Reserpine Research Articles

Hypothalamic Monoamine Metabolism in Mice: Evaluation of Drug Challenges and Neurotoxic Insult

Hypothalamic monoamine metabolism was evaluated in male and female mice that were administered monosodium glutamate (MSG, 4 mg/g) on postnatal day 4. Hypothalamic dopamine (DA) content was reduced approximately by 22% across all experiments and pituitary DA content was also significantly decreased. Despite reductions in hypothalamic DA levels, MSG-treated mice did not exhibit significant reductions in the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Hypothalamic monoamine and metabolite profiles in MSG-treated and control mice were examined after the administration of pargyline (PAR), alpha-methyl-p-tyrosine (MPT) or reserpine (RES). DA turnover as indexed by PAR and MPT techniques were not as conclusive as the metabolite measures in suggesting an accelerated DA utilization. MSG-treated mice were more resistant to the DA-depleting actions of reserpine than were the controls. No alterations were found in hypothalamic norepinephrine metabolism in MSG-treated mice, however, after drug challenges, alterations were found in serotonin metabolism. These results indicate the extent and nature of the changes that occur in hypothalamic monoamine metabolism after neonatal MSG treatment. The DA neurons that survive MSG treatment appear to exhibit neurochemical characteristics dissimilar to those of tuberoinfundibular DA neurons. Additionally, the neuropharmacological actions of MPT, PAR and RES are discussed as they relate to hypothalamine monoamine metabolism in the mouse.

Calcium and norepinephrine levels of rat salivary glands after terbutaline, dobutamine or isoproterenol

Present data show that a dose-related increase in calcium concentration [Ca] of submandibular glands of rat occurred after 6 days of twice daily administration of 25. 50 or 75 mg/kg b. wt. doses of the β 1-adrenergic agonist, dobutamine, or the β 2-adrenergic agonist, terbutaline. The β 1-adrenergic receptor was responsible for mediation of these changes with both agonists since the effects of either agonist were prevented when a 10 mg/kg dose of the β 1-antagonist, atenolol, was injected 20 min prior to the agonist, and the increase induced by either agonist was not prevented when the β 1-adrenergic antagonist, butoxamine, was given prior to each agonist. Dobutamine caused more marked increases in [Ca] than did terbutaline. The parotid gland, however, showed a decrease with both agonists, and that caused by dobutamine was greater than that caused by terbutaline. Neither antagonist had any effect on the agonist-induced changes in the parotid gland. Reasons for the differences in response of the two glands are suggested. It does not appear, however, that, as suggested previously, the increase in the [Ca] of the submandibular gland is dependent on depletion of glandular levels of norepinephrine (NE). Of the agonists, only dobutamine caused a decrease in glandular concentration of NE, as well as total NE of the gland. With isoproterenol (ISO), NE concentration of parotid and submandibular was reduced, but with terbutaline only that of parotid was reduced. Changes in total glandular NE were not found in either gland with either ISO or terbutaline. Thus, the decrease in concentration was a consequence of the increased mass of gland. With cyclocytidine (CC), both NE concentration and total NE were reduced, even though gland size increased. With reserpine (RES), NE concentration as well as total NE were markedly reduced (87–90%), and no change in gland size occurred. It is suggested, on the basis of present data, that prolonged activation of β 1-adrenoceptors is the cause of the calcium accumulation, and that reduction in NE is not the cause of the calcium increase, but may only be a coincident event. Even with sympathectomy (here induced by reserpine), activation of β-receptors over a long period of time is suggested as the cause of the calcium change, not the depletion of NE. The present data also provide the first evidence that CC causes NE depletion.

Calcium concentration of saliva and salivary glands of rat after cyclocytidine.

