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PubMed1977

Changes in drug-induced stereotyped behavior after 6-OHDA lesions in noradrenaline neurons.

Drug-induced stereotyped behaviors are often assessed by rating scales where the eventual appearance of sniffing, licking, and biting are rated as increasing intensity of dopaminergic stimulation. A 6-OHDA induced bilateral lesion (4 X 3-8 mug/4 mul 6-OHDA) in the ascending noradrenaline neurons, lateral to the medial raphe nucleus, of 180 g Wistar rats, affecting selectively noradrenaline and not dopamine or 5-hydroxytryptamine neurons, caused a change in the d-amphetamine sulphate (5-3 mg/kg s.c.) and phenethylamine hydrochloride (40 mg/kg) induced stereotyped sniffing behavior to the performance of discontinuous or continuous licking behavior; biting/gnawing was rarely induced. The site of the lesion and the partial antagonism of 6-OHDA by the uptake inhibitor protriptyline indicate a noradrenergic influence on the behavioral expression of the dopaminergically mediated stereotyped behavior.

Animals↗
PubMed1976

Evidence for involvement of central noradrenergic neurons in the cardiovascular depression induced by morphine in the rat.

Morphine caused in the anaesthetized rat reduction in brain noradrenaline (NA) turnover, hypotension and bradycardia, similarly to the antihypertensive, alpha-adrenergic agonist, clonidine. All effects of morphine were antagonized by naloxone, as well as the alpha-receptor antagonist, yohimbine. In contrast, naloxone did not affect the circulatory depression and reduction in brain NA utilization by clonidine which both previously have been found to be antagonized by yohimbine. In contrast to clonidine, morphine even in high doses did not facilitate the flexor reflex activity of acutely spinalized rats. Pretreatment with protriptylin largely attenuated the circulatory depressive effects of morphine, as it has previously been found to block the corresponding effects of clonidine. Thus, the morphine-induced cardiovascular depressive effects are primarily elicited by activation of opiate receptors. However, the inhibition of brain NA neurotransmission by morphine appears critically involved in the mediation of the circulatory depression.

Adrenergic Fibers↗
PubMed1999

Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo.

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.

5-Hydroxytryptophan↗
PubMed1976

Behavioral effects of 5, 7-dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways.

In protriptyline (25 mg/kg) pretreated rats stereotactic 5,7-dihydroxytryptamine (5,7-DHT) lesions of the medial plus laternal 5-hydroxytryptamine (5-HE) bundles in the mesencephalon increased the 5-HT fluorescence in these bundles, and reduced the in vitro uptake of [3H] 5-HT in the hypothalamus to 16% of control values after 2 mug 5,7-DHT/4mul and 12% after 4 mug 5,7-DHT/4mul, and in the cortex cerebri to 35 and 34% of control values, respectively. Selective lesion of the medial 5-HT bundle reduced [3H] 5-HT uptake both in hypothalamus and in cortex cerebri to 45-48% of control values, while selective lesion of the lateral 5-HT bundles significantly reduced [3H] 5-HT uptake only in cortex (to 73-75%). No significant change was observed in [3H] noradreanaline uptake after any injection, or in [3H] 5-HT uptake after vehicle injections. Locomotor activity in an open field 3-10 days postoperatively was significantly reduced by lesions of the medial plus lateral 5-HT bundles. 5-Hdroxytryptophan (50 mg/kg) and a peripheral decarboxylase inhibitor (MK 486, 75 mg/kg) 17 days postoperatively induced a pronounced behavioral "5-HT syndrome" in these rats with medial plus lateral lesions but not in controls. Pain sensitivity, as measured by the hot plate test, was not changed by any lesion, even when tryptophan hydroxylase was partly inhibited with alpha-propyldopacetamide (100 mg/kg). Morphine analgesia and acquisition of a one-way avoidance response also were unchanged. Apomorphine (2 mg/kg)-induced locomotor activity and stereotyped behavior, as measured in an Animex activity meter, were not significantly different from control values in the 5,7-DHT groups. It was concluded that the medial 5-JT BUNDLE INNERVATES BOTH THE HYPOTHALAMUS AND THE CORTEX CEREBRI AND THE LATERAL 5-HT bundle mainly the cortex. These ascending 5-HT neurons are involved in maintaining open field ambulation. No wupport was obtained for the view that they are involved in pain mechanisms, in morphine-induced analgesia, in apomorphine-induced motor behavior, or in one-way avoidance learning.

Afferent Pathways↗
PubMed1985

Comparison of respiratory-related trigeminal, hypoglossal and phrenic activities.

