The effects of reserpine on a strongly conditioned emotional response

Summary Twenty-six Wistar albino rats were conditioned to inhibit a leverpresssig response during a 4-minute tone period which was terminated by a strong electric shock (CER). Two groups of 10 animals, matched on the basis of rate during the pre-tone and tone periods, were tested concurrently throughout the experiment. The experimental group was administered a daily and periodically increasing dose of reserpine (0.2–0.6 mg/kg) for a period of 18 consecutive days. It was found that reserpine produced no significant effects on the CER when compared with that of the matched control group, although an increase in the restoration of lever pressing as a function of time was found to be significant for both groups. It was concluded that the partial restoration of the lever-pressing response with time was a function of partial extinction of the CER, and that reserpine does not significantly reduce a strongly conditioned emotional response.     

The acute effects of reserpine on the sleep-wakefulness cycle in rabbits

Summary The acute effects of reserpine on the sleep-wakefulness cycle were systematically studied in five male rabbits with chronically implanted electrodes for recording the EEG, the EMG of the neck muscles, and the oculogram. After careful control studies during which the rabbits became accustomed to the experimental situation and attained stable sleep-wakefulness patterns, various doses of reserpine (1.0, 0.5, 0.25, 0.1, 0.05 mg/kg) were injected intravenously and 5-hr polygraphic recordings were made. Twenty-four hours after administration, 2-hr recordings were made for all doses studied; for the dose of 1.0 mg/kg 2-hr recordings were also made 48 hours after administration. The percent times of the three stages, alert, slow wave sleep and paradoxical sleep, were calculated for the total recording time. In the unmedicated animals the percentages during 2-hr recordings were: alert, 32.9±5.7; slow wave sleep, 61.5±5.9; and paradoxical sleep, 5.6±1.1. Paradoxical sleep was also calculated for the first hour and the remaining 4 hours of the 5-hr recording period both as to percent time and the duration of single episodes. Some behavioral and polygraphic characteristics of paradoxical sleep were described. Reserpine, in doses of 1.0 to 0.25 mg/kg, caused a biphasic response; an initial alert period of 1 1/2 to 2 hours followed by a slow-wave-sleep period which endured until the end of the 5-hr recording. Suppression of paradoxical sleep was observed with doses of 1.0 to 0.1 mg/kg, although the doses of 0.25 and 0.1 mg/kg did not suppress it during the first hour after injection. The percent time of paradoxical sleep in total recording time showed a dose-dependent decrease: 0.2% for 1.0 mg/kg, 0.1% for 0.5 mg/kg, (both significant,p<0.001), 0.6% for 0.25 mg/kg (p<0.01), 2.4% for 0.1 mg/kg (p<0.05), 3.5% for 0.05 mg/kg (not significant) and 5.1% for the saline control. The duration of single episodes of paradoxical sleep was not changed by reserpine. In the 2-hr recordings made one and two days after reserpine administration the percent time of paradoxical sleep did not differ significantly from the normal level.     

The effects of reserpine on renal necrosis and urinary catecholamines of choline-deficient rats

Renal necrosis due to a choline-deficient diet was induced in a group of male weanling Sprague-Dawley rats. A control group was given Purina rat chow, and another group was given a choline chloride supplement (150 mg/100 ml in tap water) in addition to the choline-deficient diet. Reserpine, an agent that reduces catecholamines, was given subcutaneously (0.1 mg/kg) daily to one-half of each group. After 16 days the choline-deficient rats given reserpine had significantly less renal necrosis and excreted less catecholamines than choline-deficient rats. Reserpine had no effect on hepatic fatty infiltration due to choline deficiency.     

Influence of methyldopa on central effects of reserpine

Methyldopa potentiated hypnosis due to hexobarbitone in mice, as did reserpine, chlorpromazine and 5-hydroxytryptamine. Methyldopa antagonized the increase by reserpine of sleep due to hexobarbitone, but enhanced the potentiation by chlorpromazine and 5-hydroxytryptamine of hypnosis due to hexobarbitone. The sedative effect of reserpine in mice and the emetic effect in pigeons were also antagonized by methyldopa. However, the effects of reserpine on convulsions due to leptazol and in causing ptosis were not antagonized by methyldopa. It is suggested that some effects of reserpine (potentiation of hexobarbitone-sleeping time, sedation and emesis) are unrelated to changes in brain amine levels and that methyldopa, with its weak reserpine-like actions, is an antagonist to reserpine.     