Cyclocytidine (CC), in addition to its antitumor properties, also causes copious flow of saliva. Calcium concentration of CC-evoked saliva from submaxillary (SM) and parotid (PA) glands of adult rats was initially 7 meq/liter and 15 meq/liter, respectively, and thus resembled that of sympathetically evoked secretion. From previous data, as well as present data, this is expected since CC apparently causes release of norepinephrine (NE) from adrenergic nerve endings. Present data also confirm that CC causes NE release since a single dose of reserpine (RES) (5 mg/kg), administered 24 hr prior to injection of CC in order to cause depletion of NE prevented the action of CC. Furthermore, the NE released by CC acts principally on beta-adrenergic receptors since propranolol administered prior to CC caused a marked reduction in flow and [Ca] of saliva, and prevented the usual CC-induced depletion of glandular calcium. An increase in [Ca] of SM but not PA gland was also caused by chronic (daily injections of 500 mg/kg body wt for 3 days) administration of CC. The same threefold increase was observed 2 days after injection of a single dose of CC also. The increase in glandular calcium was not prevented by propranolol, thus suggesting that this effect of CC on glandular [Ca] was probably not beta-mediated. The calcium increase may, however, be the result of depletion of NE. Thus, [Ca] of SM of CC-treated rats, that of RES-treated rats, and that of rats treated with RES + CC were very similar. If the mechanism of action of the two drugs were different (not NE depletion), the combined action of the two would have been additive.

Calcium concentration of salivary glands and saliva after chemical or surgical sympathectomy

Calcium concentration of the submaxillary (SM) gland of adult rat was increased to 2–3 times control levels 24 h after a single high dose of reserpine (RES) (5 mg/kg body weight), 6-hydroxydopamine (6-OHDA) (20 mg/kg body weight), or surgical removal of a superior cervical ganglion (Sx). The increase could also be induced within 24 h after a single injection of lower doses of RES (0.05, 0.5 mg/kg body weight). Increase in calcium concentration in the parotid (PA) was not found under any of the above conditions, but did occur transiently at times within 24 h. The increase in glandular calcium concentration was found to be temporally related to depletion of norepinephrine (NE). The time frame for initiation of calcium changes was not the same for chemical and surgical sympathectomy (Sx). Increase in calcium concentration occurred after onset of sympathectomy-induced degeneration secretion; the onset varied with the kind of sympathectomy, and was seen 1 h after drug administration with either RES or 6-OHDA, but not until about 13 h after surgical Sx. Similarly, NE was markedly depleted, but later with surgical than with chemical Sx. Furthermore, with both kinds of sympathectomy, depletion of NE occurred earlier with PA than with SM, since normal basal levels of NE of SM are 3 times as great (3400 ng/g wet weight), compared with PA levels (1300 ng/g wet weight). The fact that NE was the neurotransmitter eliciting the degeneration secretion was confirmed physiologically by examination of the composition of this secretion. Thus,

Effect of tranquillisers on the reproduction of a freshwater leech,Poecilobdella viridis (Blanchard)

Effects of two well-known tranquillisers, reserpine and chlorpromazine on the reproduction ofP. viridis were investigated. There was a significant decrease on the ovarian index after reserpine (RSP) injection, whereas, chlorpromazine (CPZ) did not induce any change. But chlorpromazine has a profound effect on the testis index. Surprisingly, injection of the mixture ofRSP+CPZ induced a significant decrease in the ovarian and testis indices. Besides gonad index, the tranquillizer effect on histological profile of gonads was also studied.

Behavioral and electroencephalographic studies of the cholecysto-kinin(CCK-8)-related substance, caerulein(883-S).

Caerulein(883-S), clinically suggested to have antipsychotic activity, was administered to rats, cats and rhesus monkeys. The electroencephalograms and behavior of the animals were observed. (1) In rats and cats, 883-S (12-120 μg/kg s.c./i.m.) caused sedation and predominantly produced a resting-like EEG pattern. No marked differences could be found in the EEG pattern of cats at the same EEG level before and after administration of 883-S. Monkeys fell asleep immediately after 883-S(6-30 μg/kg i.m.) dosing, and this state lasted for 1.5 to 2 hrs. (2) Haloperidol(HPD) antagonized the EEG activating effect of amphetamine(0.5 mg/kg i.p.) and lowered the threshold intensity for eliciting the caudate spindle in rats. However, 883-S had no such effect and had little influence on those of HPD. In the resting state, rhythmic waves of high-amplitude(train waves) spontaneously appeared on the neocortical lead of rats. Chlorpromazine(CPZ), HPD and reserpine(RSP) increased the appearance of the waves, but 883-S did not. On the contrary, 883-S inhibited the enhancing action of HPD or RSP on the train waves. In monkeys, 883-S in combination with HPD or CPZ gave a power spectral array of EEG unlike that obtained after injecting each drug separately. (3) 883-S(over 30 μg/kg s.c./i.m.) depressed the behavioral dis-order(BD) in chronically methamphetamine-intoxicated cats and rats, although clear dose-dependency and selectivity of the effect could not be found. Furthermore, unlike the case of HPD, the inhibitory effect of 883-S on the BD of rats almost disappeared after the vagotomy. 883-S was ineffective against amygdaloid-kindled seizures in rats.

