% (pH 4.0). Beyond pH 4.0, however, the binding of each antidepressant increased up to 60-75% at pH 6.5. In contrast, ethanol consistently reduced the percent binding of each antidepressant to cholestyramine in 1.2 mol/L HCl until, in the presence of pure ethanol, the binding ranged from 0% (nortriptyline) to only 32% (doxepin). These findings are important since pH varies widely within the gastrointestinal tract and since ethanol may be co-ingested with cholestyramine and antidepressants.     

The interaction of trazodone with rat brain muscarinic cholinoceptors.

The muscarinic receptor binding of trazodone, a new nontricyclic antidepressant, was compared with established tricyclic antidepressants. The ability to inhibit the binding of [3H]-quinuclidinyl benzilate in vitro was used for comparing atropine-like effects. Trazodone was found to have essentially no activity at the muscarinic acetylcholine binding site in comparison to the tricyclic antidepressants.     

Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation

Abstract: The opioid receptor binding in the human thalamic area was studied with U-69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC₅₀-values for all tricyclic antidepressants tested were in the 10^-6 M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine-3-glucuronide and morphine-6-glucuronide was non-competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine-UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.     

Tricyclic antidepressants and calcium channel blockers: interactions at the (-)-desmethoxyverapamil binding site and the serotonin transporter

The activity of various calcium channel blockers at the serotonin transporter, as determined by their effects on imipramine binding and serotonin uptake, was investigated in rat brain and human platelets. In addition, the effect of tricyclic antidepressants on the binding of calcium channel blockers was evaluated. Verapamil was found to be a competitive inhibitor of both imipramine binding and serotonin uptake in brain and platelets. The inhibitory activity of verapamil was calcium-independent. Chronic verapamil treatment resulted in a significant decrease (28%) in [3H]imipramine binding in the rat hypothalamus but had no effect on [3H]imipramine binding to cerebral cortex membranes or on [3H]serotonin uptake in these two brain regions. Tricyclic antidepressants inhibited (-)-[3H]desmethoxyverapamil binding but did not affect [3H]nitrendipine binding to rat cerebral cortex membranes. Chronic imipramine treatment induced a non-significant increase (34%) in (-)-[3H]desmethoxyverapamil binding but did not alter [3H]nitrendipine binding in rat cerebral cortex. These interactions may be relevant to an understanding of the beneficial effects of verapamil in major affective disorders and may suggest an involvement of calcium channels in the pharmacological activity of tricyclic antidepressants.     

Biochemical pharmacology of pirenzepine. Similarities with tricyclic antidepressants in antimuscarinic effects only

5,11-Dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b][-1,4]-benzodiazepin-6-one dihydrochloride (pirenzepine, Gastrozepin) and some tricyclic antidepressant drugs which show a very close relationship concerning the chemical structure were investigated in numerous binding, uptake and enzymatic studies in vitro. With pirenzepine a high affinity binding could be demonstrated only to muscarinic receptors (Ki = 58 nmol/l). In all other studies pirenzepine had a very weak or no effect at all. In contrast, tricyclic antidepressants bound with high but different affinities to various receptors as known from numerous publications. The highest affinities were found with imipramine at the specific imipramine binding sites (Ki = 9.8 nmol/l) and at the alpha 1-receptor (Ki = 39 nmol/l), with desipramine at the muscarinic receptors (Ki = 88 nmol/l), with mianserin at the H1-(Ki = 3.4 nmol/l) and 5HT2-receptors (Ki = 7.3 nmol/l). Moreover, imipramine and desipramine showed their known substantial inhibition of noradrenaline and/or 5-hydroxytryptamine uptake. Thus, a homogeneous affinity or activity profile of the antidepressants studied does not exist. The only common property of pirenzepine and the tricyclic antidepressants was found to be the high affinity binding to the muscarinic receptors which might explain the common antisecretory action of these agents. Because of the unique specificity of pirenzepine lacking all other effects of the tricyclic antidepressants as demonstrated in this study, it is very unlikely that this drug exerts any antidepressant-like central action.     

