Extrapyramidal disorders: A possible underlying mechanism

Bruin Research Bulldn,

Vo!. 11, pp. 233-241, 1983.@Ankho InternationalInc. Printedin the U.S.A.

Extrapyramidal Disorders: A Possible Underlying Mechanism F. S. MESSIHA

Division of Toxicology, Department of Pathology And Psychopharmacology Laboratory, Department of Psychiatry Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX 79430

MESSIHA, F. S. Extrapyramidal disorders: A possible underlying mechanism. BRAIN RES BULL ll(2) 233-241, 1983.--In viva and in vitro studies have been presented to suggest an interrelationship between drugs used in the management of, or known for their induction of, extrapyramidal disorder and certain dehydrogenase enzymes involved in ths metabolic pathway of the biogenic amines. This relationship is discussed to advance a tentative hypothesis explaining a possible underlying mechanism and to provide an explanation for the implication of alcohol consumption in worsening of extrapyramidal symptoms during certain pharmacotherapy. The major neutral metabolites of the biogenic amines acted as substrate to or induced rat liver alcohol dehydrogenase (L-ADH) and drugs used in the management of tardive dyskinesia similarly induced L-ADH. This induction of L-ADH could enhance the metabolic biotransformation of the neutral metabolites of the monoamines. Conversely, drugs known to evoke extrapyramidal dyskinesias inhibited rat liver aldehyde dehydrogenase (L-ALDH). This inhibition of ALDH may give rise to toxic condensation products between biogenic amine aldehydes and their precursors which may be implicated in certain dyskinesias. It is proposed that one of the mechanisms underlying the biogenic amine involvement in the pathogenesis of certain extrapyramidal diseases may include a critical balance between their reductive and oxidative routes of metabolism. Akinesia Drugs

Alcohol Dyskinesias

Alcohol dehydrogenase

Aldehyde dehydrogenase

RECENT advances in pharmacotherapy of extrapyramidal disorders, both idiopathic and drug-induced, suggest the involvement of cholinergic, monoaminergic mechanisms and/or their interrelationships in the underlying pathology. For example, the finding of a striatal dopamine deficiency in Parkinson’s disease [I81 prompted Ldopa therapy, the dopamine precursor [ 111, and the postulated predominance of choline+ over dopaminergic systems has tentatively explained the clinical efficacy of anticholinergics in various akinetic states. Conversely; cholinergic agonists and dopaminergic antagonists have been used in the management of certain movement disorders thought to be associated with dopaminergic hyperactivity and/or dopaminergic receptor supersensitivity, e.g., choreatic states, tardive dyskinesia, drug-withdrawal, tremor, and drug-induced dyskinesias. Noteworthy, akinetic and dyskinetic movement disorders are managed by and could be in some instances induced by drugs acting on certain biogenic amines and both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) catalyze the respective reductive and oxidative biotransformation routes of monoamine-derived aldehydes (see Fig. 1). The present study evaluates this interrelationship by studying the in vivo and in vitro effects of some of the drugs involved in extrapyramidal diseases and of certain biogenic amine metabolites on hepatic ADH and ALDH in the rat.

Biogenic amines

Chorea

Farm, Inc., and mice were obtained from Sprague-Dawley Company, Madison, WI. They were provided with Purina pellet food and water ad lib. Animals were housed in a room with alternating 12 hr light and 12 hr complete darkness throughout the experiments. In the initial set of experiments, the effect of some biogenic amines and their major metabolites on hepatic ADH and ALDH were studied in vivo in the rat. Compounds tested were; Ldopa methylester (L-dopa), 5hydroxytryptamine (5HT), do&e (DA), 3-0-methyldopa (MD), 3-methoxytyramine (3MT), metanephrine (M), normetanephrine (NM), 3-methoxy&hydroxyphenylethanol 3-methoxy,4-hydroxyphenylglycol (MHPG), (MOPET), 5hydroxytryptophol (SHTOH), vanillyhnandelic acid (VMA), homovanillic acid (HVA), S-hydroxyindole acetic acid (SHIAA), 3,4,dihydroxyphenyllactic acid (PL) and its pyruvic derivative (PP). Agents were dissolved in saline and injected intraperitoneally (IP) once daily for seven consecutive days and the controls received saline. Animals were killed by decapitation 16 hr post terminal drug treatment. In separate sets of experiments, haloperidol (HAL) was given 10 mgikg, IP, once daily for eight consecutive days. Reserpine or tetrabenazine were injected daily 3 mg/kg, IP, for eight days. The animals were decapitated approximately 1 hr post terminal injection and the controls received the vehicle at identical time intervals. In separate sets of experiments, the effect of short-term treatment with some antiparkinsonian agents and certain

