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PubMed1993

Reserpine reconsidered: no association with serious peptic ulcer disease.

A history of peptic ulcer disease is frequently cited as a contraindication to the use of reserpine. However, the risk of ulcer disease associated with the use of reserpine at current therapeutic doses is unknown. To address this question, the authors conducted a nested case-control study of the association between reserpine use and hospitalizations for peptic ulcer disease in elderly Tennessee Medicaid enrollees. When compared with that of nonusers of reserpine, the relative risk of hospitalization for peptic ulcer disease was 0.8 (95% CI, 0.6-1.0) among current users and 0.8 (95% CI, 0.5-1.3) among former users. The authors' data provide evidence that reserpine is not associated with ulcer disease in elderly persons and suggest that a history of ulcer disease need not be a contraindication to the use of this drug.

Aged↗
PubMed1997

Effects of reserpine treatment on the dopamine receptor binding of [3H/11C]nemonapride in the mouse and rat brain.

We investigated the effect of reserpine treatment on the striatal uptake of a radiolabeled dopamine D2-like receptor ligand nemonapride (NEM). In mice, the uptake of the [3H]NEM in the striatum, cortex and cerebellum was enhanced by the reserpine pretreatment. Neither the ratio of striatum to cerebellum nor that to cortex was affected by the reserpine pretreatment. In rats, ex vivo autoradiography showed no effect of the reserpine treatment on the striatal uptake of [11C]NEM or the striatum to cortex ratio. The results suggest that the receptor binding of NEM was not significantly influenced by reserpine-induced depletion of endogenous dopamine probably because of its high affinity for the receptors.

Animals↗
PubMed2006

The partial dopamine D2-like receptor agonist terguride functions as an agonist in preweanling rats after a 5-day reserpine regimen.

RATIONALE: Treating children and adolescents with partial D2-like agonists is becoming increasingly common, although few developmental animal studies have assessed the psychopharmacology of this class of drug. Contrary to results from adult rat studies, it has been reported that partial D2-like agonists may not induce agonist-like behavioral effects in preweanling rats during states of low dopaminergic tone. OBJECTIVE: The purpose of the present study was to determine whether a partial D2-like agonist would act as an agonist in preweanling rats after a 5-day regimen of the dopamine-depleting agent reserpine or the tyrosine hydroxylase inhibitor alpha-methyl-DL-p-tyrosine (AMPT). METHODS: Sprague-Dawley rats were pretreated with reserpine (1 mg kg(-1) per day) or AMPT (3 x 200 mg kg(-1) per day) on postnatal day (PD) 16-PD 20. Either 2 h (AMPT) or 5 h (reserpine) after the last pretreatment injection, rats were treated with saline, the partial D2-like agonist terguride, or the full D2-like agonist R(-)-propylnorapomorphine (NPA). Distance traveled and repetitive motor movements were measured for 60 min. RESULTS: After repeated reserpine treatment, both terguride and NPA increased the distance-traveled scores of preweanling rats; however, only NPA, but not terguride, increased distance-traveled scores after a 5-day regimen of AMPT or an acute injection of reserpine. CONCLUSIONS: It is now apparent that partial D2-like agonists are capable of inducing agonist-like behavioral effects in preweanling rats during a state of low dopaminergic tone. For agonistic actions to be observed, the pretreatment regimen must result in substantial and prolonged dopamine depletion.

Animals↗
PubMed1999

Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.

RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine replacement therapy, but this leads to long term complications, including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of PD. OBJECTIVES: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in ameliorating the motor deficits in various mouse models of Parkinson's disease. METHODS: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Beta-adrenoceptor sensitivity of brown and white adipocytes after chronic pretreatment of rats with reserpine.

