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PubMed1996

Carbamazepine as a treatment for cataplexy.

Cataplexy is a common symptom associated with narcolepsy. We evaluated a 51-year-old female who developed symptoms of progressive daytime sleepiness with cataplexy. The diagnosis of narcolepsy was confirmed by overnight polysomnogram and was consistent with results of a multiple sleep latency study, and episodes of cataplexy were documented by video-EEG-EMG monitoring. Examination during a catapletic episode was significant for areflexia and paralysis. The frequency of cataplexy increased with fluoxetine, protriptyline and sertraline and the patient developed frank choreiform movements with protriptyline and sertraline. The cataplexy resolved following treatment with carbamazepine. We feel carbamazepine is a potential treatment for patients with refractory cataplexy.

Anticonvulsants↗
PubMed1990

Narcolepsy.

Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence.

Adult↗
PubMed1979

Tricyclic antidepressants in serum by a Clin-ElutTM column extraction and high pressure liquid chromatographic analysis.

We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.

Antidepressive Agents, Tricyclic↗
PubMed1969

Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine-resistant uptake mechanism of central and peripheral monoamine neurones in vivo and in vitro.

1. Bicyclic compounds with potential thymoleptic properties (Lu-compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.2. Biochemical and histochemical in vivo studies have been performed. The possible blocking action of Lu-compounds on the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) displacement caused by 4,alpha-dimethyl-metatyramine (H 77/77) and 4-methyl-alpha-ethyl-meta-tyramine (H 75/12), respectively, has been studied, and a positive result has been taken as evidence for membrane pump blocking activity. No certain effects were obtained on the 5-HT displacement induced by H 75/12, whereas a partial blockade of the NA displacement by H 77/77 in central NA neurones was obtained after most of the Lu-compounds (Lu-3-010, 3-049, 3-092, 4-012) and especially after the thiophthalane derivative Lu 5-003. The ED50 of the latter drug was around 8 mg/kg, that is, somewhere between protriptyline (ED50 4 mg/kg) and desipramine (ED50 15 mg/kg) in potency.3. Histochemical in vivo studies on the rat iris revealed that Lu 5-003 and especially the corresponding phthalane derivative Lu 3-010 were potent in blocking the uptake of alpha-methyl-NA in the adrenergic nerve terminals of the iris. The other Lu-compounds were less active. The releasing effects of the Lu-compounds on the extragranular accumulation of alpha-methyl-NA in the adrenergic terminals were weak compared with membrane blocking activity.4. In vitro studies on the central and peripheral catecholamine (CA) neurones have also been performed. In the same way as, for example, protriptyline the Lu-compounds only blocked accumulation of alpha-methyl-NA in the NA terminals but not in the dopamine (DA) nerve terminals. Lu 5-003 and Lu 3-010 were the most potent of the Lu-drugs when added in vitro. The Lu-drugs were also injected in vivo after which the effect on the alpha-methyl-NA accumulation was studied in vitro. In isotope experiments with labelled alpha-methyl-NA it was found that desipramine, Lu-3-010, Lu 3-092 and Lu 4-012 were equally potent in blocking uptake in the central nervous system.

Amines↗
PubMed1970

Interactions of inhibitors of noradrenaline uptake and angiotensin on the sympathetic nerves of the isolated rabbit heart.