Effects of monoamine oxidase inhibitors, cholinolytics, and other pharmacologic agents on the ulcerogenic effects of reserpine in mice

Mice rather than rats [1-3] were employed in screening studies designed to define agents effective in protecting the gastric mucosa from the damaging effects of reserpine (RP); this approach allowed utilization of smaller quantities of the agents in question. The purpose of this study was to compare the antiulcerogenic efficacy of monoamine oxidase (~AO) inhibitors (iproniazid, Niamid, pargyline, phenylzin [4, 5]), m-cholinoblockers (atropine sulfate, metamizil HCI, and their iodomethylates), the catechol-o-methyltransferase (COMT) inhibitor depaverin [6], the adrenomimetic ephedrine and the centrally acting secretagogue 2-deoxy-D-glucose in reserpine-induced gastric ulcers in mice. Selection of the drugs was based on the observation that MAO inhibitors exerted a protective effect on reserpine-treated rats [7-9], ~lile the m-cholinolytics (atropine, metamizil) appeared to be ineffective in the prevention of RPinduced gastric lesions [9]. However, individual communications report on the antiulcerogenic effects of iproniazidand atropine in mice [i0]. Using the method developed by us for evaluating the ulcerogenicity of RP, we determined to uncover the most potent antiulcer agents from each group and compare them for their effectiveness on our RP ulcer model in the mouse.

Bovine pancreatic polypeptide-like immunoreactivity in brain and peripheral nervous system: Coexistence with catecholaminergic nerves

The rat central and peripheral nervous system contains a widespread distribution of BPP-like immunoreactive neurons. Some of these neurons coexist with a catecholamine, probably mostly NE. This peptide appears to be releaseable by nerve stimulation. Catecholamine releasing agents such as reserpine do not appear to deplete the BPP. This extensive distribution and unique coexistence of a peptide with peripheral sympathetic nerves suggests a neuromodulatory role of BPP in autonomic functions.

760 DIFFERENCES IN PAROTID SALIVA SODIUM LEVELS AND RESERPINE-RESPONSIVENESS BETWEEN RAT LINES

The mechanism underlying the inhibition of Na reabsorption from exocrine secretions in cystic fibrosis (CF) is not known. In the animal CF phenocopy of Martinez, chronic reserpine (RS) administration to rats causes histological and physiological changes in exocrine glands similar to those in CF. To examine the effect of chemical sympathectomy on Na transport, we studied the onset of inhibition of Na reaborption from parotid saliva in male Sprague-Dawley (SD) rats given i.p. RS (0.5 mg/kg) daily. Saliva stimulated by i.p. pilocarpine was collected by cannulating the parotid duct. A single RS dose caused a marked increase in Na content within 24 hr in rats from our colony (OU). Na content increased linearly with the duration of RS administration. Saliva of SD rats from Sasco Inc. (SI) contained much less Na than that of OU rats at all saliva flow rates below 70 ul/min/g gland wet weight. RS administered to SI rats caused no demonstrable increase in saliva Na content until the 4th day. Na increased only to levels seen in untreated OU rats. These results indicate that both the intrinsic activity and the susceptibility to inhibition of the ductal Na transport system of exocrine glands show specific differences. Such differences complicate the use of uncharacterized rat strains for the bioassay of CF factors but may provide valuable insights into the biological regulation of Na transport in the exocrine gland duct.