The effect of pretreatment with reserpine (1.0 mg/kg i.p. daily for 7 days) on beta-adrenoceptor-mediated responses has been measured in epididymal white and interscapular brown adipocytes, left atria and vas deferens of rats in order to investigate the classification of the receptors and whether they are innervated. Lipolysis was measured in adipocytes, and from the same rats, the beta 1-adrenoceptor-mediated positive inotropic responses of isolated paced left atria and beta 2-adrenoceptor-mediated inhibition of field stimulation-induced contraction of the vas deferens were examined. The agonists used were isoprenaline, oxyfedrine (atria only) and (except in brown adipocytes) ritodrine, which was a partial agonist in white adipocytes, atria and vas deferens. Atria and brown adipocytes exhibited beta-adrenoceptor supersensitivity after reserpine pretreatment, whereas vas deferens and white adipocytes did not. Reserpine-induced reductions in food intake and body weight did not appear to influence beta-adrenoceptor-mediated lipolysis, since restriction of the diet equivalent to that of reserpine-treated rats produced no change in white adipocyte sensitivity. Responses mediated via beta 1-, but not beta 2-adrenoceptors, display supersensitivity after chronic depletion of neuronal catecholamines with reserpine and this is evidence for innervation of this receptor subtype. Thus, atrial beta 1-adrenoceptors are assumed to be innervated, whereas vas deferens beta 2-adrenoceptors are not. The present results are consistent with histochemical evidence that brown, but not white, adipocyte beta-adrenoceptors are innervated. However, they are not compatible with conventional receptor classification studies, which suggest that rat brown and white beta-adrenoceptors are similar--either both beta 1 or both atypical.

Adipose Tissue↗
PubMed1980

Effects of reserpine on fast, intermediate and slow axonal transport of proteins in rat locus coeruleus neurons.

The effects of a single injection of reserpine (5 mg/kg, i.p.) on protein turnover and axonal transport (AT) in locus coeruleus (LC) noradrenergic neurons was investigated in the rat. Reserpine pretreatment, at intervals of 1--21 days prior to [3H]-fucose or leucine injection into the LC, resulted in marked alterations in the turnover of [3H]glycoproteins and proteins in the LC and hypothalamus which were present for up to 14 days and varied according to the time after reserpine pretreatment. Reserpine produced an intermittent blockade, of variable degree, in rapidly and intermediately transported proteins for up to 2 weeks following injection. Slow AT was uniformly decreased over the first 10 post-treatment days to 2--42% of controls. Blockade and not a change in the rate or time of onset of transport appeared to be responsible for the observed changes. The suggested mechanism for these alterations is a re-ordering of metabolic priorities in the synthesis and transport of proteins in these noradrenergic cells secondary to a reserpine-induced depletion of norepinephrine in the nerve terminals.

Animals↗
PubMed1984

Reserpine and the role of axonal transport in the independent regulation of pre- and postsynaptic beta-adrenoreceptors.

The response of pre- and postsynaptic beta-adrenoreceptors to depletion of brain norepinephrine (NE) with reserpine in the rat was characterized by studying the anterograde and retrograde axonal transport of presynaptic receptors and the receptor binding changes induced in postsynaptic frontal cortex cells. Anterograde transport was shown to occur by the linear accumulation of [3H]dihydroalprenolol ([3H]DHA) binding sites (by in vitro binding assay) proximal to a 6-hydroxydopamine (6-OHDA) lesion placed in the ascending pathway of the locus coeruleus and was blocked by more proximal lesions in the pathway. Retrograde transport was demonstrated by the accumulation of [125I]iodocyanopindolol binding distal to similar lesions. Autoradiograms from sections of 6-OHDA injected brains were produced with [3H]DHA binding in the presence of the beta 2-agonist, zinterol, and suggested that the anterograde accumulation of binding sites was primarily of the beta 1-subtype. A single injection of reserpine (5 mg/kg, i.p.) produced a long lasting (6-8 weeks), biphasic decrease in cortical NE levels with nadirs and 4 and 28 days (10% and 45% of control, respectively). Frontal cortex binding of [3H]DHA increased to a maximum at 7-14 days and again at 28 days post-reserpine (230% and 167% of control, respectively). These increases were not prevented by the destruction of presynaptic noradrenergic nerve terminals with intraventricular administration of 6-OHDA 1 day prior to sacrifice and therefore appeared to take place solely in postsynaptic cells. Presynaptic, anterograde axonal transport of beta-receptors was completely blocked from 4-14 days post-reserpine, increased to 323% of control at 21 days, was blocked again at 6 weeks and returned to control by 8 weeks. Retrograde transport of beta-receptors followed a similar pattern suggesting that the presynaptic alterations in beta-receptors in noradrenergic neurons of the locus coeruleus take place independently from those in postsynaptic cortical beta-receptors as a response to NE depletion by reserpine.

