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Basal forebrain lesions with or without reserpine injection inhibit cortical reorganization in rat hindpaw primary somatosensory cortex following sciatic nerve section.

To test the hypothesis that cortical reorganization depends on acetylcholine and one or more of the monoamines, the hindpaw cortex was mapped in eight different groups of mature rats: (1) untreated; (2) after sciatic nerve transection; (3) after intraperitoneal injections of reserpine, to reduce the level of cortical monoamines; (4) after ibotenic acid lesion of the nucleus basalis of Meynert (NBM), to destroy cholinergic cells projecting to the cortex; (5) after reserpine treatment and transection; (6) after ibotenic acid lesion and transection; (7) after reserpine treatment and ibotenic acid lesion; and (8) after reserpine treatment, ibotenic acid lesion, and transection. Four days after transection, the cortex had reorganized in the transected group. However, this process of reorganization was prevented in transected animals with NBM lesions. Treatment with reserpine alone did not inhibit the process of reorganization, nor did it enhance the effect of NBM lesion. Nonetheless, the animals treated with reserpine and transected had higher response thresholds in the reorganized cortex than did the animals that were treated but not transected. These data suggest that acetylcholine plays an important role in the early reorganization that follows deafferentation, and that one or more of the monoamines may have other influences on reorganization of the primary somatosensory cortex of adult rats.

Acetylcholine↗

Reserpine and calcium: interaction at the injection site.

The subcutaneous administration of calcium prior to reserpine prevented the development of the well-known reserpine effects. Pretreatment with other bivalent cations induced a similar effect. The inhibitory effect of reserpine on the in vitro uptake of labelled catecholamines in brain homogenates was also prevented in rats pretreated with bivalent cations. On the other hand when calcium was injected at a site other than that of reserpine, there was no antagonistic effect. The latter results suggest an interaction between bivalent cations and reserpine at the injection site that prevents the systemic absorption of reserpine.

Animals↗

Brain IL-1 beta was involved in reserpine-induced behavioral depression in rats.

AIM: To investigate the mechanism of brain interleukin-1 beta (IL-1 beta) in reserpine-induced behavioral depression in rats. METHODS: Porsult swim test was used in the measurement of depressive behavior and ELISA was used in measurement of brain IL-1 beta. RESULTS: Intraperitoneal injection of reserpine (0, 4, 6, and 8 mg/kg, ip) increased floating time in the Porsult swim test in a dose-and time-dependent manner in rats. Intracerebroventricular injection (icv) of IL-1 beta receptor antagonist (IL-1ra, 6 mg/kg) blocked the increment of floating time in Porsult swim test at 48 and 72 h after reserpine injection, but not at 1 and 24 h after injection. Brain IL-1 beta increased after reserpine treatment in posterior cortex, hippocampus, and hypothalamus. The increase of IL-1 beta concentration starts at 24 hours after injection of reserpine and reached the peak at 48 h. CONCLUSION: Reserpine induced behavioral depression partially via brain interleukin-1 beta generation.

Animals↗

Noradrenergic subsensitivity and supersensitivity of the cerebral cortex after reserpine treatment.

Changes in the sensitivity of the cyclic adenosine 3', 5'-monophosphate response of rat brain cerebral cortical slices to norepinephrine were measured in vitro after the rats received i.p. injections of reserpine (1 mg/kg). Subsensitivity was evident 1 hour after a single reserpine treatment compared with saline controls. However, if reserpine was injected daily for 4 days followed by 1 day without reserpine treatment, a supersensitive response to NE was shown compared to the controls. Mean pD2 values are presented to illustrate the shifts of the dose-response curves after reserpine treatment. The present work demonstrated the induction of noradrenergic sub- and supersensitivity to norepinephrine in rat cerebral cortical slices after acute and 4-day reserpine treatment, respectively.

Animals↗

Stimulation of nerve growth factor biosynthesis in developing rat brain by reserpine: steroids as potential mediators.