1. The interaction of angiotensin and several inhibitors of the uptake of noradrenaline across the neuronal membrane (cocaine, desipramine, protriptyline. and pronethalol) on the output of noradrenaline produced by sympathetic nerve stimulation has been studied in the isolated perfused rabbit heart.2. Most of these drugs increased noradrenaline outflow-angiotensin, for example, by 175%. Cocaine (10(-4)M) did not change the amine overflow, probably because this very high concentration inhibited not only the re-uptake but also the liberation of noradrenaline.3. Desipramine, protriptyline, and pronethalol, although infused in concentrations which enhanced the noradrenaline output, were not able to impair the angiotensin-induced increase of transmitter overflow. In the presence of cocaine (10(-4)M) the increase elicited by angiotensin was slightly reduced, though lower concentrations of cocaine, as previously described, do not interfere with the effect of angiotensin.4. In contrast to the interaction between uptake inhibitors and angiotensin, the augmented output of noradrenaline caused by an uptake inhibitor could not be increased further by infusion of a second uptake inhibitor.5. It is concluded that the increase of the outflow of noradrenaline during sympathetic nerve stimulation by small doses of angiotensin is not caused by an inhibition of re-uptake. On the contrary, the transmitter liberation seems to be facilitated. This is a novel principle of drug action on the sympathetic nerve terminals.

Angiotensin II↗
PubMed1977

Effects of antidepressant drugs on noradrenaline accumulation and contractile responses in the rat anococcygeus muscle.

1 The effect of a series of antidepressant drugs on noradrenaline accumulation was studied in the isolated anococcygeus muscle of the rat. 2 The most potent inhibitors of noradrenaline accumulation were nortriptyline, desipramine and protriptyline. Opipramol, trimipramine and iprindole were active only in high concentrations. 3 Contractions of the anococcygeus muscle produced by noradrenaline were strongly potentiated by nortriptyline, desipramine and protriptyline. Other uptake inhibitors were less active in potentiating the noradrenaline response. 4 Nortriptyline, in concentrations that potentiated the action of noradrenaline, reduced or abolished the response to tyramine.

Acetylcholine↗
PubMed1981

The postsynaptic effects of antidepressant drugs in the rat anococcygeus muscle.

The effects of antidepressants of tricyclic (amitriptyline, nortriptyline, protriptyline, doxepin, imipramine, and desipramine) and atypical (maprotiline, nomifensine, tandamine, viloxazine, CGP 6085A, and YM-08054-1) structures on contractile responses to exogenously applied acetylcholine and (-) noradrenaline were studied in rat isolated anococcygeus muscle previously incubated with 6-hydroxydopamine. Atropine, amitriptyline, protriptyline, doxepin, imipramine, maprotiline and nortriptyline inhibited contractile responses to acetylcholine whereas desipramine, nomifensine, tandamine, viloxazine, CGP 6085A and YM 08054-1 did not. The contractile responses to (-)-noradrenaline were inhibited by low concentrations of tricyclic antidepressants and by higher concentrations of the atypical agents. These results illustrate that, in the preparation, the order of potency of antidepressants as muscarinic and as postsynaptic alpha-adrenoceptor antagonists is similar. The ability of tricyclic, but not atypical agents, to increase the concentration of noradrenaline bound to postsynaptic alpha-adrenoceptors may be severely limited by the antagonistic effect these agents have at this receptor.

Acetylcholine↗
PubMed1970

Guanethidine and related agents. 3. Antagonism by drugs which inhibit the norepinephrine pump in man.

Antagonism of the antihypertensive action of guanethidine by the tricyclic antidepressants, desipramine and protriptyline, has been demonstrated in controlled studies. These antidepressants also prevent the effect of the related ring-substituted guanidinium adrenergic neuron blockers, bethanidine and debrisoquin. That the rise in blood pressure when desipramine is added to guanethidine therapy is not due simply to a pressor action of the two drugs in combination was demonstrated by the lack of an increase in blood pressure when guanethidine was added to desipramine therapy. Investigations were conducted to determine whether antagonism of guanethidine's clinical effect could result from blockade by the tricyclic antidepressants of the norepinephrine pump in the adrenergic neuron membrane, thereby preventing the uptake of guanethidine into the neuron by this pump. Like guanethidine, the indirectly acting pressor amine, tyramine, enters the neuron via the norepinephrine pump. Desipramine, protriptyline, and amitriptyline in clinical doses all were found to block the pressor action of tyramine while potentiating the pressor effect of norepinephrine. The amino acid, methyldopa, does not enter the neuron via the norepinephrine pump, and its antihypertensive action is not altered by concomitant administration of tricyclic antidepressants. It is concluded from the evidence in this investigation together with the results of previous studies in experimental animals that clinical doses of desipramine-like drugs inhibit the norepinephrine pump in the peripheral adrenergic neuron in man and thereby prevent uptake of guanethidine to its site of action.