Afferent Pathways↗
PubMed1989

Repeated reserpine administration up-regulates the transduction mechanisms of D1 receptors without changing the density of [3H]SCH 23390 binding.

Behavioural studies have shown that stimulation of D1 receptors, which is uneffective in normal rats, induced strong hypermotility in rats pretreated with reserpine for 5 days. On this basis, we investigated D1 receptor plasticity using the 5-day treatment with reserpine (1 mg/kg; s.c.) as an experimental model. The function of striatal D1 receptors was determined both in binding studies with [3H]SCH 23390 and by measuring formation of cAMP in response to the selective agonist, SKF 82526. The results indicate that the responsiveness of adenylate cyclase (AC) to D1 receptor stimulation was markedly increased after reserpine administration, while no significant changes were found in [3H]SCH 23390 binding site density. Moreover, formation of cAMP after stimulation of Gs protein with GppNHp was markedly enhanced in dopamine (DA)-depleted rats; the responsiveness of AC to forskolin, which directly stimulates the AC catalytic unit, was not affected by reserpine administration. These data indicate that reserpine-induced D1 receptor up-regulation is apparently mediated by a marked enhancement of the coupling efficiency of Gs protein, suggesting that the D1 behavioral supersensitivity does not correlate with the density of D1 receptors, but is reflected by a selective up-regulation of their transduction mechanisms.

Adenylyl Cyclases↗
PubMed1991

Differential effects of reserpine on brainstem catecholaminergic neurons revealed by Fos protein immunohistochemistry.

The effects of a single systemic injection of reserpine on c-fos proto-oncogene expression in catecholaminergic neurons of the rat brainstem were studied by immunohistochemistry for Fos proteins (Fos). In control rats, a few Fos immunoreactive neuronal nuclei were observed in the tectum and mesencephalic central gray. Within hours after drug injection, a substantial number of brainstem neurons stained intensely for Fos. The staining was maximal at 6 h and returned to control levels within 24 h. Double-immunohistochemical staining with antibodies to tyrosine hydroxylase revealed that in all noradrenergic (NA) neuron subgroups except the A2 group, the majority of NA neurons stained for Fos. Most adrenergic neurons were also labeled. In contrast, aside from some cells in the ventral tegmental area, reserpine did not induce Fos immunoreactivity in dopaminergic neurons. Numerous non-catecholaminergic neurons were intensely stained with Fos in the substantia nigra pars reticulata, ventral tegmental area, mesencephalic central gray, pontine nuclei and tectum. A small number of Fos immunoreactive neurons was also observed in raphe nuclei. Injection of saline (i.p.) resulted in a moderate increase in Fos immunoreactivity in the locus ceruleus, in A1/C1 neurons and in the mesencephalic central gray. The results demonstrate that acute reserpine treatment induces Fos expression in distinct populations of brainstem neurons, comprising both catecholaminergic and non-catecholaminergic neurons. Thus, induction of Fos by reserpine does not coincide with the site of action of this drug. The distribution of Fos immunoreactive NA neurons after reserpine treatment is comparable to that reported after application of stressful stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Blockade of reserpine emesis in pigeons by metoclopramide.

Reserpine (0.5 mg/kg i.m.) produced emesis in pigeons with 60% of the animals responding. Metoclopramide HCl at 10, 20 and 40 mg/kg p.o. administered 30 min before or after reserpine injection was effective in blocking reserpine emesis. Metoclopramide was unable to antagonize reserpine-induced sedation and hypotension in rats, thus inviting discussion of its possible mechanism in blocking reserpine emesis.

Animals↗
PubMed1980

Effects of reserpine and antidepressants on dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) concentrations in the striatum, olfactory tubercle and median eminence of rats.