The stimulation of beta-adrenergic receptors by isoproterenol increases nerve growth factor (NGF) biosynthesis in C6 rat glioma cells, suggesting that norepinephrine may regulate NGF biosynthesis in vivo. We have tested this hypothesis in 21-day-old rats by depleting catecholamine stores with reserpine. Northern blot analysis of NGF mRNA, in combination with a two-site enzyme immunoassay for NGF, showed that depletion of catecholamines was associated with a 3-fold increase in NGF mRNA, which was followed by a significant increase in the NGF content of cerebral cortex. The increase in NGF mRNA was most marked 9 hr after reserpine administration (2 mg/kg, subcutaneously) and was no longer apparent 24 hr after drug administration, when brain monoamine stores were still depleted. Moreover, the lowest dose of reserpine that significantly increased NGF mRNA levels induced only a small change in the content of cortical catecholamines. These results suggest that reserpine mediates the increase in NGF production by a mechanism other than monoamine depletion. Because reserpine increases plasma glucocorticoid concentrations through the pituitary-adrenal axis, we investigated whether adrenal steroids could be responsible for the induction of NGF biosynthesis. The effect of reserpine on NGF biosynthesis was abolished in adrenalectomized rats. Moreover, dexamethasone, a synthetic glucocorticoid, given at a dose of 0.5 mg/kg, subcutaneously, increased the amount of NGF mRNA and NGF in cerebral cortex. NGF biosynthesis in the central nervous system may, thus, be regulated by adrenocortical hormonal secretion.

Adrenal Cortex Hormones↗

Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats.

Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with [3H]SCH-23390 and D2 receptors labeled with [3H]spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

[Effect of reserpine on the potency of alpha receptor blockers].

The influence of rather low doses of reserpine (0.125--2.0 mg/kg) on the pressor effect of noradrenaline (NA) was studied in pithed rats. In addition it was investigated whether the blocking activity of alpha-sympathicolytic agents is influenced by pretreatment with reserpine. 24 h after injection of these doses of reserpine this drug only increased the pressor effect of lower doses of NA without shifting the dose-response curve to the left. As a rule in rats pretreated with reserpine the affinity of alpha-blocking agents (derivatives of phenylethylamine and phenoxyethylamine) to alpha-adrenoceptors is not considerably altered. Only two phenylethylamine derivates substituted with a p-hydroxy group possessed considerably higher blocking activity in reserpine pretreated animals than in rats not pretreated. The increase in sensitivity of blood vessels against low doses of NA (250 pg and 1 ng) observed in rats pretreated with reserpine is abolished even by alpha-blocking substances with low affinity to alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗

Responses mediated via beta-1 adrenoceptors but not beta-2 adrenoceptors exhibit supersensitivity after chronic reserpine pretreatment.

The purpose of this study was to examine whether reserpine pretreatment induces supersensitivity of both beta-1 and beta-2 adrenoceptor-mediated responses. Guinea pigs received reserpine (0.5 mg kg-1 s.c. or i.p.) daily for 7 days. Isolated tissues were set up in the presence of phentolamine (5 microM) and metanephrine (10 microM) and the sensitivity to isoproterenol and, where possible, a partial agonist (ritodrine, salbutamol or prenalterol) was determined. The beta adrenoceptor-mediated responses were recorded as the increase in rate and tension of right and left atria, inhibition of carbachol-induced contractions of ileum, relaxation of aortic spirals contracted with histamine, inhibition of transmurally stimulated vas deferens and relaxation of tracheal spirals and lung strips with intrinsic tone. The atria exhibited supersensitivity after reserpine pretreatment (s.c. and i.p.) as a leftwards shift of the isoproterenol concentration-response curve and elevation of the prenalterol maximum response. The ileum was also supersensitive, but only when tissues from animals receiving i.p. reserpine were compared with shams, which themselves were subsensitive or when reserpine was administered s.c. The trachea was also supersensitive, but not the aorta, lung and vas deferens, the responses of which are mediated via beta-2 adrenoceptors. In contrast, beta-1 adrenoceptors are involved in the atrial, ileal and tracheal responses. Therefore, only responses mediated via beta-1 adrenoceptors exhibited reserpine-induced supersensitivity which supports the hypothesis that beta-1 but not beta-2 adrenoceptors receive a sympathetic innervation.

