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PubMed1980

High affinity binding of tricyclic antidepressants to histamine H1-receptors: fact and artifact.

Six tricyclic antidepressants were tested for their ability to inhibit the binding of the histamine H1-receptor antagonist [3H]pyrilamine to membrane fractions from whole rat brain. Calculated inhibition constants (Ki) for the antidepressants were in the range of 2.6 x 10(-11) to 2.3 x 10(-7) M and correlated very well with their equilibrium dissociation constants derived from biological assays of the H1-receptor. Increasing the concentration of receptors present in the binding assay resulted in an overestimation of the calculated Ki's for doxepin, amitriptyline, and nortriptyline, but not for the lower affinity compounds of the series, imipramine, protriptyline, and desipramine. These results indicate: (1) the importance of receptor concentration in determining the potency of compounds which competitively inhibit, with very high affinity, the binding of a radioactively labeled ligand; (2) the need to correlate binding data with biological data.

Animals↗
PubMed1980

Inhibition of (3H)-dopamine uptake into rat brain synaptosomes by the new non-tricyclic antidepressants, FS32 and FS97.

The effects of new non-tricyclic antidepressants, FS32 and its desmethylated compound (FS97), on the uptake of (3H)-dopamine (DA) by rat purified whole brain synaptosomes and the striatal synaptosomes were studied. The uptake into synaptosomes was time- and temperature-dependent and was saturable with a Km value of 9.1 X 10(-8) M. The inhibiting activities of both compounds were comparable to those of amitriptyline, nortriptyline and iprindole, and were nearly twice the activity of imipramine and desipramine. The kinetic constants indicated that both FS32 and FS97 were competitive inhibitors of (3H)-DA uptake. Neither drug caused a significant release of (3H)-DA from the synaptosomes.

Animals↗
PubMed1985

Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.

The effect of pretreatment with various MAO and catecholamine uptake inhibitors on the MPTP-induced reduction of endogenous catecholamine levels and [3H]catecholamine uptake in mouse striatum and cerebral cortex associated with the neurotoxic action of MPTP on dopamine and noradrenaline neurons was investigated. Pargyline and deprenyl almost completely reversed the MPTP-induced reduction of these parameters in both regions while chlorgyline was without effect. Pretreatment with the dopamine uptake inhibitor amfolenic acid preferentially counteracted the depleting effect of MPTP on striatal dopamine levels. The noradrenaline uptake inhibitors desipramine, nortriptyline and LY 139603 all antagonized the MPTP-induced reduction of noradrenaline levels in cerebral cortex, while none of these inhibitors affected the action of MPTP on striatal dopamine. The results suggest that MAO-B and the catecholamine uptake system may be critically involved at certain steps in the neurotoxic action of MPTP on catecholamine neurons. The interaction with the uptake mechanism most likely explains the selective neurotoxic action of MPTP on catecholamine neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs.

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.

Animals↗
PubMed1984

Fasciola hepatica: the effects of neuropharmacological agents upon in vitro motility.

The effects of a wide range of neuropharmacological agents on the motility in vitro of Fasciola hepatica have been determined using an isometric transducer system. The neuromuscular blocking agents tubocurarine and decamethonium cause a long-term stimulation of the basal activity of the fluke. Acetylcholine causes an inhibition of activity. This effect is mimicked by the cholinergic agonists carbachol and nicotine, antagonised by the cholinergic blocking agents atropine and mecamylamine, and potentiated by eserine, a cholinesterase inhibitor. With nicotine and atropine the effects are accompanied by an increase in muscle tone at a concentration of 1 X 10(-2) M. Noradrenaline and adrenaline also cause some inhibition of activity, an effect antagonised by guanethidine, which blocks the release of noradrenaline. In contrast, dopamine stimulates fluke motility, whilst its antagonist dihydroergotamine causes an inhibition of activity. The monoamine oxidase inhibitors iproniazid and p-chloromercuribenzoic acid induce a stimulation of activity; with the latter there is an increase in muscle tone at a concentration of 1 X 10(-3) M. The amine depleting agents chloroamphetamine and reserpine, and the monoamine uptake inhibitors desipramine and nortriptyline produce an inhibition of fluke activity, as does the serotonin uptake inhibitor fluoxetine. High concentrations of chloroamphetamine (1 X 10(-2) M) and the uptake inhibitors (1 X 10(-3) M and above) also induce an increase in muscle tone. Serotonin causes a marked stimulation of motility. The pharmacological evidence is consistent with a neurotransmitter role of acetylcholine (inhibitory), dopamine (excitatory), and noradrenaline (inhibitory). The status of serotonin is discussed.

