TRIPASS XR تري باس

 

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REVERSAL OF PHARMACOLOGICAL

AND BIOCHEMICAL EFFECTS OF

NEUROLEPTIC DRUGS ON

CHRONIC ADMINISTRATION

C. D. MARSDEN & P. JENNER

University Department ofNeurology. In stitute ofPsychiatry and

King 's College Hospital Medical School, Denmark Hili, London SES, England

Introduction

Most drug pharmacology is done by acute experiment, but the drugs are then often

given to man for months or years. Sometimes unwanted effects appear only on

chronic treatment, as is the case for tardive dyskinesias produced by chronic

neuroleptic therapy of schizophrenia.

Acute administration of neuroleptic drugs causes blockade of cerebral dopamine

receptors, and this action is held to be responsible for their anti-psychotic properties.

Tardive dyskinesias, on the other hand, appear to be the result of over-stimulation of

cerebral dopamine mechanisms. The abnormal movements characteristic of tardive

dyskinesias (the bucco-linguo-rnasticatory syndrome) are intensified by dopamine

agonists and improved by dopamine antagonists; they resemble the type of

movements provoked by levodopa administered to patients with Parkinson's

disease . Tardive dyskinesias, apparently due to over-activity of cerebral dopamine

mechanisms, appear after months or years of treatment with neuroleptic drugs,

whose acute pharmacological effect is to block dopamine receptors. This paradox has

now been resolved by chronic pharmacological studies.

It has been discovered here that the behavioural and biochemical changes that

occur when neuroleptic drugs are given acutely are quite different from those that

take place when the drug is given chronically. Behavioural and biochemical evidence

of dopamine receptor blockade on acute administration disappears when neuroleptic drugs are given for months, to be replaced by the opposite effect namely

dopamine receptor super-sensitivity.

Methods

Male Wistar rats, housed under standard conditions of lighting and temperature,

received continuously in their drinking water either trifluoperazine hydrochloride,

thioridazine hydrochloride or cis-flupenthixol for up to a year. Subsequently drug

was withdrawn and animals were observed for a further six months. Age-rnatched

control animals, drinking distilled water only , were maintained alongside drugtreated animals.

CHRONIC ADMINISTRATION OF NEU ROLEPTIC DR UGS 155

At intervals during the period of drug administration (usually two weeks, one,

three, six and twelve months) the animals were subjected to a range of behavioural

test s and a representati ve sa m pie was sac rificed for biochemical assay.

Spontaneous behaviour was ob served, and stereotypy induced by apomorphine

(0.125-2 .0 mg kg-I s.c.) was assessed.

Concentrations of dopamine, homovanillic acid (DVA) and 3,4-dihydroxyphenyl

acetic acid (DOPAC) were determined in the striatum. The ac tivity of doparninesensitive adenylate cyclase, and binding of (3H]-spiperone in striatal homogenates

also were assayed. Details of the techniques employed are given in Clow, Jenner &

Marsden (1979) and Clow, Theodorou, Jenner & Marsden (l980a, b, c).

Results

The full results of these various experiments are available in Clow, Jenner,

Theodorou & Marsden (1979), Clow et al. (1979) , Clow et al. (1980a,b ,c).

The main conclusions will be summarised here. The initial catalepsy and

inhibition ofspontaneous locomotion produced by all drugs disappeared after about

three months and thereafter. Likewise, the initial inhibition of apomorphine-induced

stereotypy also disappeared by about three months, to be replaced by an enhanced

stereotypy response after six and twelve months drug intake. In particular, the high

intensit y components of sterotypy (gnawing and chewing) were markedl y increased

in Iong-terrn treated animals. Such animals also exhibited a greatly increased

incidence ofspontaneous mouth mo vements after twelve months drug intake. These

data demonstrated that initial dopamine receptor blockade by the neuroleptic drugs

was repl aced by an enhanced behavioural response of cerebral dopamine systems

while animals were still continuing to recei ve the drugs.

The neuroleptic drugs initially increased striatal HVA and DOPAC. However,

within a month metabolite levels had returned to control values.

The activity of dopamine-sensitive striatal adenylate cycla se initially was inhibited

by neuroleptic drugs, but within three months ofdrug administration enzyme activity

had returned to control values, and by six and twelve months dopamine actually

stimulated striatal adenylate cyclase excessively.