The dopamine, noradrenaline and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of various rat brain areas (median emience, olfactory tubercle, rostral and caudal part of the striatum) were measured. The effects of reserpine and antidepressants: amitriptyline, nomifensine and EGYT 475 (1-benzyl-4-/2'-piridylcarbonyl/piperazine) were investigated. The dopamine content of the median eminence proved to be the most sensitive to the depletory effect of reserpine. Reserpine (1 mg/kg i.p.) caused a decrease of dopamine in the median eminence, in the olfactory tubercle and in the rostral striatum but not in the caudal striatum. Amitriptyline and EGYT 475 antagonized the reserpine-induced dopamine depletion in the olfactory tubercle. In the median eminence amitriptyline attenuated the effect of the depletor while nomifensine augmented it; EGYT 475 was without effect. The antidepressants antagonized the reserpine-induced increase of DOPAC in the rostral part of the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Effects of sympathetic denervation or chronic reserpine on potassium (42K) and chloride (36Cl) efflux from guinea-pig vas deferens.

Potassium (42K) or chloride (36Cl) efflux curves were determined in guinea-pig vas deferens from control, reserpine-treated animals (1 mg/kg/day i.p. for 5 days), and from animals whose vas deferens had been sympathetically denervated 1 week before. Steady-state 42K turnover in control tissues was 0.0052 +/- 0.0002 min-1; neither reserpine treatment nor sympathetic denervation changed this parameter signicantly. Control 36Cl turnover was 0.058 +/- 0.002 min-1 and it was unaffected by either procedure. Methoxamine (3 x 10(-6) to 10(-4) M) induced dose-related increases in the fractional exchange of 42K and 36Cl. These were of greater magnitude after sympathetic denervation or reserpine treatment. Furtrethonium also produced dose-dependent increases in 42K efflux; its dose-response curve was shifted 2.6-fold to the left of the control curve by reserpine treatment. These results indicate that interruption of adrenergic transmission to the guinea-pig vas deferens is associated with increased changes in membrane permeability to Cl and possibly K in response to drug activation of alpha-adrenergic and cholinegic receptors. It is suggested that the supersensitivity phenomenon observed in the guinea-pig vas deferens after reserpine or sympathetic denervation is, in part, related to improved transduction of drug-receptor interaction into ionic permeability changes.

Animals↗
PubMed1982

Reversal by serotonergic agents of reserpine-induced hyperalgesia in rats.

Reserpine (4 mg/kg) induced a time-dependent reduction in pain threshold (hyperalgesia) as observed by the tail-flick technique in rats. Serotonin, its precursor 5-hydroxytryptophan or the receptor agonist, quipazine reversed the reserpine-induced hyperalgesia. On the other hand, piribedil, amantadine, imipramine or desipramine treatment failed to reverse the reserpine-induced hyperalgesia. Similarly, intracerebroventricular administration of dopamine or noradrenaline also had no effect on reserpine-induced hyperalgesia. These observations not only suggested a role of serotonin in hyperalgesia but also that reserpine hyperalgesia is suitable for selective study of serotonin-mediated responses in rats.

5-Hydroxytryptophan↗
PubMed1987

Reserpine-induced supersensitivity in adenylate cyclase preparations from guinea-pig heart.

The effects of a reserpine treatment inducing supersensitivity to the cardiac effects of agonists (2.5 mg/kg per day for 2 days) was studied on guinea-pig cardiac adenylate cyclase (AC) activity. Reserpine treatment had no effect on basal or Gpp(NH)p (10(-7) M)-stimulated activities. Histamine (2 X 10(-6) and 10(-4) M) stimulation of guinea-pig AC was not influenced by the reserpine treatment. Epinephrine stimulation of AC was affected by reserpine and was characterized by an upward shift of the epinephrine dose-response curve with no change in the epinephrine EC50. The results indicate that the enhancement of cyclic AMP production is an important factor in the reserpine-induced cardiac supersensitivity to beta-adrenoceptor agonists.

Adenylyl Cyclases↗
PubMed1983

Pancreatic structure and function in the immature reserpinized rat.