Methamphetamine処置ラットのStereotypyおよび自発運動におよぼすReserpine連用後のα-Methyl-p-tyosineの効果

Previously we have found such "bizarre stereotypy" as persistent and bloody biting activity at the legs or the tail of himself or of the cage mate given methamphetamine (MAPT, 10 mg/kg) 24 hrs-48 hrs after long term-administration of reserpine (RE). The present investigation examined the effect of inhibition of dopamine synthesis in brain on MAPT-induced "bizarre stereotypy" and hypermotility of RE-treated rats. Male albino Wistar rats aged 4 weeks were injected intraperitoneally with RE (1.25 mg/kg) or 0.9% saline solution (1.25 ml/kg) every two days for 13 days. Twenty-two hrs after the last injection, rats received alpha-methyl-para-tyrosine ( alpha-MPT, 50 mg/kg, 125 mg/kg, 250 mg/kg i.p.) or its vehicle (1 ml/kg i.p.) and 2 hrs later, MAPT. MAPT induced continuous licking and biting at the metal wire of the cage floor in saline-treated rats and also "bizarre stereotypy" in RE-treated rats, but these activities were completely suppressed by pretreatment of alpha-MPT in each dose given (especially in 125 mg/kg, 250 mg/kg). Pertaining to the locomotor activities of saline-treated rats, the horizontal movements were especially enhanced by MAPT, however, the vertical movements remained unchanged. Alpha-MPT partially inhibited such horizontal movements while it potentiated the vertical movements. Locomotor activities of RE-treated rats were depressed one day after the last injection of RE, however, after the MAPT, these activities counts were increased considerably and were also higher in comparison to the counts of saline-treated rats given MAPT. These hypermotilities in RE-treated rats were partially antagonized by pretreatment with alpha-MPT. It is suggested that MAPT-induced "bizarre stereotypy" of RE-treated rats is mediated by the accelerative effect of RE on MAPT-induced dopamine synthesis, while MAPT-induced hypermotility of RE-treated rats is partially related to such an acceleration of dopamine synthesis.

EFFECTS OF TRICYCLIC ANTIDEPRESSANTS ON TETRABENAZINE-INDUCED DEPLETION OF BRAIN MONOAMINES IN RATS. 2. DOPAMINE

AbstractWe studied the effects of tricyclic antidepressants on the tetra-benazine (TB)-induced depletion of brain dopamine (DA) using rats. The test drugs were generally administered orally 3 hours before sacrifice and 2 mg/kg of TB or reserpine (RES) was administered subcutaneously 2 hours before sacrifice. The TB-induced DA depletion was enhanced by pretreatment with desmethylimipramine (DMI, 12.5–100 mg/kg), Imipramine (12.5–100 mg/kg), chlorimipramine (25–100 mg/kg), ami-triptyrine (100 mg/kg), maprotyrine (50 mg/kg) and chlorpromazine (5–20 mg/kg i.p.), while these drugs did not enhance RES-induced depletion. Observations to elucidate the action mechanism of antidepressant-induced enhancement were as follows. After TB administration, brain DA content was at the minimal level at 30 min after and on the way to recovery at 2 hours, but it approached the minimal level at 2 hours after RES administration. DMI pretreatment did not enhance the DA depletion at 0.5 hours after TB administration. In pargyline-pretreated rats, TB produced a decrease of brain DA with an increase of 3-methoxy-tyramine (3-MT), while RES showed only a slight effect on DA and 3-MT up to 2 hours. Amphetamine sulfate (20 mg/kg i.p.) slightly increased, while combinations with DMI decreased brain DA. These results suggest that tricyclic antidepressants inhibit DA reuptake from the synaptic cleft in vivo.

Effects of tricyclic antidepressants on tetrabenazine-induced depletion of brain monoamines in rats. 2. Dopamine.