Neuroleptic administration initially decreased striatal dopamine receptor numbers

(Bmax) and affinity (increased Ko) probably due to the competing effect of drug in the

tissue homogenate analysed. However , Ko subsequently fell towards control levels

by six months, at wh ich time Bmax had increased. Thereafter Bmax continued to

increase further while Ko again increased. These changes in (3H]-spiperone binding

to striata l preparations indicate the de velopment of increased dopamine receptor

numbers with altered affinity in the course ofchronic treatment.

On drug withdrawal, the enhanced stereotyped response to apomorphine persisted

for a furt her month but then disappeared. The increase in dopamine receptor

numbers persisted for up to three months but then disappeared; dopamine receptor

affinity reverted to control levels within two weeks. The increased stimulation of

striatal adenylate by dopamine , however, remained enhanced for the full six months

period after drug withdrawal.

In other experiments awaiting publication, similar changes have been found to

occur in mesolimbic areas of the rat brain (nucleus accumbens and tuberculum

olfactorium) during chronic administration of trifluoperazine. These changes in

dopamine function appear to be specific, for no change could be detected in receptor

binding characteristics of muscarinic receptors identified by (3H]-dexetamide, HI

histamine receptors identified by [JH]-mepyramine, GABA receptors identified by

(3H]-muscimol, or a r-noradrenergic receptors identified by (3H]-WB 4101. Nor was

any increase found in the binding of (3H]-apomorphine to rat striatal homogenates,

although there are technical difficulties with this ligand in this species.

156 C. D. MARSDEN & P. JENNER

Discussion

The surprising conclusion from this work is that a drug having one action when given

acutely may have quite the opposite elTect when given chronically. The neuroleptic

drugs studied all blocked cerebral dopamine receptors on acute administration, but

after about six months chronic use they caused increasing dopamine receptor supersensitivity. This may weil explain the paradox of why tardive dyskinesias, which

appear with chronic drug treatment, have characteristics associated with dopaminergic over-activity. These fmdings also raise questions as to the mode of

therapeutic action of these drugs in schizophrenia. Their anti-schizophrenie

properties are conventionally attributed to dopamine receptor blockade, but here

evidence is provided that this property disappears with chronic use. It could be

argued, however, that provided a sufficient dose of drug is given during chronic

therapy it will still exert adequate dopamine receptor blockade despite the emergence

of increased dopamine receptor numbers. Dopamine receptor blockade by neuroleptic drugs is competitive, so in theory a large enough dose would maintain the

effect . It would be predicted, however, that either regular breakthrough of psychosis

should occur or the need for an increasing dose ofthe drugs should be apparent. Both

these c1inical points require careful scrutiny. Another possibility is that adequate

dopamine receptor blockade still persists in brain areas other than those that have

been studied. In particular, blockade of cerebral cortical dopamine receptors

conceivably might persist during chronic therapy despite the changes that have been

observed in mesolimbic and striatal dopamine receptors. These results, however, do

raise the possibility that the anti-schizophrenie properties of neuroleptic drugs may

be due to an action quite separate from that on dopamine mechanisms.

The results also raise questions concerning the interpretation of changes in

dopamine receptors discovered in the brains of patients with schizophrenia at post

mortem. The increase in dopamine receptor numbers in the schizophrenie brain may

weil be due to drugs rather than the disease. Indeed, the currently fashionable

dopamine hypothesis for schizophrenia requires some re-examination. This

hypothesis was based on the observation that all drugs known to control

schizophrenia were capable of blocking cerebral dopamine receptors. This

observation led to the suggestion that schizophrenia itself might be due to dopamine

over-activity in the brain. Now it has been found that neuroleptic drugs on chronic

administration lose the capacity to block dopamine receptors, and the most positive

piece ofevidence in favour ofthe dopamine hypothesis for schizophrenia, namely the

increased numbers of dopamine receptors found in the schizophrenie brain at post

mortem, may be due to the drugs themselves. In fact, the original basis for the

hypothesis was suspect. An exactly similar hypothesis could be made for acute

psychotic disturbance, whatever its cause. Thus, neuroleptic drugs are equally

effective in controlling the mental disturbance and behavioural disorders of acute

toxic confusional states and acute organic brain disease. Indeed, a dopamine

hypothesis for acute psychotic disorder is much more plausible than one restricted

solely to schizophrenia.

References

Clow, A., Jenner, P., Theodorou, A. & Marsden, C. D. (1979). Striatal dopamine receptors

become super-sensitive when rats are given trifluoperazine for six months. Nature, 278,

59--61.