In decerebrate, paralyzed and vagotomized cats, we recorded activities of hypoglossal and phrenic nerves and of the mylohyoid branch of the trigeminal nerve. At normocapnia, a respiratory-modulated trigeminal discharge could be discerned in most cats. This discharge was characterized by a diminution of activity during neural inspiration and a peak in expiration. In hypercapnia or hypoxia, peak activity increased and its time of occurrence moved to late inspiration. Augmentations of peak trigeminal, hypoglossal and phrenic activities were proportional. Peak trigeminal and hypoglossal activities increased more than phrenic following administrations of protriptyline, strychnine and, in some cats, cyanide or doxapram. Peak trigeminal activity fell more than phrenic after diazepam. Pentobarbital or halothane reduced peak hypoglossal, but not trigeminal, activity more than phrenic. However, after these anesthetics, trigeminal activity became restricted to the inspiratory-expiratory junction. We conclude that trigeminal and hypoglossal activities are more dependent upon processes within the reticular formation than is the bulbospinal-phrenic system. Central and peripheral chemoreceptor influences are distributed equivalently upon trigeminal, hypoglossal and phrenic motoneurons.

Animals↗
PubMed1979

A reward-reduction model of depression using self stimulating rats: an appraisal.

A potential model of depression using a "reward reduction" technique with intracranial self-stimulation (ICSS) has been suggested. A number of rats with electrodes chronically implanted in the medial forebrain bundle were trained on this paradigm. The model involved the use of progressively increasing fixed ratio (IFR) schedules. Two tricyclic antidepressants, imipramine and protriptyline, were administered. Neither of these drugs resulted in the response enhancement which had been predicted. Only d-amphetamine (0.5 mg/kg) produced the predicted "antidepressant" action. It was concluded that response instability made this test difficult to operate and that even animals with adequately stable baselines did not produce a response pattern which could be categorised as specifically antidepressant.

Amphetamine↗
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↗
PubMed1991

Genotoxicity evaluation of five tricyclic antidepressants in the wing somatic mutation and recombination test in Drosophila melanogaster.

Five tricyclic antidepressants were tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Three-day-old larvae trans-heterozygous for 2 linked recessive wing hair mutants (multiple wing hairs and flare) were fed the test compounds in water mixed with a standard dry food for 48 h. Wings of the emerging adult flies were scored for the presence of spots of mutant cells which can be the consequence of either somatic mutation or mitotic recombination. Desipramine and imipramine were clearly genotoxic at concentrations above 1 mM whereas amitriptyline, nortriptyline and protriptyline were not genotoxic at concentrations up to 100 mM. This seems to implicate the nitrogen atom at position 5 in the 7-membered ring of the tricyclic molecule as being responsible for the genotoxic property of the compounds in Drosophila.

Amitriptyline↗
PubMed1987

Analgesic properties of intrathecally administered heterocyclic antidepressants.

Antinociceptive activities of heterocyclic antidepressants (HCAs) were studied after intrathecal (i.t.) administration in mice. HCAs with selective norepinephrine reuptake blocking properties (noradrenergic HCAs), such as desipramine and protriptyline, produced different antinociceptive profiles from HCAs with selective serotonin reuptake blocking properties (serotonergic HCAs), such as fluoxetine and citalopram. Noradrenergic HCAs were antinociceptive in all of the three nociceptive tests employed in the present study, i.e., tail-flick (TF) test, i.t. substance P-induced behavioral (SPB) test and intradermal hypertonic saline-induced behavioral (HSB) test. Intrathecal noradrenergic HCAs potentiated systemic or i.t. morphine-induced antinociception in the TF test. Serotonergic HCAs were partially antinociceptive in the SPB and HSB test, but inactive in the TF test. Furthermore, serotonergic HCAs did not enhance the antinociception produced by systemic or intrathecal morphine. The present data suggest that the efficacy of HCAs in the control of chronic pain stems, at least partially, from their action in the spinal cord, their analgesic activities probably involve blockade of monoamine reuptake. and the spinal serotonergic system probably possesses a dual action in regard to spinal nociception, while the noradrenergic system does not.

Analgesics↗
PubMed1985

Medical therapy of obstructive sleep apnea.