METHOD

Adult male and fernal;: rats were purchased from Holtzman

233

234

lLIb1SSIHA

DOPA------+

DOPAMINE -

NOREPINEPHRINE ------+

EPINEP~RINE

DOPA -

DOFAMINE _____+

NOREFIMEMRHJE

EPlNEPHRtNE

___+

SEROTONIN

FIG. 1. Overview of the major metabolic pathway of the catecholamines with reference to pathways catalyzed by akohof dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The abbreviations used are as follows: Monoamine oxidase (MAO), catechol O-methyl transferase (COMT), dihydroxyp~nyIet~o1 (DOPET) and its O-methylated derivative (MOPET), dehydroxyphenyIace~c acid (DOPAC) and its co~es~n~~ 0-methylated analogue (3-MT), homov~~lic acid (HVA), vani~yim~deiic acid (VMA), dihydroxym~a~ic acid (DOMA). dihyd~xyphenyi~ycol (DOPEG) and its 0-methytated anaiogue (MHPG), S-hydroxytryptophol (SHTOH) and 5-hydroxyindole acetic acid (5-HIAA).

drugs used in clinical trials of tardive dyskinesia were tested on hepatic ADH and ALDH in the adult rat. Drugs were dissolved in saline or in the vehicle and injected IP. The daily dosages were as follows: amantadine HCI (100 mg/kg), apomorphine (3 mg/kg), benzotropine mesylate (0.02 mg/kg), t~exphenidy1 (0.10 mglkg) and diazepam (5 n&kg). They were given once daily for seven consecutive days. Choline chloride (100 mg/kg) and cyclobenzaprine NC1 (50 mgikg) were injected once daily for eight and five days, respectively. Estradiol (0.3 mg/kg) was injected once. Animals were killed by decapitation 16 l-u post terminal injection. The controls received the vehicle IP for same duration of time. In further experiments the effect of short-term oral administration of clozapine and ethynylestradio1 were tested its a function of sex in two species. An oral daily dosage of 50 mg/kg of clozapine or 0.1 mg/kg of ethynylestradiol was given to groups of mice and rats of both sexes, respectively. Clozapine was dissolved in distilled water and ethynylestradbl was administered in olive oil. Animals were decapitated 16 hr after final dose delivery. Experiments in vitro tested the effect of &-amphetamine sulfate, aminophylline, iproniazide and triazide on L-ADH and L-ALDH in adult rats both sexes. Drugs were added to the reaction mixture at 10e3 M concentration. Determination of vln, and the apparent K, were made according to the Lineweaver-Burk method [26]. In separate sets of experiments the in vitro effect of some alcoholic (neutral) metabolites of the biogenic amines, i.e., MOPET, MHPG and JHTOH, on rat hepatic ADH and

of

ALDH were tested and compared to that of ET and acetaldehyde as substrates. Cellular fraction was performed to obtain the mitochondrill and the cytoplasmic fractions of the rat liver preparations [38]. The results were expressed as means-+SE of the mean of specific activity, ~MoIiminfmg protein, measured at 3W by established analytical procedures [3,4] and were analyzed for statistical significance by two tailed Student’s f-tests far independent means. RESULTS

Table 1 shows the effect of short-term admi~stration of equimolar dosage (0.5 Molikg, IP) of L-dopa, S-HT and some of their major acidic and neutral metabolites, given once daily for seven consecutive days, on endogenous rat L-ADH and L-ALDH. Little changes occurred in specific activities of both enzymes in rats treated with the monoamines or with their 0-methylated derivatives from saline controls. There was an increase in L-ADH to 17.921.9, ~~o~~~rng protein, from 12.222.0 units of control by the SHTOH treatment @
A HYPOTHESIS