Antidepressive Agents↗
PubMed1975

Interaction between centrally acting hypotensive drugs and tricyclic antidepressants.

From clinical experience it is known that the hypotensive action of clonidine and alpha-methyl-DOPA is antagonized by desipramine. This antagonism was investigated in detail in chloralose-anaesthetized cats. Both the centrally acting hypotensive agents and the tricyclic antidepressants where infused into the left vertebral artery. (1) The central hypotensive action clonidine was antagonized by desipramine, imipramine, amitriptyline, protriptyline and mianserine. For the inhibition of the hypotensive action of clonidine by protriptyline a parallel shift of the dose-response curve was obtained, indicating the possibility of a competitive antagonism. The central hypotensive action of alpha-methyl-DOPA was antagonized by desipramine and imipramine and that of amphetamine by imipramine. (2) The modest central hypotensive action of tricyclic antidepressants themselves and that of cocaine is explained by means of the inhibition of noradrenaline re-uptake in the CNS, brought about by these compounds. (3) It seems likely that the antagonism occurs at the level of central alpha-adrenoreceptors in the brain stem. (4) The antagonism probably reflects a general interaction between centrally acting hypotensive drugs and tricylclic antidepressants. The alpha-sympatholytic properties of the tricyclic antidepressants probably give rise to a blockade of the central alpha-adrenoreceptors, stimulated by clonidine, noradrenaline (via amphetamine) and alpha-methylnoradrenaline (from alpha-methyl-DOPA). The cocaine-like activity of antidepressants does not play a part.

Amphetamine↗
PubMed1975

Blockade of amine depletion by nisoxetine in comparison to other uptake inhibitors.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a new inhibitor of norepinephrine uptake. Nisoxetine antagonized 6-hydroxydopamine-induced depletion of norepinephrine in mouse heart with an ED50 of 0.9 mg/kg but had no effect on p-chloroamphetamine-induced depletion of serotonin in mouse brain at doses up to 32 mg/kg. Using the antagonism of these depleting agents to estimate inhibition of uptake into noradrenergic and serotoninergic neurons, we compared nisoxetine to several known amine uptake inhibitors. The order of effectiveness in antagonizing 6-hydroxydopamine action was protriptyline greater than desmethylimipramine greater than EXP 561 greater than nisoxetine greater than nortriptyline greater than chlorpheniramine greater than desmethylchlorimipramine greater than imipramine greater than doxepin greater than amitriptyline greater than chlorimipramine, with fluoxetine and its N-demethylated metabolite (103947) having no effect. In blocking p-chloroamphetamine, the order of effectiveness was EXP 561 greater than fluoxetine greater than 103947 greater than chlorpheniramine greater than chlorimipramine, with desmethylchlorimipramine, protriptyline, and nortriptyline having marginal effects and nisoxetine and the other drugs no effect at the highest dose tested, 32 mg/kg. Nisoxetine is thus one of the more potent and specific inhibitors of norepinephrine uptake, differing remarkably from fluoxetine to which it is related structurally.

Amines↗
PubMed1992

Effect of repeated administration of antidepressants on serotonin uptake sites in limbic and neocortical structures of rat brain determined by quantitative autoradiography.