Immature rats were reserpinized to determine whether the model used for adults may be suitable for the study of pancreatic exocrine insufficiency seen in infants with cystic fibrosis. Rats were reserpinized by injections either into pregnant dams or into newborn rats. The dose of reserpine used by others was lethal to immature rats, so lower doses were used. Pancreas from 1-day-old fetal-treated pups was hypoplastic, but concentration of chymotrypsinogen was elevated. At age 7 days hyperplasia was seen. When rats were reserpinized as neonates, hypoplasia and decrease in all parameters measured was observed at age 7 days. Progressive recovery occurred during the following 2 weeks in both groups. Electron microscopic study of the fetal-treated 24-hr-old pancreas revealed evidence of acinar cell degeneration with the presence of abnormal zymogen granules. At age 7 days the pancreas from neonatal-treated rat pups appeared to have a reduced number of granules. At ages 14 and 21 days the pancreas was similar to that seen at age 7 days except that the granules were larger and some acinar lumina were filled with a finely granular, homogeneously dense material. It is concluded that prenatal and neonatal reserpinization of rats induces changes in pancreas similar to those found in cystic fibrosis.

Amylases↗
PubMed1984

Increase of the peroxidase activity of mouse submaxillary gland by reserpine.

The peroxidase activity of mouse submaxillary gland was found to be elevated by about 128% at 22 hr. after the administration of reserpine (0.5 mg/kg). This effect of reserpine was observed in rat also. Neither pretreatment with 6-hydroxy dopamine (6-OH dopamine) nor surgical sympathetic denervation could abolish the increase of the peroxidase activity elicited by reserpine. Also, treatment with propranolol, dibenamine or atropine sulfate failed to reverse the effect of reserpine. These results suggest that neither catecholamine nor acetyl choline is involved in this reserpine action.

Animals↗
PubMed1993

Role of 5-HT1A receptors in the forced swimming wheel test in reserpine-treated mice.

The antidepressant-like effect of 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a selective 5-HT1A receptor agonist, was studied in the forced swimming wheel test in reserpine-treated mice. 8-OH-DPAT and the antidepressant imipramine, dose-dependently increased the number of turns of a water wheel made by mice. This effect of imipramine (30 mg/kg, i.p.) was enhanced by reserpine treatment 24 hr before the test. The effect of 8-OH-DPAT (0.3 mg/kg, i.p.) was also enhanced in reserpine-treated mice. This enhanced effect of 8-OH-DPAT was blocked by pretreatment with the 5-HT1A receptor antagonists, (-)-propranolol (3 mg/kg, i.p.) and NAN-190 (1 mg/kg, i.p.), but was not blocked by a beta-blocker, (-)-atenolol (3 mg/kg, i.p.). 8-OH-DPAT did not affect locomotor activity in the reserpinized mice and did not affect the reduction of monoamine content induced by reserpine. These results suggest that the effect of 8-OH-DPAT in increasing the number of turns of the wheel made by mice was exerted through a 5-HT1A receptor and that this effect did not reflect only changes in the locomotor activity of the mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Dopamine D1 and D2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice.

In mice, rendered poikilothermic by a prior (18 hr) subcutaneous administration of reserpine (3 mg/kg), the subcutaneous administration of apomorphine increased dose-dependently the body temperature. This effect was potentiated by the specific D2 dopamine antagonist sulpiride. On the contrary, it was reduced by the specific D1 dopamine antagonist SCH 23390. A desensitization of D2 receptors was produced by the repeated administration of the specific D2 agonist RU 24926. This pretreatment led to an increased efficacy of apomorphine in antagonizing reserpine-induced hypothermia. Similarly, a desensitization of D1 receptors was created by the repeated administration of the specific D1 agonist CY 208-243. This pretreatment significantly diminished the efficacy of apomorphine in antagonizing reserpine-induced hypothermia. The repeated administration of the D1 agonist CY 208-243, in non-reserpinized mice, significantly increased the hypothermic effect of apomorphine (1 mg/kg). Thus, it appears that, in normal mice, but especially in reserpinized mice, the stimulation of D1 receptors by apomorphine induces an increase in body temperature that is masked, especially in normal mice, by the hypothermic effect, resulting from the simultaneous stimulation of D2 receptors.

Animals↗