235

TABLE 1 EFFECTS OF SHORT-TERM ADMINISTRATION

OF SOME BIOGENIC AMINES AND THEIR MAJORMRTAROLITRSON RAT LIVER CYTOSOLICALCOHOL(L-ADH) AND ALDEHYDE-DEHYDROGENASE

(L-ALDIll

(nMol/min/mg protein) Compound

tn)

L-ADH

L-ALDH

Precursors

saline-control Ldopa 3-O-methyldopa 5hydroxytryptamine

(6) (6) (6) (6)

12.0 -+ 2,5 12.7 k 1.2 12.8 1.1 13.6 2 0.4

4.9 f 0.7 3.9 + 0.5 3.7 0.5 4.5 2 0.3

Monoamine

saline-control dopamine

(6) (6)

12.1 + 1.9 13.5 It 0.4

5.1 2 0.7 5.0 f 0.3

Monoamines (O-methylated)

saline-control 3-Metoxytyramine Metanephrine Normetanephrine

(9) (8) (7) (7)

18.4 2 3.2 17.8 1.2 20.5 f 2.7 18.4 + 2.6

6.1 f I.1 5.4 1.0 7.3 + 1.5t 6.1 k 0.8

Neutral Metabolites

saline-control 3-methoxy 4, hydroxyphenylethanol 3-methoxy 4, hydroxyphenyl-glycol 5hydroxytryptophol

(5) (5)

12.2 f 2.0 12.3 2 2.3

3.9 r 1.0 2.9 2 0.7t

(6)

9.8 2 0.8

3.1 2 0.4

(5)

17.9 r I.98

5.6 f 0.3$

saline-control Vanillylmandelic acid Homovanilic acid 5Hydroxyindol acetic acid

(8) (8) (4) (5)

14.6 17.7 16.2 4.0

4.9 3.5 4.6 5.0

saline-control 3,4 Dihydroxyphenyllactic acid Dihydroxyphenylpyruvic acid

(5) (5)

12.7 f 0.7 9.1 2 0.9*

4.7 2 0.4 5.1 k 0.4

(5)

14.8 +- 1.3

3.8 ” 0.3t

Classification

Acidic Metabolites (Major)

Acidic Metabolites (Minor)

+ f + +

0.5 0.9 1.1 0.4

k 2 + f

0.7 0.2t

0.3 0.5

Equimolar concentration of the compounds listed were injected IP once daily (0.5 Movkg) for 7 consecutive days and the animals were sacrificed 16 hr after the. terminal treatment. The controls received the vehicle, physiological saline. Seventy to 90 day old Sprafpte Dawley male rats were used. Values am for means f SE of the mean of enzymatic specific activity (nMoUmin/mg protein) for the number of animals @en between parenthesis accounting for a total of I28 rats. *p
Table 2 lists specific activity of L-ADH and L-ALDH as a function of treatment with drugs known to evoke adverse extrapyramidal reaction. Administration of HAL, 10 mg/kg, IP, once daily for eight consecutive days decreased endogenous L-ALDH to 22.0225, ~@ol/min/mg protein, from mean control value of 28.5k2.3 units. However, this decrease was not statistically significant (pCO.1). Conversely, the HAL-treatment produced an induction of endogenous L-ADH from respective controls (pCO.05). Similarly, reserpine treatment enhanced mean control specific activity of L-ADH from 17.321.4 units to 22.621.6 units (~~0.01). Tetrabenazine-treated rats did not show changes in hepatic enzymes measured compared to controls. Table 3 lists specific activities of rat hepatic ADH and ALDH as a function of short-term injection of some of the antiparkinsonian drugs and of other drugs utilized in clinical management of tardive dyskinesia. There was a 13.6% (~~0.1) and a 37.4% (pcO.02) enhancement in endogenous L-ADH from controls by the anticholinergics acting benzo-

n-opine mesylate and trihexphenidyl, respectively. Conversely, the cholmergic agent, i.e., choline chloride, inhibited rat L-ADH by approximately 28% Q~0.05) compa& to controls. Hepatic L-ALDH was markedly enhanced by the choline chloride treatment (pcO.02). Single injection of estradiol moderately decreased specific activity of L-ALDH by 16% from controls which was not statistically signifIIant @CO.1). Table 4 shows the effect of short-term adminsitration of clozapine and ethynylestradiol, a synthetic estrogen, on hepatic ADH and ALDH as a function of sex in mice and rats, respectively. Cloxapine intake induced L-ADH in viva by approximately 16% f.r~O.05) of male but not of female mice from corresponding controls. This is compemd to ap proximately 23% (~~0.01) enhancement in L-ALDH of the female but not of the male rat by the estrogen treatment. Table 5 shows the in virro effect of CNS-stimulants and some enzymatic inhibitor of rat liver ADH and ALDH as a function of sex. Iproniaxide, a MAO inhibitor, increased