Animals↗
PubMed1983

Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs.

Testing for competitive inhibition of sparteine oxidation in the 9000 x g supernatant fraction from human liver provides an in vitro means to identify drugs which can bind to the same form of cytochrome P450 which oxidizes sparteine. There has so far been only two outcomes of this test: either the drug examined competed with sparteine for a common binding site, or it did not inhibit the reaction. The results of such in vitro testing implicated the involvement of guanoxan, nortriptyline, desipramine, imipramine, amitriptyline and chlorpromazine with this enzyme. Amobarbital, tolbutamide and guanethidine in therapeutic concentrations did not interfere with sparteine oxidation by this preparation.

Antidepressive Agents, Tricyclic↗
PubMed1987

Discriminative stimulus properties of oxazepam in the pigeon.

Five pigeons were trained to discriminate IM injections of oxazepam (4.0 mg/kg) from vehicle with responding maintained under a fixed-ratio 30 schedule of food delivery. Under test conditions, responding increased in a dose-dependent manner in all pigeons after the administration of other benzodiazepines including diazepam (0.01-1.0 mg/kg), temazepam (0.01-3.0 mg/kg), halazepam (0.1-56.0 mg/kg), and midazolam (0.1-1.0 mg/kg) as well as the barbiturate pentobarbital (2.0-8.0 mg/kg) and the non-benzodiazepine anxiolytic CL 218,872 (1.0-8.0 mg/kg). At the higher doses of each of these compounds, over 80% of responding occurred on the oxazepam-appropriate key. Cocaine (0.5-4.0 mg/kg), bupropion (3.0-56.0 mg/kg) and nortriptyline (3.0-56.0 mg/kg) failed to substitute for oxazepam even at doses that decreased rates of responding. The discriminative stimulus (DS) effects of the lowest doses of oxazepam and CL 218,872 that produced 100% drug-appropriate responding were blocked by the benzodiazepine antagonist Ro 15-1788. This antagonism was reversed by increasing the dose of the agonists. The DS effects of diazepam were antagonized partially by Ro 15-1788 (3 of 5 pigeons), and the antagonism was reversed by higher doses of diazepam in two of these pigeons. The DS effects of pentobarbital were antagonized by Ro 15-1788 in 2 of 5 pigeons, but the blockade was not reversed by higher pentobarbital doses.

Animals↗
PubMed1992

Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: possible Ca(2+)-channel inhibition.

Fluoxetine, a selective 5-HT uptake inhibitor, inhibited 15 mM K(+)-induced [3H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations greater than 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K+ used to depolarize the synaptosomes and the concentration of external Ca2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [3H]5-HT release induced by the Ca(2+)-ionophore A 23187 or Ca(2+)-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K(+)-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca2+ channels and Ca2+ entry. Whereas fluoxetine and paroxetine inhibited binding of [3H]nitrendipine to the dihydropyridine-sensitive L-type Ca2+ channel, the less selective uptake inhibitors did not alter binding. The dihydropyridine antagonist nimodipine partially blocked fluoxetine-induced inhibition of release. Moreover enhanced K(+)-stimulated release due to the dihydropyridine agonist Bay K 8644 was reversed by fluoxetine. Fluoxetine also inhibited the K(+)-induced increase in intracellular free Ca2+ in fura-2 loaded synaptosomes. These data are consistent with the suggestion that fluoxetine inhibits K(+)-induced [3H]5-HT release by antagonizing voltage-dependent Ca2+ entry into nerve terminals.

