Mode of Action of Psychomotor Stimulant Drugs

MODE OF ACTION OF PSYCHOMOTOR STIMULANT DRUGS By Jacques M. van Rossum Department of Pharmacology, Catholic University, Nijmegen, The Netherlands

I. Psychomotor Stimulant Drugs . . . . . . . . A. History of Central Stimulant Drugs . . . . . . B. Survey of Psychomotor Stimulant Drugs and Anorectic Agents C. Chemical Structure and Psychomotor Stimulant Action . D. Absolute Configuration and Psychomotor Stimulation . . 11. Effects of Psychomotor Stimulant Drugs in Man . . . . A. Effects of Amphetamines in Therapeutic Doses . . . B. Toxic Effects of Psychomotor Stimulants in Man . . . C . Addiction to Psychomotor Stimulant Drugs . . . . D. Amphetamine Psychosis Induced by Psychomotor Stimulant . . . . . . . . . . . . Drugs 111. Effects of Psychomotor Stimulant Drugs in Animals . . . A. Locomotor Stimulant Effects . . . . . . . B. Psychomotor Stimulants on Operant Behavior . . . . C. Psychomotor Stimulants on Self-Stimulation . . . . D. Stereotyped Behavior through Psychomotor Stimulants . . E. Action of Psychomotor Stimulant Drugs on Social Behavior . IV. Kinetics of Absorption, Distribution, and Elimination of Amphetamines . . . . . . . . . . . A. Physicochemical Properties of Amphetamines . . . . B. Kinetics of Absorption of Amphetamines . . . . . C. Kinetics of Distribution of Amphetamines . . . . D. Kinetics of Metabolism of Amphetamines . . . . . E. Kinetics of Elimination of Amphetamines . . . . V. Antagonism of Amphetamine Action and Interaction with Other . . . . . . . . . . . . Drugs . A. Antagonism with Neuroleptics . . . . . . . B. Amphetamine Action in Reserpinized Animals . . . . C. Interaction of Monoamine Oxidase Inhibitors with Amphet. . . . . . . . . . . . amines D. Interaction of Thymoleptics with Amphetamines . . . E. Interaction of Amphetamines with Sympatholytic Drugs . F. Interaction of Amphetamines with Cholinolytic and Other . . . . . . . . . . . Drugs VI. Psychomotor Stimulant Action and Brain Catecholamines . . A. Effects of Amphetamine on Brain Monoamines . . . B. Inhibition of Synthesis of Catecholamines and Psychomotor . . . . . . . . . Stimulant Action . C. Inhibition of Synthesis of Noradrenaline and Psychomotor Stimulant Action . . . . . . . . . . 307

.

309 309 310 312 319 323 323 324 3% 325 327 327 329 331 334 335 337 337 339 341 343 346 347 348 351 353 354 355 355 356 356 357 360

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JACQUES M. VAN ROSSUM

D. Inhibition of Synthesis of Brain Serotonin and Psychomotor . . . . . . . . . Stimulant Action . VII. Mechanism of Action of Psychomotor Stimulant Drugs . . . A. Significance of Brain Noradrenaline Receptors . . . B. Significance of Brain Dopamine Receptors . . . . C. The Midbrain Reticular Foxmation and Psychomotor Stimulant . . . . . . . . . . . . Action D. The Neostriatum and Psychomotor Stimulant Action . . References . . . . . . . . . . . .