TABLE2 THE li\i VIVU EFFECT OF DRUGS WHICH CAN INDUCE EXTRAPYRAMIDAL ADVERSE REACTIONS ALCOHOL DEHYDROGENASE (L-ADH) AND MITOCHONDRIAL ALDEHYDE DEHYDROGENASE

~nMo]e~min~rn~protern I

Treatment Drug

Classification

Haloperidol

Reserpine Tetrabenazine

Antipsychotic drug

Monoamine depletors

ON RA I- LlVtK CL-ALDH)

Daily Dosage fmgikg)

Duration (days)

(n)

Vehtcle

8

(6)

1742

IO

8

(6)

21.2 f 1.0..

21.0 f 7.5;

Saline 3 3

8 8 8

(6) (6) (61

17.3 :t 1.4 22.6 i I h-’ 18.2 T 2 9

29.0 -~ 2.3 27 I .- 2 6 3l.Y L 0.4

I.-ADH

l--A LDH 28.5 + 7.3

I4

Adult male rats, 60 to 80 day old, were used. Drugs were dissolved in saline and injected intraperitoneaIly for the duration of time indicated. They were sacrificed one hr after the terminal injection. Values are means t SE of the mean of the number of determination given between parenthesis, *~<0.05; tp
TABLE

3

EFFECTS OF SHORT-TERM ADMINISTRATION OF SOME OFTHE DRUGS USED IN THE MANAGEMENT OF PARKINSON‘S DISEASE AND OF TARDIVE DYSKINESIA ON MALE RAT LIVER ALCOHOL DEHYDROGENASE (L-ADH) AND MITOCHONDRIAL ALDEHYDE DEHYDROGENASE (L-ALDH)

Treatment Drug

Property

Saline Amantadine HCI Apomo~hine Benzotropine

mesylate

Vehicle Estradtol

inMol/minlmg protein) Duration (days)

(n)

L-ADH

L-ALDH

16) (6)

14.7 2 i.0 14.3 i 0.7

19.0 c I.9 18.0 i: I .6

(5)

20.2 t

1.9i

20.0 rt 1.0

17.4 + 1.3

38.5 _t 2.3

s

(6) (6) (8) (5)

12.6 t 1.6” 17.0 t 1.1 17 2 t 1.9

36.3 2 1.6’1 27.3 t 1.0 18.0 r I.2

0.3

(6) (6)

16.4 ‘t I.5 17.7 t 0.9

76.X -t 4.3 71.02 73;

7

Antiparkinsonian~ dopamine agonist Antiparkinsonlan~ anticholinergtc drugs

Trihexyphenidyl Saline Choline chloride Cyclobenzaprine Diazepam

Dally Dosage rmg/kg)

100

7

3 0.02

0. IO

Chohnergic Muscle relaxants

Estrogen

100 50

7 7

Drugs were dissolved in saline with exception of estradiol which was dissolved in organic solvent and the latter evaporated in water bath over olive oil. They were injected intraperitoneally in the daily dosage and for the duration of time indicated. A total of 70 rats. aged 80 to 100 days old, were used. Values are means -c SE of the mean of enzymatic specific activity for the number of determination given between parenthesis. *pP
A HYPOTHESIS

231

TABLE 4 IN VfVO MODULATION OF

HBPA’MCALCOHOL AND ALDEHYDE-DEHYDROCENASES BY CLOZAPINE AND ETHYNYL~ ESTRADIOL AS A P-UNCTIONOF SEX IN RODENTS Treatment (nMol/min/mg protein)

Duration (days)

Sex

Daily Dosage (mgkg)