Animals↗

Treatment of refractory depression with combination reserpine and tricyclic antidepressant therapy.

Chronic reserpine use has been reported to precipitate severe depression in some individuals as a result of its amine-depleting action. However, early clinical studies demonstrated that acute administration of high doses of parenteral reserpine in combination with a tricyclic antidepressant could produce rapid improvement in depressive symptoms. Because these early studies defined treatment resistance as failure to respond to a brief course of treatment with a single tricyclic antidepressant, we performed a more stringent, placebo-controlled evaluation of high dose reserpine in nine depressives refractory to at least six previous drug treatments. Overall, neither reserpine nor placebo produced a meaningful decrease in depression ratings within 1 week of treatment; however, one patient did respond to a second course of reserpine. Side effects were mild to moderate in severity, and there were no cases of profound hypotension. Although the efficacy of this drug combination in severely refractory depressives was not confirmed, reserpine may still prove a useful adjunctive agent in some tricyclic-resistant depressed patients.

Adult↗

Influence of reserpine on in vivo localization of injected lymph node cells in the mouse.

The effects of reserpine, and other agents that affect the storage and availability of 5-hydroxytryptamine (5HT), on the localization of injected 51Cr-labelled syngeneic lymph node cells have been investigated. A high dose (5 mg/kg) of reserpine to the recipients reduced localization in the lymph nodes and prevented the usual accumulation of lymphocytes in lymph nodes draining the site of an antigen (sheep erythrocytes: SE) injection. These effects were partially reversible by the monoamine oxidase inhibitor nialamide. This dose of reserpine produced deep sedation throughout the period of the experiment. Lower doses, up to 2.5 mg/kg, produced little sedation and had no effect on the localization of lymphocytes. Other workers had previously reported reduced localization of cells in delayed-type hypersensitivity (DTH) lesions after treatment of the recipients with 5 mg/kg reserpine, and had interpreted this in terms of a role of 5HT in promoting vascular permeability and egress of blood cells. The effect of lower doses of reserpine was not reported. We suggest that the effects on cell localization in both sets of experiments may have been secondary to the general state of sedation and not attributable to a direct local influence of 5HT. Other effects of reserpine included prolonged retention of lymphocytes in lungs and blood, and a reduction of cellularity and DNA synthesis in the thymus, spleen and lymph nodes.

Animals↗

Effect of reserpine pretreatment on calcium transport and Ca++-Mg++ adenosine triphosphatase activity of guinea-pig cardiac microsomes.

A previous report from this laboratory showed that reserpine pretreatment, in appropriate doses and under restricted conditions, increased the inotropic responsiveness of guinea-pig hearts to calcium. The enhanced responsiveness was characterized by a selective increase in the rate of ventricular relaxation (-dP/dt). We therefore hypothesized that reserpine might alter calcium uptake or (Ca++-Mg++) adenosine triphosphatase (ATPase) activity of guinea-pig ventricular sarcoplasmic reticulum (SR). Pretreatment of guinea pigs with reserpine (2.5 mg/kg/day, 2 days) significantly elevated ATP-dependent, Tris oxalate-facilitated SR Ca++ uptake and increased the calcium-sensitive component of the SR (Ca++) ATPase activity. These changes appeared to be functionally related to a reserpine-induced potentiation of ventricular relaxation rate, as estimated by the relationship between negative and positive left ventricular dP/dt of isolated working guinea-pig hearts. An alternative dose of reserpine (5 mg/kg, -24 hr), which had been demonstrated to produce an equivalent degree of catecholamine depletion, had no effect on either the inotropic responsiveness to calcium or on the SR calcium uptake or ATPase activities. The exact mechanism for these reserpine-induced alterations in calcium homeostasis remains to be elucidated.

Animals↗

Effect of metiamide, a histamine H2-receptor antagonist on reserpine-induced gastric ulcers and acid secretion.