360 361 361 365

369 370 373

Amphetamine or “Weckaminen” and a number of related drugs are classified as psychomotor stimulant drugs. Alertness, suppression of fatigue and sleepiness, stimulation of motor activity, and other symptoms of central excitation are a characteristic effect of the psychomotor stimulant drugs. The various members of this category in varying degrees have side effects in the peripheral and central nervous system (Welsh, 1962; Kalant, 1966). In the peripheral nervous system, the sympathomimetic effects of amphetamine and the local anesthetic effects of cocaine occur; in the central nervous system, the anorectic effects of amphepramon and phentermine predominate (Welsh, 1962). The amphetamines have little therapeutic value with regard to their central excitatory effects, but they are frequently used as appetite suppressants (Welsh, 1962; Editorial, 1968). Abuse of amphetamine and related drugs is widespread both as agents to increase performance and endurance in sport events (doping) and to induce excessive stimulation and euphoria in addicts (“Speed,” etc.), Kalant, 1966; Connell, 1958). The toxic effects of the amphetamines with respect to the sympathomimetic and central stimulant actions are severe. Cardiovascular collapse and drug-induced psychosis are often seen after chronic abuse of amphetamines ( Connell, 1958; Kalant, 1966). Amphetamine and related drugs have been used in many experimental pharmacological and neuropharmacological studies. AS a consequence an immense amount of data on these stimulants is now available and certain aspects of the mechanism of actnon have been elucidated. Evidence is available that the amphetamines act at neurons where catecholamines are transmitter substances. Braindopamine in particular appears to have a predominant role in psychomotor stimulant action.

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

309

I. Psychomotor Stimulant Drugs

Dexamphetamine is the prototype of the category of psychomotor stimulant drugs. The pharmacology, the clinical application, and the toxic effects have been described in a number of monographs (Leake, 1958; Bett et al., 1955; Bonhoff and Lewrenz, 1954; Welsh, 1962; Kalant, 1966; Connell, 1958). A. HISTORY OF CENTRAL STIMULANTDRUGS Throughout the history of mankind, stimulants of plant origin have been used. Interesting surveys with many references are found in monographs by von Bibra ( 1855), Hartwich (1911), and Lewin ( 1927). The old Chinese herb Ma Huang (Ephedra vulgaris) has certain central stimulating properties. The active principle is the sympathomimetic drug levoephedrine, which has central stimulating properties and is now mainly used for the treatment of asthma and nasal congestion (Table I ) (Chen and Schmidt, 1924). The old Inca drug coca (Eythroxylon coca) is still used by the Indians living in the mountains of Peru (indos serranos), but the inhabitants at sea level seem to use this stimulant less. The Aymaras people who speak the Quecha language chew the leaves of the coca plant and thereby gain body strength and postpone fatigue and sleepiness (Hartwich, 1911; Mortimer and Golden, 1902; Lewin, 1927). The main alkaloid of the coca plant is ( - )-cocaine which has all the characteristics of a psychomotor stimulant ( Molina, 1946; Gutierrez-Noriega and Zapata-Ortiz, 1947). QAt, Cat, or Kafta, as it is variously called, are the fresh leaves and young shoots of the West African plant Catha edulis, grown in the highlands of Ethiopia (Hartwich, 1911; Beitter, 1901). The use of QAt provides strength to the people while it prevents the development of fatigue and hunger (Lewin, 1927; Beitter, 1901). The active principle of Catha is the alkaloid cathine or norpseudoephedrine (see Table I). Catha does contain other amines, but cathine alone is responsible for its psychomotor stimulant effects (Alles et al., 1961). Although deoxyephedrine, now known as methamphetamine and Pervitin, was synthesized early in this century, it was only after the discovery of amphetamine that the central stimulant properties became generally known. Amines of simple chemical structure were

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JACQUES M. VAN ROSSUM

TABLE I STRUCTURES OF PSYCHOMOTOR STIMULANT ALHALO~DS

b'

ephedrine I-I,lR;ZS

mNH2 qHflN-c cocaine

-1 2R;3S

?H

\

4:

C'

OH

b

hyoscyamine 3a;l'S

CH3

nor pseudo ephedrine I+) Cathine 1s; 2 s

m3NH amphetamine (+I 2s

synthesized ( Alles, 1927), and amphetamine appeared to exert predominant sympathomimetic and central stimulant effects ( Haley, 1947). During World War 11, amphetamine and Pervitin were used extensively by army troups as energy tablets to combat fatigue and sleepiness and to improve endurance (Bett et a?., 1955; Bonhoff and Lewrenz, 1954; Hauschild, 1939). The structure of amphetamine is related to that of cathine and ephedrine; cocaine contains a piperidine base, but it is not related stereochemically to atropine or hyoscyamine ( see Table I ) .