Guidelines for the medical therapy of obstructive sleep apnea are difficult to define precisely. While some elegant investigations have been completed, most study populations have been small. Also, the long-term effects of most forms of therapy are not known. Some patients will respond to a given form of therapy or combination of therapies while others will not. In most instances the responders cannot be recognized prior to the institution of therapy and a cycle of trial and error ensues. One of the best nonsurgical approaches appears to be weight loss, albeit unsuccessful in most cases. Almost all experts would agree, however, that in nonemergent situations weight loss should be strongly suggested. Nasal CPAP appears to be the single most promising device. Protriptyline may have a role, although in our opinion its true efficacy remains to be determined. Oxygen will probably serve more an adjunctive role in therapy, and medroxyprogesterone appears to be beneficial only in the treatment of the obesity-hypoventilation syndrome. A reasonable approach to the medical treatment of the obstructive sleep apnea patient should include, first, by history, physical examination, and appropriate laboratory testing, elimination of anatomically correctable, pharmacologic, or endocrinologic causes of OSA. If apnea length, degree of desaturation, cardiac arrhythmias, or levels of hypersomnolence are so severe as to be potentially life threatening, immediate tracheostomy is suggested. In specialized centers, nasal CPAP would be used. In less severely affected patients, medical management, as discussed above, should begin. We believe that in view of the lack of controlled trials demonstrating which form of therapy is best, the clinician must recommend therapy on the basis of local clinical experience and patient acceptance. Of fundamental importance is the need for serial reevaluation so that the impact of therapeutic failure can be minimized.

Almitrine↗
PubMed1991

Relative efficacy of drugs for the treatment of sleepiness in narcolepsy.

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Adult↗
PubMed1983

Liquid chromatographic separation of antidepressant drugs: I. Tricyclics.

A simple normal-phase (silica), high-performance liquid chromatographic (HPLC) assay of amitriptyline (AMI), doxepin (DOX), imipramine (IMI), nortriptyline (NORT), desmethyldoxepin (DESDOX), desipramine (DESIP), and protriptyline (PRO) in serum with no coelution is described here. Trimipramine and promazine were used as internal standards. Extraction of the 1.0-ml serum samples (collected in plastic) was done with Bond-Elut C18 columns. The compounds of interest were eluted with 10 mM methanolic ammonium acetate. The eluates were evaporated at 56-58 degrees C and reconstituted with 200 microliters of the mobile phase. The mobile phase was absolute ethanol-acetonitrile-tert-butylamine (98:2:0.05, vol/vol/vol). Detection of eluted drugs was at 254 nm at 0.01 absorbance units full scale (AUFS), except for PRO, which was detected at 229 nm at 0.02 AUFS. Absolute recoveries were 87-97%. A 5-micron silica (4.6 X 250 mm) HPLC column was used; results with a 10-micron silica column (3.9 X 300 mm) are also presented. Peak height ratios with trimipramine were linear for each analyte between 25 and 1200 ng/ml. Peak height ratios with promazine as the internal standard were linear for each analyte between 25 and 600 ng/ml. Detection limits under the conditions described were 2 ng/ml for AMI, DOX, and IMI, 4 ng/ml for NORT, DESDOX, and DESIP, and 10 ng/ml for PRO. Coefficients of within-day and day-to-day variation at three concentration levels were less than 9.8% and less than 11.2%, respectively. The hydroxylated metabolites of IMI, DES, NORT, and the cis isomer of DOX are discussed. Steady-state daily dosages and corresponding serum levels are presented for 69 patients. The total assay time was less than 10 min for DESIP and 12 min for PRO. This assay can be used in correlating serum levels with clinical effects, compliancy, and pharmacokinetic studies.

Amitriptyline↗
PubMed1974

Interaction of cannabis and general anaesthetic agents in mice.

1 A cannabis extract (I) (in a concentration equivalent to 10 mg Delta(9)-tetrahydro-cannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.2 The cannabis extract (I) (equivalent to 10 mg Delta(9)-THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.3 A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Delta(9)-THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.4 Delta(8)-THC, Delta(9)-THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Delta(9)-THC. Cannabinol (10 mg/kg) was inactive.5 The effects of cannabidiol and Delta(9)-THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Delta(9)-THC and cannabidiol when given in combination.6 Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, alpha-methyl tyrosine or parachlorophenylalanine did not affect the extract I-induced prolongation of pentobarbitone anaesthesia.7 It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis-induced prolongation of anaesthesia is probably unrelated to any effect on central 5-hydroxytryptamine or catecholamine neurones.

Anesthesia, General↗
PubMed1980

Prostaglandins and the cardiotoxic effects of doxepin in rabbits and guinea-pigs.