The effect of metiamide on reserpine-induced gastric ulcers and on gastric secretion during 6 h after ip administration was investigated in conscious intact rats and in rats with chronic gastric fistula. Reserpine, 3 mg/kg ip increased substantially the concentration of gastric acid in the first 4 h. Metiamide given every 3 h in a low dose (0.01 mumol/kg) intensified reserpine-induced gastric ulcers and also significantly increased the reserpine-induced acid concentration and output. In larger doses, (50-100 mumol/kg) metiamide considerably diminished gastric ulcer development and decreased gastric acid concentration. Given every 2 h metiamide in doses of 50-100 mumol/kg almost completely abolished gastric ulcer formation and markedly reduced the secretion of gastric acid in reserpinized rats. Anti-ulcer effect of metiamide was stronger than its antisecretory action, suggesting also the antiulcer action of metiamide other than inhibition of acid secretion. The results suggest that in conscious rats histamine H2-receptors are involved in reserpine-induced gastric ulcer development and gastric acid secretion. The antiulcer effect of metiamide may in part depend on its antisecretory action.

Animals↗

Effect of reserpine on Mg++-induced calcium fluxes and reactivity of the rat aorta.

The effect of reserpine on 45Ca++ fluxes and reactivity of the rat aorta in Mg++-free and Mg++ (1.2 or 3.6 mM) media to various agonists was examined to gain further insight into mechanism(s) responsible for the altered sensitivities in vascular smooth muscle. Incubation of rat aorta in Mg++-free and high Mg++ (3.6 mM) media containing ethylene diamine tetra-acetic acid (EDTA 0.03 mM), respectively, increased and decreased the sensitivity to noradrenaline (NA), 5-hydroxytryptamine (5-HT) and KCl. Mg++-free medium significantly enhanced maximal response to 5-HT whereas high Mg++ (3.6 mM) medium reduced the maximal responses to KCl and 5-HT but not to NA. Mg++-free medium had no effect on 45Ca++ uptake, while it enhanced 45Ca++ efflux from the aorta. Reserpine treatment induced supersensitivity in the aorta to KCl, but not to either NA or 5-HT in normal medium, whereas in Mg++-free medium, it induced partial contraction and inhibited both maximal responses and sensitivity to NA and 5-HT but not to KCl. Reserpine in high Mg++ (3.6 mM) medium had no effect on sensitivity and maximal responsiveness to all these agents. Reserpine reduced 45Ca++ uptake by aorta in either Mg++-free or normal Mg++ medium and it reduced 45Ca++ efflux for aorta in Mg++-free but not in normal Mg++ medium. These observations suggest that reserpine may promote membrane permeability rather nonspecifically to divalent ions. However, the presence of EDTA in the media may have partially reduced the antagonistic effects of Mg++ due to reserpine treatment in this tissue.

Animals↗

Tension development and associated calcium influx of control and reserpine pretreated rabbit aortae in response to norepinephrine, isoproterenol and acetylcholine.

The influence of reserpine (3mg/kg) pretreatment on phasic and tonic components of the contractile responses of rabbit aortae to maximally effective concentrations of norepinephrine, acetylcholine, and isoproterenol and on agonists-induced movements of 45Ca during these responses were studied. Four hours after reserpine administration, there were no histological changes, in extracellular space, and no change in tissue water, sodium, calcium or magnesium. Potassium contents were slightly decreased and the catecholamine content was depleted by 95%. The responses to the three agonists were enhanced in the reserpine pretreated tissues. The absence of calcium eliminated the slow tonic componenet of the responses. Reserpine induced an increase in lanthanum (La3+) resistant 45Ca uptake. The three agonists induced an increase in La3+ resitant 45Ca uptake of equal magnitude in both reserpine pretreated and control tissues. Lanthanum ion affected 45Ca efflux similarly in both reserpine pretreated and untreated tissues. The results suggest that a major portion of the enhanced responsiveness of rabbit aortic strips following reserpien administration is the result of a change in calcium retention in those tissue stores mobilized by these agonists to initiate the fast, phasic componenet, and is, therefore, a reflection of an increased agonist intrinsic activity.

Acetylcholine↗

[Effect of reserpine on monoamine uptake by rat brain synaptosomes].