Effects of some antidepressants on the volume-induced reflex contractions of the rat urinary bladder: lack of correlation with muscarinic receptors affinity

It has been suggested that tricyclic antidepressants such as imipramine, might exert their anti-enuretic action by a blockade of muscarinic receptors in the detrusor muscle of the urinary bladder. We have therefore investigated the effects of two tricyclic (imipramine and nortriptyline) and three atypical (citalopram, amineptine and mianserin) antidepressants on the micturition reflex and muscarinic receptors in rats. The micturition reflex pathway was monitored indirectly by recording the rhythmic intravesical pressure waves which occurred when the bladder was distended and maintained under constant saline-volume. The activity of the antidepressants was correlated to their potencies as antagonists of [3H]QNB binding to rat brain (mainly M1 receptors) and bladder (mainly M2 receptors) membranes, as well as antagonists of carbachol-induced contractions of rat bladder strips. Only imipramine and citalopram dose dependently inhibited the voiding contractions, whereas nortriptyline, imipramine and mianserin (in order of potency) were active both in binding studies and as competitive antagonists of carbachol-induced bladder contractions, but were inactive in inhibiting the micturition reflex. The present data seem to suggest that affinities for muscarinic receptors are unrelated to the inhibition of micturition reflex.     

Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa

The interaction of adenylate cyclase with histamine H2 receptor agents and with tricyclic antidepressants was studied in guinea pig gastric mucosal membranes. The H2 receptor antagonist tiotidine acted as a competitive inhibitor of histamine-stimulated adenylate cyclase. The tricyclic antidepressants imipramine and amitryptyline were also competitive inhibitors. The dissociation constant of imipramine was the same whether histamine or dimaprit was used to activate the enzyme. In membrane preparations that had been stored frozen, there was a marked increase in the concentration of histamine or dimaprit required to cause half-maximal enzyme stimulation, and the dissociation constants of some classical H2 receptor antagonists were greatly increased. In contrast, the dissociation constants of the antidepressants were either unchanged or decreased. These results suggest that antidepressants are potent blockers of H2 receptors in gastric mucosal membranes, but there are differences between antidepressants and classical H2 receptor antagonists in their interaction with H2 receptors.     

Dopamine and depression — Striatal dopamine D2 receptor SPECT before and after antidepressant therapy

Ten unmedicated and ten medicated patients with major depression and ten controls were investigated with IBZM-SPECT. The ten unmedicated patients were reinvestigated after treatment with tricyclic antidepressants. Dopamine D₂ receptor occupancy was not different between patients and controls, or medicated and unmedicated patients. IBZM binding was increased in four patients with psychomotor retardation. Antidepressant therapy led to a decrease in IBZM binding in the five improved patients. Dopamine D₂ receptor binding remained unchanged in nonresponders. It is concluded that striatal dopamine D₂ receptor binding is not changed in depression or by tricyclic antidepressants; however, it is affected by psychomotor activity. The changes observed might be the result of increased tonic dopamine release in the basal ganglia, but several other explanations exist.     

Effects of minaprine and sulpiride injected into the amygdaloid nucleus on the duration of immobility in rats forced to swim

We examined the effects of minaprine and sulpiride injected into the medial amygdaloid nucleus on the duration of immobility in rats forced to swim. Minaprine (50 micrograms/microliter) significantly reduced the duration of immobility, while sulpiride (50 micrograms/microliters) remarkedly enhanced it. These results suggest that the medial amygdaloid nucleus might be involved in the suppressive effect of minaprine on the duration of immobility, as was seen with the tricyclic antidepressants. The pattern of behavior seen with sulpiride administrations differs considerably from that seen with the tricyclic antidepressants.     

Hepatotoxicity and surface activity of tricyclic antidepressants in vitro.

Cytotoxicity to isolated rat hepatocytes of the tricyclic antidepressants, chlorimipramine, nortriptyline, amitriptyline, imipramine, and of doxepin was determined by the leakage of cytoplasmic and lysosomal enzymes into surrounding media. The rank order of toxicity was: chlorimipramine > nortriptyline > amitriptyline > imipramine > doxepin. All tricyclic antidepressants tested lowered the surface tension of the salt solution contained in the tissue culture media. The rank order of surface activity was the same as that of hepatotoxicity in vitro. These results suggest that the differences in membrane damage produced by tricyclic antidepressants may be related to surface activity which in turn may determine the extent of adsorption onto cell membranes.     

Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluvoxamine is a new antidepressant which potently and specifically inhibits neuronal reuptake of serotonin. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from facilitation of serotoninergic neurotransmission as a result of reuptake inhibition. Studies suggest that fluvoxamine has overall therapeutic efficacy comparable with that of imipramine and clomipramine in depressive illness. It causes fewer anticholinergic-type and cardiovascular side effects than the tricyclic antidepressants but it is associated with a higher incidence of nausea and vomiting. Elderly patients also respond well to fluvoxamine. Studies are now required to compare fluvoxamine with other second generation antidepressants and to establish whether some types of depressive illness respond more readily to fluvoxamine than other agents. Thus, in patients with depressive illness, fluvoxamine offers a suitable alternative to tricyclic antidepressants and may be especially valuable in patients with concomitant cardiovascular disease, and those unresponsive to or unable to tolerate tricyclic antidepressants.     

Tricyclic antidepressants block N-methyl-D-aspartate receptors: similarities to the action of zinc.

1. Using the radioligand [3H]-MK801, we have examined drug interactions with the phencyclidine recognition site of the N-methyl-D-aspartate receptor. 2. The tricyclic antidepressants desmethylimipramine and imipramine inhibited [3H]-MK801 binding with IC50 values of 7.4 and 22.5 microM, respectively. Other related tricyclic antidepressants and neuroleptics were also effective but less potent. 3. Desmethylimipramine, imipramine and chlorimipramine slowed the dissociation rate of [3H]-MK801 in a similar manner to Zn2+. Phencyclidine and related compounds had no effect on the dissociation rate of [3H]-MK801. 4. Desmethylimipramine, imipramine and ketamine also prevented the Ca2+ influx into cultured cortical neurones of the rat produced by N-methyl-D-aspartate. 5. As the actions of tricyclic antidepressants in this system are not competitive with respect to N-methyl-D-aspartate, glycine or MK-801, and as they slow the dissociation of [3H]-MK801, we conclude that tricyclic antidepressants may be acting at the Zn2+ recognition site on the N-methyl-D-aspartate receptor.     

Chemistry,Pharmacology, Pharmacokinetics,Adverse Effects,and Efficacy of the Antidepressant Maprotiline Hydrochloride

Maprotiline, a tetracyclic antidepressant with sedative properties, exhibits strong inhibitory effects on norepinephrine uptake across nerve cell membranes but interferes relatively little with serotoninergic mechanisms. The biological half-life of unchanged maprotiline in blood averages 43 hours. Though several studies suggest a more rapid onset of antidepressant effects with maprotiline than with amitriptyline or imipramine, this issue remains unresolved. The adverse effect profile of maprotiline is similar to that of the tricyclic antidepressants, except that rashes are about twice as frequent with maprotiline as with amitriptyline or imipramine. The most frequent adverse reactions are anticholinergic effects and sedation. Data suggest less frequent and severe anticholinergic side effects with maprotiline than with amitriptyline. Maprotiline may be less likely to induce orthostatic hypotension and tachycardia than standard tricyclic antidepressants, but clinically important differences in cardiovascular effects remain to be conclusively demonstrated. Many patients benefit from the convenience of once daily dosing. Maprotiline is comparable in antidepressant efficacy to the tricyclic antidepressants.     

Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative

The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase. Unlike the tricyclic antidepressants, it was not antimuscarinic in the guinea pig ileum, nor did it have any appreciable affinity for brain alpha-1 adrenergic or histamine-1 binding sites. Wy-45,030 was also without affinity for alpha-2 or beta adrenergic, benzodiazepine, serotonin-1, serotonin-2, dopamine-2, and opiate receptors. Such a profile is predictive of antidepressant activity devoid of the side-effects common to tricyclic therapy.     

3H-Rauwolscine binding in platelets from depressed patients and healthy volunteers

3H-Rauwolscine binds specifically and with high affinity to alpha 2-adrenoceptors in human platelets. In a study comparing the binding of 3H-rauwolscine in platelets obtained from 26 control volunteers with 19 hospitalised, untreated, severely depressed patients, the mean maximal binding (Bmax) and mean dissociation constant (Kd) of 3H-rauwolscine binding were found to be identical in both groups. After 7-12 days, treatment with different tricyclic antidepressant drugs there was a significant improvement in the depressive symptoms but no change in the 3H-rauwolscine binding. After an average of 23 days treatment with tricyclic antidepressants, and when the Hamilton Depression Rating Scores had returned to normal, the Kd and Bmax of 3H-rauwolscine binding were still unchanged.     