Clow, A., Jenner, P. & Marsden, C. D. (1979). Changesin dopamine-mediated behaviour during

one year's neuroleptic administration. Eur. J. Pharmac., 57,365-375.

Clow, A., Theodorou, A., Jenner, P. & Marsden,C. D. (l980a). Changesin rat striatal dopamine

tumover and receptor activity during one year's neuroleptic administration. Eur. J.

Pharmac.,63, 135-144.

CHRON IC A DM IN ISTRA TI ON OF NEU ROLEPT IC DRUGS 157

Clow, A., Th eodor ou , A., Jenner, P. & Marsden . C. D. (I980b). Ce rebra l dopa mine function in

rats followi ng withdrawal from one year of co ntinuo us neu rolept ic administratio n. Eur. 1.

Pharm ac.. 63, 145-157.

Clow, A., T heodo ro u, A., Jenner, P. & Marsden . C. D. (I980c). A co mparison of striatal and

mesolimb ic dopam ine functio n in the rat duri ng six months tr ifluoperazine adrninistra tio n. Psychopharmac.. in press.

u-ADRENOCEPTORS AND THE

CLINICAL PHARMACOLOGY OF

CLONIDINE

S. Z. LANGER & R. MASSINGHAM

Department 01Biology, L.E.R.S..

58 rue de la Glaciere.

75013Paris.

France

There is now considerable evidence to support the view that two ditTerent sub types of

a-adrenoceptor exist (Langer, 1974, 1977). The al-adrenoceptor is preferentially

activated by phenylephrine and blocked by prazosin while aradrenoceptors are

preferentially activated by clonidine and blocked by yohimbine. The neurotransmitter, noradrenaline, is equally active on both ar and aI-adrenoceptors,

The al-type of adrenoceptor corresponds to the postsynaptic receptor in the

periphery and in the central nervous system. The artype of adrenoceptor

corresponds to the presynaptic inhibitor receptor that modulates noradrenergic

neurotransmission but it is also present in non-neural tissues like platelets, adipose

cells and smooth muscle (Langer, 1979, 1980), An analysis of the overall pharmacological etTects ofagonists or antagonists acting on a-adrenoceptors must take into

account the relative affmity ofthese drugs for a l as weil as a radrenoceptors,

Clonidine is an antihypertensive agent which is a preferential agonist at a 2-

adrenoceptors. Activation of both presynaptic as weil as postsynaptic

aradrenoceptors by clonidine is involved in the main therapeutic etTectsofthe drug:

antihypertensive and bradycardic. In addition, aradrenoceptors and possibly

histamine Hj-receptors might be involved in the side etTects observed during treatment with clonidine.

Role of central and periphcral a2-adrenoceptors in the

cardiovascular effects of clonidine

Stimulation of presynaptic inhibitory aradrenoceptors by clonidine reduces the

stimulation-evoked release ofnoradrenaline in the periphery as weil as in the central

nervous system (Langer & Luchelli-Fortis, 1977; Starke, 1977; Pelayo, Dubocovich &

Langer, 1980), Drugs that inhibit neuronal uptake of noradrenaline like cocaine or

desipramine antagonize the presynaptic etTects of clonidine and other imidazoline

derivatives on noradrenergic neurotransmission (Pelayo et al., 1980; Langer &

Dubocovich, 1980). Yet inhibition of neuronal uptake favours rather than reduces

the presynaptic inhibition mediated by a-adrenoceptor agonists of the

a -ADRENOCEPTORS AND CLO NIDINE 159

catecholamine-type (Langer & Dubocovich, 1980; Pelayo et al.. 1980). This reduction

by clonidine of noradrenergic neurotransmission might contribute to the overall

decrease in sympathetic tone produced by this drug. Such an effect can be cleariy

demonstrated in the heart, where the postsynaptic adrenoceptors that mediate the

physiological response to noradrenaline are of the ßI type. In the anaesthetized dog,

an injection of 2 ~g clonidine into the coronary sinus artery produces a negative

chronotropic effect without affecting systemic blood pressure. Under these

conditions, a small dose of phentolamine (50 ~g) also injected intra-arterially into the

coronary sinus fully reverses the bradycardic effect of clonidine without modifying

mean arterial pressure (Cavero & Roach, 1980; Langer, Cavero & Massingham,

1980).