Reserpine administration

In addition to impairing norepinephrine storage and thereby enhancing its catabolism, reserpine impairs the vesicular uptake of dopamine, the immediate precursor of norepinephrine. Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation and form norepinephrine, reserpine administration impairs norepinephrine synthesis. The combined effects of the blockade of dopamine and norepinephrine vesicular uptake lead to transmitter depletion. 

Iwamoto K, Kato T. Effects of cocaine and reserpine administration on RNA editing of rat 5-HT2C receptor estimated by primer extension combined with denaturing high-performance liquid chromatography. Pharmacogenomics J 2002 2 335-340. 

The exact mechanism of this peripheral adrenergic neuron blocking agent is not well defined. Reserpine administration results in depleted stores of norepinephrine, dopamine, and serotonin in multiple organs. The decreased peripheral resistance and cardiac output that results is manifested as a decrease in blood pressure. A central nervous system (CNS) effect may also play a role in decreasing blood... 

Grimm LJ, Blendy JA, Kellar KJ, Perry DC. Chronic reserpine administration selectively up-regulates P,- and alb-adrenergic receptors in rat brain an autoradiographic study. Neuroscience 1992 47 77-86. 

Carlsson discovered that DA is present in large amounts in the brain, and disappears when a person is given the drug reserpine. Administration of the precursor of DA, L-dihydroxyphenylalanine (L-dopa), brings about the reappearance of DA in the brain. Carlsson said, I would put the discovery of dopamine and its role for normal brain functions as a winner, no doubt about it. A good second place would go to the research into the role of dopamine in mental disorders, such as schizophrenia, followed by the third finding the mode of action of antipsychotic drugs. ... 

Iproniazid also prevents the reserpine syndrome in rats. Reserpine blocks vesicular uptake of monoamines which, as a consequence, leak from the storage vesicles into the cytosol. Although these monoamines would normally be metabolised by MAO, they are conserved when a MAO inhibitor (MAOI) is present, and so co-administration of reserpine and a MAOI leads to accumulation of monoamines in the neuronal cytosol. It is now known that, when the concentration of cytoplasmic monoamines is increased in this way, they are exported to the synapse on membrane-bound monoamine transporters. The ensuing increase in monoamine transmission, despite the depletion of the vesicular pool, presumably accounts for the effects of iproniazid on the behaviour of reserpine-pretreated rats. 

A second, more extensive experiment involved oral administration of three daily doses (100 mg/kg) of parachlorophenylalanine (PCPA). This tryptophan hydroxylase inhibitor (47), like reserpine, enhanced the behavioral effects of LSD (13) moreover, hypersensitivity occurred when 5-HT, but not other monoamine, concentrations were below normal in both forebrain and hindbrain (13). That is, effects were observed at 5 and 12 days (when 5-HT was depleted to 10-20% and 60-70% of normal) but not at 21 days (when 5-HT had returned to normal). Control experiments (13) indicated that (a) the interaction of PCPA, 5-HT, and LSD was probably not caused by generalized hyperactivity or hyperirritability sometimes seen after PCPA (73) (b) PCPA does not affect threshold doses of other psychoactive but nonserotonergic compounds, such as d-amphetamine (0.3 mg/kg) and (c) pretreatment with a-methylparatyrosine, a tyrosine hydroxylase inhibitor which depletes catecholamines rather than indoleamines, does not alter sensitivity to LSD. 

Studies in mice have shown a hypericum extract to increase exploration in an unfamiliar environment, prolong sedative sleep time, and antagonize the effects of reserpine. Other antidepressant-like effects are found on the water-wheel test, and chronic administration decreased aggression in socially isolated male mice (Okpanyi and Weischer 1987). 

The level of DOPA accumulation (decreased by agonists and increased by antagonists) in different brain parts after the administration of dopaminergic test compounds can be taken as an indirect measure of the DA synthesis rate. Such a biochemical test model can be used in normal animals and in reserpine or GBL pretreated animals (see below). 

Laboratory evaluation [241] of acute and chronic toxicity of prenylamine indicates that, in high doses, convulsions accompanied by respiratory paralysis (often with pulmonary oedema) led to death. Doses inadequate to produce this result led only to phenomena characteristic of reserpine-like dmgs. Chronic administration failed to produce recognizable changes in any organs or tissues studied. No toxic effects, unattributable to amine depletion, have appeared during several years clinical use. 

Depression. Depression is our most common mental problem. One in four women and one in ten men will have a major depression during their lifetime.1095 More than 15 million people in the United States are affected by severe depression in any given year and more than 30,000 may commit suicide.1096 1097 Worldwide psychiatric problems, mostly depression, account for 28% of all disabilities.1098 The biogenic amine hypothesis states that depression results from the depletion of neurotransmitters in the areas of the brain involved in sleep, arousal, appetite, sex drive, and psychomotor activity. An excess of transmitters is proposed to give rise to the manic phase of the bipolar (manic-depressive) cycle that is sometimes observed. In support of this hypothesis is the observation that administration of reserpine precipitates depression, which may be serious in 15-20% of hypertensive patients receiving the drug. Similar effects are observed with the dopa decarboxylase inhibitor a-methyldopa... 

It therefore appears that the main action of reserpine is to produce a biochemical change so that the cells no longer retain a high concentration of serotonin. In other words, the binding of serotonin is prevented. Thus, after the administration of 5-hydroxytryptophan (a precursor of serotonin) to rabbits pretreated with reserpine, serotonin is rapidly formed but remains in a free form. Presumably, free serotonin, before it is metabolized to 5-hydroxyindole acetic acid by amine... 

Reserpine is absorbed rapidly following oral administration. Maximum blood concentrations are reached in approximately 2 hours with reported values of O.lU to... 

A biological half-life in whole blood of 386 hours and a biological half-life in plasma of 271 hours have been reported(32) Detectable levels of reserpine may be found after 11 days from administration of the drug. Reserpine is not removed either by hemodialysis or by peritoneal dialysis(36). 

Drug-induced Parkinsonism may arise following the long-term administration of neuroleptics that block central dopamine receptors or reserpine-like drugs that deplete dopamine stores. Because of their mode of action, neuroleptics should never be coadministered to patients being treated with L-dopa or vice versa. 

The randomized controlled clinical trials performed by Freis and his colleagues at the Veterans Administration Hospitals have provided some of the first solid evidence that moderate permanent hypertension has an improved prognosis when actively treated by sodium depletion (hydrochlorothiazide), by interruption of the sympathetic nervous system (reserpine) and with a vasodilator (hydralazine) (262). In parallel, the beneficial effects of this triple therapy were demonstrated in spontaneously hypertensive rats by the spectacular prevention and cure of their cardiac, vascular, and renal lesions (263). 

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