Mouse

Male Male Female Female

Vehicle 50 Vehicle 50

(7) 17) (9) (8)

12.8 14.9 18.2 17.1

i 0.5 r 0.7* 2 0.6 3t 1.0

12.4 11.3 13.1 14.6

it + rt c

Rat

Male Male Female Female

Vehicle 0.10 Vehicle 0.10

(7) (9) (7) (9)

13.8 15.2 20.1 22.1

+ i * It

19.8 17.3 31.2 24.3

-c 2.1 +: 0.9 t 1.1 t 1.2t

Drug

Species

Clozapine

Ethynylestradiol

(n)

L-ALDH

L-ADH

1.5 0.9 0.7 1.7

1.4 1.0 0.7 0.8

The male and female Sprague Dawley mice and rats used were 8 weeks and 70 days old at the beginning of the experiments, respectively. Drugs were given per OS (PO). Values are specific activities derived from number of animals given between parenthesis. *p
TABLE 5 THE IN VfTffO EFFECT

OF SOME ENZYMATIC INHIBlTORS AND CNS-STIMULANTS ON RAT HEPATK ALCOHOL (L-ADPI) AND ALDEHYDE-DEHYDROGENASE (L-ALDW)AS A FUNCTION OF SEX (nMol/min/mg protein)

Compound

Property

Iproniazide

MAO-inhibitor

Triazole

S-Amphetamine

Aminophylline

Catalase inhibitor

SO,

CNS-stimulant

CNS-stimulant

Cont. (Mel)

Sex

(n)

10-a M 10-s

Female

(5). (5) (5) (5)

13.6 16.8 8.5 9.1

+ 1.5 ” 0.5t r?r:1.4 f. 1.6

14.7 17.5 14.5 18.2

f r k +

1.9 2.0 3.1 3.2

19.0 29.6 17.3 31.4

rt t 2 rt

1.1 1.18 1.2 0.7ll

lo+ M 1O-s M

Female

(4) (4) (5) (5)

15.9 12.1 7.9 7.7

1: 1.7 f 0.9t +: 1.6 -t 1.1

14.9 12.8 15.6 15.7

t r + *

2.1 0.6 2.1 2.2

20.9 21.7 18.0 24.5

+ t -t +

1.8 0.8 1.3 1.9

10-3 10-3

Female

(6) 16) (5) (5)

13.6 9.4 8.5 4.0

+: 1.5 rt 1.0* k 1.1 2 0.6$

16.2 16.4 14.5 19.2

+ t c it

1.4 1.1 3.1 3.3

20.9 35.4 18.7 32.7

t + rt J-

1.8 2.08 1.0 l.SB

10-s IO”

Female

(6 (6) (4) (4)

16.2 11.4 10.0 6.4

z!z0.7 rt 0.3§ rt 2.5 tt I.4

14.5 14.9 10.2 10.3

-c r t f.

1.2 1.2 0.8 1.0

19.0 32.8 17.2 27.5

-t- 1.1 rt 2.99 r 1.6 r?: 2.01

Male

Mate

Male

Male

L-ADH

L-C-ALDH

L-hi-ALDH

Values represents the means + SE of the mean of specific activities (nMol/min/mg protein) of alcohol-(L-ADH) and aldehydedehydrogenase measured in the cytoplasmic (L-C-ALDH) and mitochondrial (L-M-ALDH) fractions of rat liver preparations for the number of determinations given between parenthesis; Animals were 70 to 90 days old. The enzymatic activity assayed in the absence of the drug fcontrol) is compared with that obtained in the presence of ImNol of the drugs listed. *p
FEMALE

MALE

DRUG CONC 1 Mel)