B. SURVEY OF PSYCHOMOTOR STIMULANT DRUGS AND ANORECTIC AGENTS The amphetamines now available are of a variety of chemical

structures. However, all stimulants except cocaine are phenylethylamine derivatives ( see Table 11). Some psychomotor stimulants have one or more centers of asymmetry, so optical antipodes and/or stereoisomers may exist. In general, one of the antipodes is more potent than the other. The dextrorotatory isomer of amphetamine or dexamphetamine is about three times as potent as the levorotatory antipode ( Alles, 1939; Jarowski and Hartung, 1943).

TABLE I1 STRUCTURES AND ABSOLUTE CONFIGURATION OF PSYCHOMOTOR S T l M U L A N T DRUGS

0”i””’ dexamphetamine * 1+12S; DexedrineR

alfetamine AletamineR

methamphetamine* I+)2s; PervitinR

*

dimet hamphetamine

I+)2 5 MetrotoninR

cypenamine

dextrofemine

1+I 2S

NH-C-C

p hen met razine three[+) 1 S ; Z S

**

fencam famine ReactivanR

zylofuramine threo 2S;35

l+l

PreludinA

C=O,n

F

Q

c-o\,/,o

0% \

facetoperan

methylphenidate Ritalin R 1+1threo 1R:ZR

I-)threo 1S;ZS LidepranR

pipradrol

1+1 Z R

Meratran

cmNHz C

pernoline TradonR

*

**

xylopropamine Esantn

also in use as anorectic drug to be considered as a dangerous addictive drug

-

Prolintane Catovit R

312

JACQUES M. VAN ROSSUM

Dexamphetamine, methamphetamine, and phenmetrazine are the best-known psychomotor stimulant drugs ( Leake, 1958; Kalant, 1966). Sympathomimetic side effects are predominantly present in amphetamine and methamphetamine. Ephedrine is mainly a sympathomimetic, so the weak central stimulant effects are accompanied by strong peripheral side effects.Most of the other drugs have slight or no sympathomimetic properties. Some of the psychomotor stimulants are used therapeutically as appetite suppressants, eventually in combination with a sedative in order to reduce central stimulation or with a laxative to prevent an increase in dosage by the patient (Welsh, 1962). Others are mainly stimulants that lack anorectic properties. This is the case for zylofuramine and pipradrol (Harris d al., 1963; van Rossum and Simons, 1969) and also pemoline. A number of psychomotor stimulant drugs are predominantly appetite suppressants showing central stimulation in higher or slightly higher doses (see Table 111). This is the case for regenon ( Melander, 1960) and phentermine (van Rossum and Simons, 1969). Phenmetrazine, although used as an anorectic drug, is classified here as a stimulant since this drug has stimulant properties in doses that are lower than needed for the anorectic effect (van Rossum and Simons, 1969). In addition there are a number of anorectic drugs that are to a large extent completely devoid of stimulant properties (Gylys et al., 1962; le Douarec et aE., 1966) (see Table IV). The anorectic agents, although related to dexamphetamine, are not considered psychomotor stimulant drugs ( compare Tables 11, 111, and IV). Only the drugs presented in Table I1 are the psychomotor-stimulant drugs currently available. As pointed out before, a number of anorectic agents show psychomotor stimulation in doses higher than those employed for treatment of obesity. Since tolerance to anorectic action occurs, psychomotor stimulation may appear when doses are augmented during chronic treatment.