With regard to the inhibition of monoamine-uptake the concentration response curve of reserpine shows a biphasice turn. The first phase produces a maximum dopamin-uptake inhibition of 55% (EC50:8 X 10(-9) mol X 1(-1)) which is of a competitive manner only in the presence of a very low reserpine concentration (1 X 10(-9) mol X 1(-1)). Higher concentrations of reserpine inhibit the dopamine-uptake non competitively. This specific irreversible vesicular reserpine effect used therapeutically forms a plateau within a concentration rank from 10(-7) mol X 1(-1) to 10(-5) mol X 1(-1). A second mode of action of reserpine affects obviously the carrier mechanism located at the synaptosomal membrane (EC50: 5 X 10(-5) mol X 1(-1)). This second phase differs both from the first vesicular reserpine effect and from the synaptosomal action of tricyclic antidepressant drugs by its kinetic behavior (Km, Vmax).

Animals↗

Comination effect of reserpine with antitumor agents in L1210.

The antileukemic combined effect of reserpine with 1-gamma-chloropropyl-2-chloromethylpiperidine hydrobromide (CAP-2) and other antitumor agents was studied on mouse leukemia L1210 in comparison with the effects of other Rauwolfia alkaloids and sympatholytic drugs. When reserpine was administered by a single ip injection (2.5 mg/kg) on day 1, the effect of subsequent administration of CAP-2, mitomycin-C, or vinblastine was synergistically enhanced. In this combination with reserpine, the acute lethality of CAP-2 on the host animals was apparently decreased. Among other sympatholytic drugs, rescinnamine, a central nervous system depressant, slightly potentiated the antitumor effect of CAP-2. On the other hand, when reserpine-induced hypothermia was prevented by maintenance of the ambient temperature at 30 degrees, the synergistic combined effect of reserpine was diminished. Chlorpromazine-induced hypothermia did not influence the antitumor effect of CAP-2. It may be concluded that the antileukemic synergism depends partially on the interaction between reserpine and CAP-2 or other antitumor agents in relation to body temperature and/or action on the central nervous system in leukemic mice.

Animals↗

Reserpine inhibits amphetamine action in ventral midbrain culture.

Although amphetamine releases catecholamines from isolated secretory vesicles, a number of in vivo experiments have indicated that the vesicular amine transport blocker reserpine does not block amphetamine-induced release. To address this paradox, we examined the effect of reserpine on amphetamine-induced dopamine release from postnatal ventral midbrain neurons in culture. These cultures provide a preparation in which intracellular, extracellular, and releasable dopamine pools can be measured simultaneously. We found that 1 microM reserpine for 90 min reduced stimulation-dependent dopamine release by > 95%. In parallel, reserpine reduced amphetamine-induced dopamine release by > 95% compared with cells not exposed to reserpine or by 75% compared with reserpine-treated cultures. This shows that amphetamine acts principally by redistributing dopamine from synaptic vesicles to the cytosol.

Amphetamine↗

An electron microscopic study on the effects of reserpine on the subclavian glomera of the rabbit.

Young male and female New Zealand white rabbits were given a daily subcutaneous injection of reserpine (Serpasil, Ciba; 3 mg/kg) for two days and were sacrificed 24 hours after the last injection. The subclavian glomera (aortic bodies) were processed for electron microscopy to determine the effects of this biogenic amine depleting agent on the electron-opaque cytoplasmic granules of the parenchymal type I cells. Observations of glutaraldehyde-osmium tetroxide fixed glomera from reserpinized animals showed a slight decrease in granule density of the type I cells. Glomera fixed in glutaraldehyde and incubated in potassium dichromate (pH 4.1) demonstrated a reduction in granule opacity following reserpine treatment. Control glomera incubated in potassium dichromate displayed electron-opaque granules. These results indicate that reserpine does deplete the amines without granule disappearance or changes in granule population. The positive reaction of the control tissue granules to potassium dichromate incubation suggests that the predominant biogenic amines in the electron-opaque granules are unsubstituted monoamines. Persistence of the opaque granules following reserpinization and glutaraldehyde-osmium tetroxide double fixation, may be due to amine-binding protein within the granules. The mode of granule depletion could not be ascertained with certainty.

Animals↗