Short- and long-term effects of reserpine on rat cardiac beta-adrenoceptors

1. In order to explore the mechanism of reserpine-induced supersensitivity, we examined the effects of various doses of reserpine (R) on rat cardiac beta-adrenoceptors (beta AR). 2. 24 hr after a single administration of R (1 mg/kg, i.p.) beta AR were up-regulated, while with higher doses (2.5-5 mg/kg) beta AR density was not changed but beta AR coupling, evaluated by the proportion of high-affinity agonist binding states, was impaired. 3. Long-term effects of R (2.5 mg/kg/day, 2 days) included beta AR down-regulation and uncoupling 24 hr treatment (day 1), followed by up-regulation at day 7, while all parameters were similar to controls at day 14. 4. It appears that R induces either an increase or a decrease of cardiac beta AR density and coupling, dependent on the dose and the time at which beta AR are measured after treatment.     

Time-dependent effects of reserpine on retention of passive avoidance

Reserpine produced amnesia for a one-trial passive avoidance task when given 2, 3, 4, 5 hr before but not when given 1, 8, 12, 24 hr or 30 min before, immediately, 90 min or 2, 4, 5, 6, 8, 9, 12, 24 hr following training. The results were discussed in terms of the reserpine effect on biogenic amines and their possible role in memory formation.     

The depletion effects of chlorpromazine, reserpine and ascorbic acid on tissue histamine of guinea-pigs

1. 30 mg kg-1 chlorpromazine (CPZ) depleted more than half of the tissue histamine from lungs, stomach, ileum and skin of the normal guinea-pigs. However, the drug increased the tissue histamine content in scorbutic animals. 2. In contrast, reserpine depleted histamine from the four tested tissues in both normal and scorbutic animals, except those in the lungs of the control animals. 3. Ascorbic acid only depleted histamine from the stomach and ileum. 4. A 24 hr period was the time limit for CPZ to deplete the histamine in all the four tested tissues. 5. Histamine partially or completely recovered in the tissues after the next 24 hr.     

The effects of reserpine and other agents upon leptazol convulsions in mice

Reserpine and tetrabenazine reduced the survival time of mice infused with leptazol. This effect was antagonized by pretreatment with iproniazid. The survival time of iproniazid-treated mice was prolonged by 5-hydroxytryptophan but not by 3:4-dihydroxyphenylalanine. These findings suggest a relation between leptazol sensitivity and brain levels of 5-hydroxytryptamine.     

The effects of long term administration of psychotropic drugs on human sleep: II. The effects of reserpine

Reserpine 0.50 mg/day was administered over a period of four weeks to a group of normal young males. Laboratory sleep, home sleep, and mood were studied throughout the period of administration and for a month afterwards. Results were compared to identically administered long-term placebo.Total sleep was slightly increased at first; D-time and the number of D-periods were clearly increased by reserpine. These effects were prominent from day three, through the second week. D-latency and length of the sleep-dream cycle was decreased. Subjective aspects of sleep were not greatly changed. Mood scales indicated an increase in fatigue and a decrease in vigor during reserpine administration.This work was supported in part by National Institute of Mental Health Grant # MH 14520.     

The runway model of drug self-administration

Behavioral scientists have employed operant runways as a means of investigating the motivational impact of incentive stimuli for the better part of the past 100 years. In this task, the speed with which a trained animal traverses a long straight alley for positive incentive stimuli, like food or water, provides a reliable index of the subject's motivation to seek those stimuli. The runway is therefore a particularly appropriate tool for investigating the drug-seeking behavior of animals working for drugs of abuse. The current review describes our laboratory's work over the past twenty years developing and implementing an operant runway model of drug self-administration. Procedures are described that methodologically dissociate the antecedent motivational processes that induce an animal to seek a drug, from the positive reinforcing consequences of actually earning the drug. Additional work is reviewed on the use of the runway method as a means of modeling the factors that often result in a “relapse” of drug self-administration after a period of abstinence (i.e., a response reinstatement test), as are runway studies that revealed the presence of opposing positive and negative consequences of self-administered cocaine. This body of work suggests that the runway method has served as a powerful behavioral tool for the study of the behavioral and neurobiological basis of drug self-administration.     