FIG. 2. The in vitro dose response effect of &hetamine (AMP), aminophylline (APL) and iproniazide (IPR) on specific activity of rat liver mitochondrial aldehyde dehydrogenase (L-MT-ALDH) as a function of sex. Values of L-MT-ALDH were obtained in the absence (control) or in the presence of drugs in the concentration range between 1 mMo1and 0.1 mMol. Each point represents mean + SE of specific activity of L-MT-ALDH, qMol/min/mg protein, for 6 to 8 independent determinations.****p
FIG. 3. The in tvtro double reciprocal plots of the velocity of rat hver mitochondrial aldehyde dehydrogenase (L-MT-ALDL-I)reaction as a function of acetaidehyde concentration in the absence (control) and in the presence of 1 mMol of a-amphetamine (AMP), aminophylline (APL) or triazol (TRZ). Adult male rats were used for the mitochondrial preparation. Each point represents the mean&SE of 4

specific activity of mitochondrial L-ALDH from corresponding controls by approximately 56% (p
The type of inhibition produced by concentration. &hetamine, aminophylline and triazole was noncompetitive. The V,,, determined for &hetamine was less than that of aminophylline or triazole compared to the control. The smallest apparent K, was obtained ht the presence of aminophylline, followed by that of d-amphetamine, and that of triazole. Figure 4 shows the utilization of various neutral metabolites of the biogenic amines as substrates compared to ethanol. Equimolar concentration ( 10e3 M) was added in vitro to the reaction mixture for the L-ADH assay. A reaction mixture including all reaction ingredients but excluding the substrate was used as a blank. Values are expressed as specific activity, i.e., nMo1 of amounts required for the conversion of one Mol NAD to NADH using rat liver cytoplasmic preparation. The use of ethanol as a substrate resulted in 14.3?2.0,~Mol/min/mg protein, compared to 14.42 1.7 and 2.5kO.4 units when MOET or MHPG were used as the substrate, respectively. The use of SHTOH resulted in only 0.15+0.08 units. The lower panel of Fig. 4 shows the dose response for MOET showing a linear increase in the velocity of the enzymatic reaction in the concentration range between lo+ M and 3x 10e4 M.

to 6 independent assays.

DISCUSSION

The present results show that certain major neutral metabolites of the biogenic amines possess varied degrees of substrate specificity towards a hepatic N~AD-dependent cytoplasmic dehydrogenase enzyme which may be identifiable with ethanol metabolizing enzymes, i.e., ADH. This is demonstrated by the simiiar rate of in vitro substrate utilization of MOPET as compared to ethanol and by the in viva induction of endogenous L-ADH by 5-HTOH, the major neutral metabolites of dopamine and serotonin, respectively.

A HYPOTHESIS The in vitro data indicate the nonspecificity of the enzymes measured, i.e., modulation of L-ADH and ALDH by the MAO and catalase inhibitors used. The latter enzyme has been implicated in the pathogenesis of Parkinson’s disease due to the decrease of catalase activity found in substantia nigra and putamen of the parkinsonian brain which may result in decreased HnOZ metabolism and in a subsequent reduction of melanin synthesis 111. The modulation of L-ADH and L-ALDH by various drugs affecting motor function tested suggests a relationship between these enzymes and certain extrapyramidal disorders of movement. For example, short-term treatment with haloperidol or chlorpromazine [43], which are known to evoke extrapyramidal adverse reactions, inhibited rat L-ALDH. This inhibition may yield endogenous toxin(s), i.e., the reactive biogenic amine aldehydes and related derivatives 168, 10, 12, 13,22,23,54]. These may accumulate in cases where Ldopa is given alone [10,50,51] or combined with peripheral decarboxylase inhibitors which also inhibit L-ALDH in vitro [9] and in vivo [32,33]. These inhibitors can divert Ldopa metabolism towards the transmination route [37] resulting in the formation of the pyruvic acid derivative which has been shown in this study to inhibit L-ALDH. Consequently, these metabolic events may lead to a prolonged and profound inhibition of L-ALDH and thus enhance the formation of and the accumulation of certain condensation products between the unreacted monoamine precursor(s) and the respective aldehyde metabolite, e.g., tetrahydropapaverolines and /3carbolines’[6, 10, 13, 231, of which the latter has been shown to inhibit L-ALDH in vivo [36,39]. These endogenous products may conceivably contribute to some of the toxic manifestations of L-dopa therapy and/or of the neuroleptic medications, particularly these related to dyskinetic states. Conversely, drugs used in the management of tardive dyskinesia, i.e., reserpine, clozapine, or Li-salts [42], were found in this study to be primarily associated with induction of rat L-ADH with some, i.e., choline or LiCl [42], being an inducer of L-ALDH. The induction of L-ADH by drugs used in the management of dyskinetic symptoms may enhance the metabolism of and the elimination rate of the biologically active neutral metabolites of the biogenic amines, which can penetrate the brain. This suggests that metabolic removal of these metabolites may be of critical value in alleviating certain dyskinetic movement disorders. Moreover, some of these drugs may decrease the formation of toxic condensation products of the biogenic amine aldehydes mentioned earlier due to their induction of L-ALDH. The enzymes measured in the present study are primarily known for their sequential metabolism of ethyl alcohol and its toxic metabolite acetaldehyde in addition to their various roles in alcoholism. There may be a low incidence of alcoholism [ 17,481 or a lack of it [24,25] in certain extrapyramidal disorders as in Parkinson’s disease. However, 16% of 125 patients surveyed in one study 1251 experienced subjective effects of alcohol on the parkinsonian symptoms and transient parkinsonism has been reported during alcohol withdrawal and during chronic severe alcohol intoxication [5]. Moreover, alcohol consumption has been shown to induce various extrapyramidal reactions as choreiform dyskinesia [20]; tremor 1441and Gilles de la Tourette syndrome 1521 in addition to alcohol evoked extrapyramidal neurological symptoms, i.e., akathisia and dystonia in patients on neuroleptic medications [2, 21, 281. These findings have suggested an interrelationship between ethanol and certain