We studied the effects of tricyclic antidepressants on the tetrabenazine (TB)-induced depletion of brain dopamine (DA) using rats. The test drugs were generally administered orally 3 hours before sacrifice and 2 mg/kg of TB or reserpine (RES) was administered subcutaneously 2 hours before sacrifice. The TB-induced DA depletion was enhanced by pretreatment with desmethylimipramine (DMI, 12.5-100 mg/kg), imipramine (12.5-100 mg/kg), chlorimipramine (25-100 mg/kg), amitriptyrine (100 mg/kg), maprotyrine (50 mg/kg) and chlorpromazine (5-20 mg/kg i.p.), while these drugs did not enhance RES-induced depletion. Observations to elucidate the action mechanism of antidepressant-induced enhancement were as follows. After TB administration, brain DA content was at the minimal level at 30 min after and on the way to recovery at 2 hours, but it approached the minimal level at 2 hours after RES administration. DMI pretreatment did not enhance the DA depletion at 0.5 hours after TB administration. In pargyline-pretreated rats, TB produced a decrease of brain DA with an increase of 3-methoxy-tyramine (3-MT), while RES showed only a slight effect on DA and 3-MT up to 2 hours. Amphetamine sulfate (10 mg/kg i.p.) slightly increased, while combinations with DMI decreased brain DA. These results suggest that tricyclic antidepressants inhibit DA reuptake from the synaptic cleft in vivo.

Effects of chronic amphetamine or reserpine on self-stimulation responding: animal model of depression?

The mood-altering properties of amphetamine (AMPH) in humans (euphoria and depression) have been postulated to be related to the increases and decreases respectively which this drug produces in the sensitivity of the reward system of the brain. The present study further evaluated this relationship by testing the effects of chronic reserpine (RES), another treatment that produces depression in humans, on self-stimulation responding. Separate groups of animals implanted with stimulating electrodes in the medial forebrain bundle were administered daily injections of saline, d-AMPH (5 mg/kg X 7 days followed by 10 mg/kg X 7 days), or RES (0.05 mg/kg X 18 days). At treatment termination, both drug groups showed a significant elevation of the reinforcement threshold, with no recovery occurring during 18 subsequent days. Thus, drug-induced depression of self-stimulation responding may serve as an animal model for studying the underlying physiological basis for clinical depression, or at the very least, for drug-induced depression.

Further studies on catecholamine-containing specific endothelial granules in carp cerebral veins. A fluorescence histochemical and electron microscopy study.

The effects of noradrenaline (NA), L-3, 4-dihydroxyphenylalanine (L-DOPA), 5-hydroxydopamine (5-OHDA), 6-hydroxydopamine (6-OHDA), and reserpine (RES) on the uptake, accumulation, and release of amines in catecholamine-containing specific endothelial granules (SEG) of carp cerebral veins and their mode of formation were examined by fluorescence histochemistry and electron microscopy. The intramuscular injection of NA (4 mg/kg) or L-DOPA (200 mg/kg) resulted in an increase in both the fluorescence and electron density of SEG. After the administration of false neurotransmitters. 5-OHDA (190 mg/kg) or 6-OHDA (200 mg/kg), the venous endothelial fluorescence almost completely disappeared but the SEG electron density increased. Following the injection of RES (15 mg/kg), the fluorescence intensity and SEG electron density showed no sign of decrease, as was expected, but in fact increased. It is suggested that the SEG are able to take up and accumulate exogeneous amines and that these mechanisms are RES-resistant. The electron density of SEG increased in proportion to the amount of amines in the SEG. The swelling and fragmentation of rough endoplasmic reticulum cisternae and the accumulation of dense material within the cisternae suggests the possible participation of these organelles in SEG formation.

Review of the Critical Findings Contained Within DHHS Publication No. NIH 80-1749: Bioassay of Reserpine for Possible Carcinogenicity

Review of the Critical Findings Contained Within DHHS Publication No. NIH 80-1749: Bioassay of Reserpine for Possible Carcinogenicity

Combination antitumor effect with central nervous system depressants on rat ascites hepatomas.

Combined effect of twenty-one central nervous system depressants with several antitumor agents was studied in the in vitro and in vivo experimental systems, using rat ascites hepatoma call lines, AH13 and AH44, sensitive and insensitive to alkylating agents, respectively. Reserpine remarkably enhanced the cytotoxic effect of 1-(gamma-chloropropyl)-2-chloromethylpiperidine hydrobromide (CAP-2) both on AH13 and AH44 cells. In the in vivo combined experiments, reserpine also synergistically enhanced the life-prolonging effect of CAP-2 on AH13-bearing rats and, although CAP-2 was not potent on the prolongation of life span of AH44-bearing rats and reserpine was also ineffective at the doses examined, the life span of tumor-bearing rats receiving the combined administration was apparently prolonged compared with control groups. Thus, there was a parallelism between in vitro and in vivo experiments. These findings suggested that the antitumor-enhancing effect of reserpine might be due to the direct action on the tumor cells, and a possible mechanism that reserpine inhibited the DNA damage-repairing activity of the cells was contradictory. Other mechanisms are also discussed.