The binding of 3H-cyanoimipramine, a selective radioligand for the serotonin (5-HT) transporter, was measured by quantitative autoradiography on sections of rat brain to determine if 5-HT uptake sites are regulated by repeated administration of antidepressants. The drugs studied included selective inhibitors of the uptake of 5-HT (citalopram, sertraline) or norepinephrine (protriptyline). Also, effects of inhibitors of monoamine oxidase (MAO) that inhibit both type A and type B MAO (phenelzine), or just type B MAO (deprenyl), were investigated. In addition, the atypical antidepressant mianserin, which has antagonist properties at both alpha 2 adrenoceptors and 5-HT2 receptors, was studied. A total of 19 limbic areas and 4 regions of the parietal cortex were quantitated. The binding of 3H-cyanoimipramine was increased (14% to 31%) by phenelzine and deprenyl in a total of 3 brain areas and decreased (15% to 21%) by sertraline in 4 brain areas. Citalopram, protriptyline, and mianserin produced no statistically significant effect in any brain region examined. The results indicate that different types of antidepressants do not exert consistent or substantial regulatory effect on the density of uptake sites for 5-HT in the limbic system or parietal cortex.

Animals↗
PubMed1991

Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments.

This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125I-iodopindolol (125I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus. Repeated treatment of rats with citalopram, sertraline, or trazodone or with drugs lacking clinical antidepressant efficacy caused no significant effects on the binding of 125I-IPIN to either subtype of beta adrenoceptor in any region of brain. These results demonstrate that amygdaloid beta-1 adrenoceptors are particularly susceptible to regulation by certain antidepressant treatments and implicate the amygdala as an important site of action for antidepressants with pharmacological activity on noradrenergic neurons.

Adrenergic beta-Antagonists↗
PubMed1995

Pharmacologic treatment of obstructive sleep apnea.

From this review it is obvious that no one pharmacologic agent is universally useful in the treatment of OSA. However, as mentioned in the introductory remarks above, the expectation of beneficial results in a heterogenous population of patients with OSA by specific-acting pharmacologic agents may be somewhat irrational. In addition to this problem, studies performed to date are often not controlled and are usually investigations in small numbers of subjects. However, from the data produced it is apparent that OSA precipitated by endocrinologic problems will improve with hormone replacement. Medroxyprogesterone has been shown to be especially useful in patients with an obesity-hypoventilation component to their disease. Protriptyline may also be useful, but its usefulness is impaired by significant adverse effects. Most likely, both medroxyprogesterone and protriptyline would be more tolerable in female OSA patients, but unfortunately, most of the OSA patient groups studied to date have been composed exclusively of male subjects. Therefore, we do not know if these agents would be more effective and better tolerated in female patients with OSA. The roles of ACE inhibitors and buspirone are not yet established. Serotonin-active agents may be useful in some patients with OSA, but the characteristics of responders are not defined for appropriate patient selection. Much work remains ahead to identify effective pharmacologic agents for OSA. Once identified, these agents must be tested in representative patient groups with a double-blind, placebo-controlled study design in multicenter trials to test the value of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine System Diseases↗
PubMed1977

Measurements of noradrenaline fluorescence in axons of chick embryo sympathetic ganglia grown in three day culture.

Chicken embryo sympathetic ganglion fragments, grown in culture for three days, were incubated for short periods in appropriate experimental and control media to provide information on axonal uptake of exogenous noradrenaline in the presence and absence of the uptake-blocking drugs, protriptyline and phenoxybenzamine. The cultures were dried, gassed in formaldehyde vapour and examined by fluorescence microscopy. Spot readings were taken on axon-bundles using a microspectrophotometer. Readings were corrected for the amount of tissue present in each field, using graticule and interferometric methods. Brightness was uniform along individual axon-bundles, but varied from bundle to bundle within the same culture. Despite this range in brightness the readings fell into a normal distribution about the mean. Dose-dependent increases in brightness were obtained following incubation with noradrenaline. A clear indication of the effect of the blocking drugs was observed but the range in brightness prevented reliable quantitative data on these effects from being obtained. It was concluded that the wide range of brightness within each culture reflected a lack of equivalence in the intrinsic noradrenaline-uptake properties of the axon-bundles developing in such cultures.

Animals↗
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↗