239

FIG. 4. Comparison of substrate utilization between major neutral metabolites of the catecholamines and ethanol by rat cytoplasmic NADdependent preparation. The upper panel shows enzymatic specific activity using equal mM concentration of ethanol (ETOH), 3-methoxy, 4-hydroxypheny1ethanol (MOPET), 3-methoxy,khydroxyphenylglycol (MHPG) or tryptophol 6HTOH) as a substrate. Each bargraph represents the meau+SE ofthe mean of specific activity of the number of independent assays given between parentheses. The lower panel shows dose response of MOPET as a substrate. The data are expressed as mean_cSE of the mean of 8 to 9 independent assays of specific activity plotted against semi-lag molar concentration of MOPET.

biogenic amines. However, a common locus of action could not only reside in an interrelationship between nigrostriatal dopaminergic system and ethanol but may also include the enzymes responsible for the detoxification of ethanol and acetaldehyde which are involved in the oxidative and reductive pathways of biogenic amine-derived aldehydes (Fig. 1). Moreover, the diversion of the biogenic amines metabolism from the predominant oxidative to the reductive pathway 114,151 by alcohol consumption and the modulation of the enzymes, i.e., ADH and ALDH, controlling this reaction by the drugs studied suggest an interrelationship between alcohol evoked neurological manifestation on extrapyramidal function, biogenic amine related products, ADH and/or ALDH. It is likely that some of the monoamine metabolites may be associated with movement disorders [45] and they could also compete with ethanol as substrates for L-ADH which may trigger toxic manifestations in the presence of alcohol

1411. This suggests that alcohol consumption should be contraindicated in patients with extrapyramidal diseases particufarly those undergoing pharmacotherapy. Caution should be exercised when certain psychoactive drugs as &hetamine, which evokes stereotyped behavior and precipitates various extrapyramidal choriform symptoms [29.49] even during abstinence [27], are administered concomitant with alcohol consumption because inhibition of L-ADH will give rise to higher blood ethanol concentration and intoxication may occur. Likewise, oral contraceptiveinduced chorea [19, 46, 531 may be further accentuated by alcohol intake due to inhibition of L-ALDH and the build-up of acetaldehyde by the estrogen component [35,4OJ of the oral contraceptive medication

The present correlative observations between inhibition of L-ALDH and the development of certain dyskinetic states as contrasted with induction of L-ADH by certain drugs used in their management may be fortuitous. Nonetheless, it provides indirect experimental evidence for the importance of the metabolic pathway involved. It is likely that certain changes in peripheral biogenic amine levels 13l] which may resemble these occurring centrally during extrapyramidal manifestation [30,443 may be enzymatically related. Accordingly, a detailed evaluation of brain ADH and ALDH should be undertaken, at least in animal model for experimentallyinduced extrapyramidal dysfunction, e.g.. in primates [ 16, 30, 471. Conceivably, derangements in biogenic amines may be secondary to altered enzymatic activity

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