Pharmacokinetic study of yohimbine and its pharmacodynamic effects on salivary secretion in patients treated with tricyclic antidepressants.

The pharmacokinetic parameters and the time course of the effect after acute oral administration of yohimbine on salivary secretion in patients treated with tricyclic antidepressants were investigated. Yohimbine (10 mg) increased both salivary outflow and plasma noradrenaline levels for 4 h. Pharmacokinetic parameters (t1/2, tmax, Cmax and AUCexp) and plasma concentrations of noradrenaline were higher in patients treated with tricyclic antidepressants than in controls. At this dose, yohimbine induced a relatively large number of side effects. A lower dose (4 mg) increased salivary secretion for 3 h without any side effects in patients treated with tricyclic antidepressants but not in healthy volunteers. These data describe an interaction between yohimbine and tricyclic antidepressants and thus show that a relatively low dose (4 mg) of yohimbine could be useful in the treatment of dry mouth due to tricyclic antidepressants.     

Tricyclic antidepressants block N-methyl-D-aspartic acid-induced lethality in mice.

It has been suggested on the basis of in vitro studies that tricyclic antidepressants interact with the N-methyl-D-aspartic acid (NMDA)-receptor complex to block the action of NMDA. The present study showed that tricyclic antidepressants prevented lethality produced by a large dose of NMDA. The potency of the drugs in preventing NMDA-induced lethality correlated with the inhibition of [3H]-MK-801 binding at the NMDA receptor complex, and not with effects on amine uptake. These in vivo data support the in vitro data of Reynolds & Miller (1988a,b).     

Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants

In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR.Antidepressants produce a significant concentration-dependent decrease in the duration of clusters of single-channels (eight fold at 20 muM). They also decrease the peak amplitude and increase the decay rate of currents elicited by rapid perfusion of ACh to outside-out patches. In equilibrium binding assays, antidepressants promote the typical high-affinity desensitized state and inhibit binding of [piperidyl-3,4-(3)H (N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([(3)H]TCP) to its locus in resting and desensitized AChRs. The results indicate that tricyclic antidepressants: (i) interact with resting (closed), open, and desensitized channels; (ii) do not affect significantly channel opening and closing rates; (iii) do not act as fast open-channel blockers; (iv) inhibit activation of resting channels; and (v) may increase the rate of long-lived desensitization from the open state.     

Long-term desipramine or chlorpromazine treatment and rat brain N-methyl-D-aspartate receptor.

The effects of tricyclic antidepressants and antipsychotic drugs on the NMDA receptor in rat brain were investigated. Both types of drugs, in the micromolar concentration range and with Hill coefficients greater than unity, inhibited the binding of [3H]TCP to rat brain membranes. Tricyclic antidepressants containing secondary amine on the aliphatic side chain were more potent than the corresponding tertiary amine derivatives. Antipsychotic drugs containing large side chains were much less active than chlorpromazine. Neither tricyclic antidepressants nor antipsychotic drugs had an inhibitory effect on [3H]CPP binding to the glutamate site of the NMDA complex. Chronic administration of desipramine or chlorpromazine did not change the binding parameters of [3H]TCP to rat cerebral cortex membranes. It is possible that these psychoactive drugs bind to a site adjacent to the [3H]TCP binding site within the ionic channel of the NMDA receptor complex.     

Loss of rat cerebral cortical opiate receptors following chronic desimipramine treatment

The characteristics of central opiate and beta-adrenergic receptors were studied after giving the tricyclic antidepressant desimipramine (DMI) to rats. Administration of DMI for 1 or 7 days did not alter cortical opiate or beta-adrenergic receptors. However, after 21 days of treatment there was a significant subsensitivity of both these receptors in the cortex. A specific loss of receptor sites for opiate binding was detected with no change in affinity. After a similar time of treatment, opiate receptors in the corpus striatum and hippocampus were the same as the controls. The data suggest that change in cortical opiate receptors may be important in the mechanism of action of antidepressants.