Effects of Tricyclic Antidepressants on Tetrabenazine-Induced Depletion of Brain Monoamines In Rats. 1. Norepinephrine

We studied the effects of tricyclic antidepressants on the tetrabenazine (TB)-induced depletion of brain norepinephrine (NE) using rats. The test drugs were generally administered orally 3 hr before and 2 mg/kg of TB or reserpine (RES) administered subcutaneously 2 hr before sacrifice. The TB-induced NE depletion was enhanced by pretreatment with desmethylimipramine (DMI, 25--100 mg/kg), imipramine (IM, 25--100 mg/kg), chlorimipramine (100 mg/kg), maprotyrine (50 mg/kg), amitriptyrine (50--100 mg/kg), chlorpromazine (CPZ, 5--20 mg/kg i.p.,) and amphetamine sulfate (10 mg/kg). DMI partially suppressed TB-induced NE depletion at 0.5 hr after TB administration. The RES-induced NE depletion was not enhanced with these drugs except for amphetamine. DMI, IM, and CPZ suppressed it instead. DMI also enhanced the yohimbine (2 mg/kg)-induced decrease. The brain NE content showed a tendency toward recovery 2 hr after TB administration, but approached the minimal level at 0.5 hr after TB administration or at 2 hr after RES administration in non-treated rats. In pargyline-pretreated rats, TB produced a decrease of brain NE with an increase of normetanephrine, while the action of RES was weaker than that of TB, up to 2 hr. These results suggest that enhancement of the TB-induced brain NE depletion by tricyclic antidepressants reflects the blockage of NE reuptake from the synaptic cleft.

Analysis of anomalous pKb values for metiamide and atropine in the isolated stomach of the mouse.

1 In the isolated, lumen-perfused, stomach preparation of the mouse, metiamide was found by kinetic analysis to behave like a simple competitive antagonist of histamine-stimulated acid secretion. However, the pK(B) estimate of 5.08 was significantly lower than that found in guinea-pig atrium (6.0) or rat uterus (6.1) suggesting that H(2)-receptors might not be homogeneous.2 A similar analysis showed that atropine also behaved like a simple competitive antagonist of bethanechol-stimulated acid secretion and the estimated pK(B) (7.65) was significantly lower than the standard estimate of this parameter in guinea-pig ileum (9.0). Either the muscarinic cholinoceptors in mouse stomach were also anomalous or the preparation was introducing a systematic error. Lumen perfusion might distort this type of kinetic analysis by allowing steady-state conditions but not true equilibrium to develop at the receptor compartment due to loss of antagonist into the gastric secretion. Drug interactions at receptors in the muscle layers of the stomach would be expected to be much less sensitive to this error.3 When the atropine-bethanechol interaction was measured on the contraction of the isolated, lumen-perfused, stomach of the mouse the necessary conditions for simple competition were not met even though the sensitivity to atropine was obviously increased. The criteria for the expected simple competition were being obscured by events at low antagonist concentrations. Alterations in agonist or antagonist concentrations could be more or less eliminated so that physiological antagonism, perhaps by release of 5-hydroxytryptamine, was considered. This was supported, to some extent, by finding that, when stomachs from animals pretreated with reserpine were used, the kinetic analysis was normalized and gave a pK(B) of 8.99. Apparently, the muscarinic receptors in mouse stomach are homogeneous with those in other tissues.4 Therefore, we conclude that our results no more point to heterogeneity among histamine receptors than they point to differences in muscarinic cholinoceptors because this type of kinetic analysis can be readily distorted by special features of the measuring system.

Reserpine: no changes advised for now

Reserpine: no changes advised for now

More on the subject of reserpine

More on the subject of reserpine