GABAergic effects of reserpine following chronic treatment

Reserpine-induced depression has been used as an animal model to screen for antidepressant agents. Chronic (14-day) tretment with reserpine resulted in a significant increase in -adrenergic receptor binding in the cerebral cortex and the hippocampus, which was partially prevented by chronic treatment with either the antidepressant imipramine, the GABA-A agonist THIP or, the GABA-B agonist baclofen. Chronic treatment with reserpine also significant increased ³H-GABA receptor binding, which was partially prevented by chronic treatment with either imipramine or THIP. Both subchronic and chronic administration of reserpine resulted in a decrease in GABA concentrations in the cerebral cortex and hippocampus. These data demonstrate the effect of reserpine treatment on the GABA-ergic system, and add further support for a functional coupling between the noradrenergic and GABA-ergic systems, which may be important for the mechanism of action of antidepressant agents.     

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in a runway

Three experiments examined the effects of d-amphetamine (1 mg/kg) administration on the partial reinforcement extinction effect (PREE) using a multitrial procedure. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Experiments 1 and 2 used 6 trials/day with an intertrial interval (ITI) of 5 min. In Experiment 1 the drug was administered only during acquisition, whereas in Experiment 2 it was administered throughout acquisition and extinction. Experiment 3 used 3 trials/day with a 20 min ITI. The drug was administered throughout acquisition and extinction. In all three experiments, amphetamine-treated animals showed a normal PREE, i.e., increased resistance to extinction in PRF as compared to CRF animals. These results stand in marked contrast to the amphetamine-induced abolition of the PREE with 1 trial/day procedure.     

Differential effects of reserpine and alpha-methyl-p-tyrosine on norepinephrine and dopamine induced behavioral activity

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intraperitoneal pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methyl-p-tyrosine (125 mg/kg-1 or 8 days). While the hyperactivity produced by norepinephrine was potentiated 24 h after reserpine, the response to dopamine was reduced by reserpine. Chronic, but not acute, alpha-methyl-p-tyrosine enhanced the effect of norepinephrine without altering the dopamine-induced activity. These results indicate: 1. dopamine-induced hyperactivity is due to its conversion to norepinephrine, and 2. prolonged depletion of central catecholamines may result in post-synaptic receptor supersensitivity.This research was supported by NIMH Grant No. MH18065 and No. MH23209.The authors gratefully acknowledge the surgical assistance of P. Josephine Branson and Edward Forney.This study is part of a dissertation submitted by the first author in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of California, San Diego.     

The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain.

1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.     

The action of reserpine on teleost melanophores

Reserpine caused darkening of both pencil fish and angelfish, this effect lasted for at least 10 and 25 days respectively.The aggregation of pigment granules within the melanophores evoked by stimulation of the nerves supplying the melanophores was inhibited by reserpine in both species. Reserpine caused a lowering of the catecholamine content of pencil fish skin. The time course both these effects paralleled the time course of darkening. The response of the melanophores of the angelfish to adrenaline, noradrenaline, dopamine, and melatonin was not affected by treatment with reserpine for 3 days. However, reserpine treatment for 14 days induced a marked sensitivity to noradrenaline. Reserpine partially abolished the response to tyramine in both pencil fish and angelfish. Small doses of noradrenaline and adrenaline given to reserpine-treated angelfish partially restored the response of the melanophores to nerve stimulation. No action of ACTH, MSH, nor direct effect of reserpine could be demonstrated on melanophores of either species. It was concluded that reserpine acts on the melanophores of pencil fish and angelfish in an indirect way by depletion of catecholamines from the sympathetic nerves supplying the melanophores.