Intravenous administration of tricyclic antidepressants to rabbits leads to dysrhythmias largely attributable to their non-specific membrane effects. Further experiments with doxepin (Dx) were conducted to assess an eventual contribution by prostaglandins (PG) to these events. Dx infused intravenously to conscious or anaesthetized guinea-pigs proved as cardiotoxic as amitriptyline but more toxic than protriptyline, thus confirming our previous results in rabbits. PG F2 alpha given intravenously before or during the Dx infusion failed to antagonize cardiotoxicity. In conscious rabbits, pretreatment with drugs (aminophenazon, indomethacin, tolfenamic acid) known to inhibit PG synthesis failed to modify the Dx cardiotoxicity as also did PG F2 alpha which elevated blood pressure, however. PG F2 alpha also failed to counteract the ouabain cardiotoxicity in anaesthetized guinea-pigs and major Ba++-induced dysrhythmias in conscious rabbits. Our results suggest that a) at least Dx induced dysrhythmias are unresponsive to PGs, and that b) previous speculations about PGs as antiarrhythmic agents may be exaggerated.

Amitriptyline↗
PubMed1997

Nocturnal respiratory failure as an indication of noninvasive ventilation in the patient with neuromuscular disease.

Patients with neuromuscular disease may suffer from nocturnal respiratory failure despite normal daytime respiratory function. The physiological reduction in muscle tone during sleep may be life-threatening in a patient with impaired muscle strength. Nocturnal respiratory failure may occur in patients with the postpolio syndrome, amyotrophic lateral sclerosis, myasthenia gravis, myotonic dystrophy, and muscular dystrophy. Diagnosis of obstructive, central and mixed apneas, hypopneas, and hypoventilation is best made using polysomnography. Therapeutic options include noninvasive ventilation such as continuous positive airway pressure, bilevel positive airway pressure, intermittent positive pressure ventilation and, rarely, tracheostomy, oxygen, or protriptyline. Evaluation by a sleep specialist should be initiated in any neuromuscular patient with nocturnal symptoms such as air hunger, intermittent snoring or breathing, orthopnea, cyanosis, restlessness, and insomnia. Daytime symptoms may include morning drowsiness, headaches and excessive daytime sleepiness. Polycythemia, hypertension, and signs of heart failure may also be seen. Effective treatment is available, and may improve the quality of life, and possibly increase survival.

Adrenergic Uptake Inhibitors↗
PubMed1975

Hostility, somatic symptoms and recovery with antidepressants.

Patients were treated with protriptyline or nortriptyline (double-blind). They were assessed on the Zung Depression Scale and on the Hostility and Direction of Hostility Questionnaire (HDHQ). A good response was heralded by low ratings on criticism of self and others,and on projected (paranoid) hostility. The outcome was better with initial low scores on depressive symptoms, particularly unworthiness, restlessness and constipation. As to reported side effects, initial loss of interest augured badly for drowsiness, lack of clear mind for blurred vision, loss of libido for constipation and ideas of suicide for dry mouth.

Depression↗
PubMed1980

The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels.

The authors present a clinical approach for predicting and using plasma concentrations of tricyclic antidepressants in the treatment of depressed patients. They review the pharmacokinetics of this group of drugs and their side effects and toxicity. There is a suggested therapeutic range for plasma concentrations of imipramine, amitriptyline, and nortriptyline; more definitive studies are needed to determine the necessary plasma levels for achieving clinical response with the other tricyclic antidepressants (desmethylimipramine, protriptyline, doxepin, clomipramine, impiramine N-oxide, and butriptyline). A more thorough knowledge of the clinical pharmacokinetics of tricyclic antidepressants should lead to more rational use of these drugs, with a higher response rate and fewer adverse reactions.

Amitriptyline↗
PubMed1994

Symptomatic cataplexy in pontomedullary lesions.

Cataplexy is a cardinal manifestation of the narcolepsy syndrome. Although symptomatic narcolepsy is well described, isolated cataplexy is extremely rare. We reviewed clinical and radiologic data in two patients with isolated symptomatic cataplexy and associated CNS disease. In an HLA-DR2-positive patient with chronic progressive MS, we confirmed cataplexy by observation of reported spells. MRI revealed diffuse white-matter lesions involving the medial medulla, pons, and subcortical white matter; protriptyline provided symptomatic relief. A second patient with a pontomedullary pilocytic astrocytoma developed infrequent but recurrent cataplectic attacks in association with sleep fragmentation due to nocturnal cough and nausea. MRI revealed an enhancing lesion involving the dorsal pons and medulla. Genetic predisposition and sleep fragmentation may precipitate symptomatic cataplexy in patients with structural pontomedullary lesions.

Adult↗