C. CHEMICAL STFKJCTURE AND PSYCHOMOTOR STIMULANTACITON Most amphetamine-like drugs except pemoline are relatively simple organic bases. They are primary, secondary, or occasionally tertiary amines. The phenylethylamine structure can be found in

TABLE I11 STRUCTURES OF ANORECTIC AGENTSWITH CENTRAL STIMULANT PROPERTIES

levamphetamine

1-1 R Levedrine

ethyl amphetamine [ d l ) Adiparthrol ApetinilR

furfenorex

mefenorex Anexate R

benzphetamine [+12S OidrexR

vNH phenlermine Mirapront R

mNH-c cYfHz \

\

levo -methamphetamine

diphemethoxidine CleofilR

&f::;

?H

norpseudo ephedrine I+)threo 1S;ZS CathineR

phendimetrazine [+) threo 1S;2S

Plegine R

pent orex Modatrop R

metarnfepramone

Id[)

fenbutrazate

0

amfepramone [ d l l Regenon R

aminorex

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JACQUES M. VAN ROSSUM

TABLE IV STRUCTURES OF ANORECTIC AGENTSWITH LITTLEOR CENTRALSTIMULANT PROPERTIES

NO

mNHp ort etamine

f o r m e torex

amphecloral Acutran

mNH PNH‘ CF3wNH

CI

chlorphentermine Lucofen R

~ N H $ O - C - C

Cl

6

c F3

fenfluramine PonderalR

NH-C

\

trifluorex rri f lutamine R

mNH

n Pent

il cloforex

clominorex

fludorex

fluminorex

amfepentorex

fenmetramide

practically all drugs of this category (Tainter et al., 1939; Jacobsen, 1939; Schulte et a,?.,1939; Chen et a,?.,1929; Alles, 1933). Phenylethylamine is a very weak central stimulant since this drug is rapidly metabolized in most species. In rats pretreated with

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

315

a monoamine oxidase inhibitor, phenylethylamine behaves as amphetamine (Stein, 19fXa,b; van der Schoot, 1961) (see Fig. 1 and Table V). The phenylethylamine structure is essential. Shortening or lengthening of the C-C bridge between the phenyl ring and the amino group results in a complete loss of activity (van der Schoot, 1961) ( see Table V ) . The phenyl ring that is separated by two carbon atoms from the

0265 82 b

FIG.1. Cumulative records of locomotor stimulant effects in mice ( m )or rats ( T ) following intraperitoneal (i.p.) administration of various central stimulant drugs by use of the light-beam method. ( a ) phenylethylamine simultaneously with the monoamine oxydase inhibitor pargyline; ( b ) the amino acid L-a-methylmetatyrosine in animals pretreated one hour before with the monoamine oxydase inhibitor nialamide; ( c ) the natural amino acid L-dioxyphenylalanine in an animal pretreated 30 min before with a periferal L-DOPAdecarboxylase inhibitor Ro4-4602; ( d ) dexamphetamine alone. Qualitative similar effects are obtained. The onset of action, the intensity, and the duration are different. The rather long onset of action of treatments ( b ) and ( c ) indicate accumulation of bioactive metabolites.

316

JACQUES M. VAN ROSSUM

TABLE V STRUCTURES AND ACTIVITIES~ OF AMPHETAMINE ANALOQS

0"j'"" WNH2 amp het amine 11001

phenylisobutylamine

101

C

@NH2 1-phenylet hylamine 10)

rNH2 2-phenylethylamine ( 2 ) [ a f t e r MA01 20)

a-methyldopamine

10)

methylene-a-methyldopamine (15)

WNH2 furyl-isopropylarnine

135)

propylhexedrine 115)

tetrahydro 8naphjylamine 1101

Locomotor activity in percent of activity of amphetamine.

amino group may be replaced by an isosteric planar aromatic nucleus such as thiophene and furane (Alles and Feigen, 1941). Substitution on the amino group of amphetamine results in a loss of activity except for substitution of one methyl group as in methamphetamine. Methamphetamine is the most potent drug in this category now available (Schulte et al., 1939). Since enzymatic dealkylation is easily carried out in most animal species, metabolites may be responsible for the psychomotor stimulant action of certain amphetamines. This is, for example, the case for dimethylamphetamine (Section IV,D). There is no correlation of the central stimulant effects with sympathomimetic effects ( Jacobsen and Wollstein, 1939). Although amphetamine may be regarded as a sympathomimetic amine most members of this category are less or not at all sympathomimetic (Jacobsen, 1939). By introduction of heavier substituents on the