Animals↗
PubMed1995

Influence of antidepressant drugs administration on the morphine inhibitory effect in mice vasa deferentia.

The effect of chronic and acute antidepressant drug administration on peripheral opioid mechanisms was investigated. For this purpose, the inhibitory effect of morphine on electrically-induced contractions of mouse vas deferens was measured. Acute antidepressant administration did not induce any change in morphine inhibition. Chronic fluvoxamine and chlorimipramine treatment induced strong and significant hypersensitivity to morphine-inhibition. Chronic desipramine, desmethylclomipramine and nortriptyline treatment induced the opposite effect. These results seem to show differential opioidergic regulation depending on the monoaminergic antidepressant used. The level of this interaction remains to be elucidated.

Animals↗
PubMed1982

Antidepressant drugs normalize the increased social behaviour of pairs of male rats induced by short term isolation.

In a situation in which a short-term isolated (I) and a group-housed (S) rat were placed together, the influence of various drugs on social behaviour was analysed. It was found that a single intraperitoneal injection of 7.5 mg/kg of the antidepressant drugs clomipramine, nortriptyline and mianserine normalized the increased social interactions of the isolated rat to the level of the group-housed rat, without affecting the social behaviour of that animal. This action of the drugs was not due to changes in locomotor activity. An opiate (morphine), an opiate antagonist (naloxone), a tranquilizer (diazepam), a neuroleptic (haloperidol) and a psychostimulant (amphetamine) did not preferentially influence the social behaviour of the isolated rat. Chronic treatment with the antidepressants did not reduce the increased social interactions of isolated animals. In spite of this it is clear that the increased social behaviour of short-term isolated rats was specifically affected by the antidepressant drugs. This suggests that this behavioural procedure might be useful for predicting antidepressant activity.

Animals↗
PubMed1985

Serotonin and antidepressant drugs antagonize melatonin-induced behavioural changes after injection into the nucleus accumbens of rats.

Small doses of melatonin (0.1-100 ng), injected into the nucleus accumbens of rats, decreased locomotor activity and rearing, and increased grooming and sniffing behaviour when the animals were tested in small test-cages. Larger doses of melatonin appeared to be less effective. The action of melatonin is apparently not mediated by dopaminergic systems, because the behavioural changes were not antagonized by local pretreatment with haloperidol or sulpiride. Injection of serotonin antagonists (methysergide and cyproheptadine) into the nucleus accumbens resulted in similar behavioural changes as was found after treatment with melatonin. Treatment with serotonin and various antidepressant drugs (zimelidine, mianserin, nortriptyline, clomipramine, desipramine) injected into the nucleus accumbens, completely inhibited the melatonin-induced behavioural responses. The antidepressants did not significantly interfere with the decrease of locomotor activity and rearing induced by injection of small doses of the dopamine agonist, apomorphine, into the nucleus accumbens. These results suggest that there is an interrelationship between melatonin and serotonin systems in the nucleus accumbens and showed that various antidepressant drugs, similar to serotonin, antagonized the behavioural effects of melatonin after injection into the nucleus accumbens.

Animals↗
PubMed1995

Simultaneous HPLC analysis of tricyclic antidepressants and metabolites in plasma samples.

A sensitive, selective and rapid reverse-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of imipramine, desipramine, amitriptyline and nortriptyline in human plasma. The procedure consisted of extracting the drugs and the internal standard (clomipramine) from 1 ml plasma with hexane:isoamyl alcohol (99:1, v/v) in alkaline medium. A newly marketed column, LiChrospher 60 RP-select B (dp 5 microns) of Merck was employed. The mobile phase, consisting of acetonitrile/0.25 N sodium acetate buffer at pH 5.5 (50:50, v/v), was delivered at a flow rate of 1.0 ml/min, and detection at 254 nm. The precision, linearity and limit of quantification of the method were within acceptable limits. The method was considered adequate and has, therefore, been used in routine analysis for the therapeutic control of depressed patients.

Adult↗
PubMed1984

Effects of norepinephrine and serotonin uptake inhibitors on the schedule-controlled behavior of the pigeon.

The effects of nortriptyline, amitriptyline, desipramine, chlorimipramine, protriptyline, doxepin, nisoxetine, fluoxetine and iprindole were determined on responding by pigeons under a multiple fixed-ratio 30-response, fixed-interval 10-minute schedule of grain presentation. Those drugs which have been shown to block uptake of norepinephrine decreased fixed-interval quarter-life values. Those which are considered most selective as norepinephrine uptake inhibitors also increased overall fixed-interval responding. These increases in fixed-interval responding, both on local and overall rates, in pigeons appear to be due to the actions of these drugs to inhibit uptake of norepinephrine rather than to other actions.

Amitriptyline↗
PubMed1985

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats.

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amitriptyline, (-) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.

Animals↗
PubMed1982

Lithium + L-tryptophan compared with amitriptyline in endogenous depression.

Endogenously depressed in-patients were treated for four weeks with either lithium + L-tryptophan (N = 22) or amitriptyline (N = 21) in an open study. Before and weekly during treatment the patients were evaluated by means of Hamilton rating scale, and blood samples were collected for determination of serum concentration of lithium, or amitriptyline and nortriptyline. Both groups responded significantly and the two treatments were not significantly different in antidepressive efficacy. No significant correlation could be demonstrated between clinical improvement and steady-state serum drug levels. From this study it appears that lithium combined with L-tryptophan may be effective in the treatment of endogenous depression.

Adult↗
PubMed1993

Hypnotics as concurrent medication in depression. A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant.

The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam.

Adult↗
PubMed1996

Predictive value of tryptophan/large neutral amino acids ratio to antidepressant response.

The molar ratio of total plasma tryptophan to the sum of other large neutral amino acids (viz., valine, isoleucine, leucine, tyrosine, phenylalanine), thought to reflect brain serotonin formation, was estimated in 69 patients with major depression before and after 1 week of treatment with different serotonin reuptake inhibitors, fluvoxamine (n = 28), fluoxetine (n = 10), citalopram (n = 7), mixed serotonin-noradrenaline reuptake inhibitor amitriptyline (n = 11), clomipramine (n = 8) and the preferentially noradrenaline reuptake inhibitor, nortriptyline (n = 5). A significant difference among 'good', 'intermediate' and 'poor' responders for the percentual variation of tryptophan/large neutral amino acids ratio after 1 week of therapy was found, while pretreatment values of tryptophan/large neutral amino acids ratio, basal Hamilton Depression Rating Scale scores and its percentual variation after 1 week of therapy did not show any significant differences. These results suggest that the percentual variation of tryptophan/large neutral amino acids ratio could be a useful tool in predicting drug response.

Adult↗
PubMed1981

Depression, antidepressants, and plasma DBH.

Plasma levels of dopamine-beta-hydroxylase (DBH) were determined in 16 unmedicated patients with major depressive episodes (nonpsychotic) and in an equal number of normal subjects, before and after 4 weeks of treatment with tricyclic antidepressants. Some eight patients were treated with amitriptyline, and the remainder received desipramine. The controls remained medication free during the entire experimental period. Degrees of depression were quantified before and after treatment with the Hamilton Rating Scale of Depression (HRSD). There were no significant differences between the depressed patients and the controls on levels of DBH. Similarly, there were no within-group, pre-posttreatment differences on the enzyme levels in either group. Pre- and posttreatment HRSD scores did not correlate with corresponding plasma DBH levels. Plasma levels of amitriptyline, nortriptyline (product of amitriptyline in the body), and desipramine at the end of 4 weeks of treatment also failed to correlate with the enzyme levels.

Adult↗