ACITON OF PSYCHOMOTOR STIMULANT DRUGS

317

amino group the sympathomimetic action diminishes, so that benzphetamine is not sympathomimetic. Relatively potent peripheral vegetative effects are encountered when an OH group is present in the same position as in noradrenaline and ephedrine. Norpseudoephedrine having the OH group in the opposite position, is a much stronger central stimulant than ephedrine but a much weaker sympathomimetic. It may be concluded that there is a dissociation between the psychomotor and the peripheral sympathomimetic effects of the amphetamines. Amphetamine and a number of other psychomotor stimulant drugs such as phenmetrazine and phentennine are in use as anorectic agents. Through substitution of a chlorine group or a trifluoromethyl group in the 3 or 4 position in the phenyl ring of amphetamine, the central stimulant properties diminish whereas the anorectic properties remain. Thus chlorphentermine, f e d u r amine, and fluminorex are anorectic drugs that lack central stimulant effects. There appears to be a scale of related drugs that are pure stimulants, others are pure anorectic drugs, and a number are mixed in action (van Rossum and Simons, 1969). For instance, amphepramon is an anorectic in low doses and a central stimulant in higher doses. Amphetamine and certain analogs cause a rise in body temperature in animals and man. The fact that xylopropamine has less central stimulating properties than amphetamine, but, in contrast, has stronger pyretic effects suggests that the psychomotor stimulant action has no relation to the possible effects on temperature regulation (van der Schoot, 1961; Mantegazza et al., 1970). The typical psychomotor stimulant action in animals and man may be characterized by an alerting effect, stimulation of motor activity, and suppression of fatigue with adequate doses. Higher doses cause constant motor activity and psychotic behavior. Although most psychomotor stimulants are strongly related to amphetamine, it is possible to distinguish certain subcategories on the basis of the following structural features.

1. The amphetamines as presented in Table 11. Many phenylethylamine analogs have been synthesized that have effects similar to amphetamine. 2. Pemoline is not a basic amine but an acid. The Mg salt is well known for its well-publicizcd but dubious effects on learning

318

JACQUES M. VAN ROSSUM

(Plotnikoff, 1966a,b; Frey and Polidora, 1967; R. G. Smith, 1967). Although pemoline is similar in action to amphetamine, its cellular mechanism of action may be different. Naphtyridine is also an acidic stimulant ( Aceto et al., 1966). 3. The structure of cocaine is completely different from the phenylethylamines (see Table I ) . Cocaine presumably has a different mode of action than amphetamine (van Rossum et al., 1962) in that it potentiates the action of noradrenaline by inhibiting the re-uptake of noradrenaline in sympathetic neurons. The steroisomeric form pseudococaine has the same local anesthetic properties as cocaine but is devoid of central stimulant properties and the noradrenaline potentiating effects (Schmidt et al., 1961). Other local anesthetics do not have a psychomotor stimulant action. 4. Certain amino acids such as dopa and a-methyl-m-tyrosine in sufficient dosages may induce a psychomotor stimulant action in animals (see Fig. 1 and Table VI) (van der Wende and Spoerlein, 1962; Porter et al., 1961). These amino acids are converted into corresponding amines (Blaschko and Chrusciel, 1960; van Rossum, 1963; Carlton, 1963). The corresponding amines, e.g., dopamine, do not pass the blood-brain barrier and therefore can act only when they are formed in the brain. a-Methyl-m-tyrosine does not act as

r

TABLE VI STRUCTURES OF APOMORPHINE AND AMINO ACIDSWITH CENTRAL STIMULATING PROPERTIES

HO OH

L-DOPA

1-1 2s

HO

apomorphine

1-1 R

ilH L-a-methylmetat yrosine

1-1 2 s

3 19

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

such but by virtue of its amphetamine-like metabolites both with respect to increase of locomotor stimulation (van Rossum, 1963) and shock avoidance behavior ( Carlton and Furgiuele, 1965). 5. Apomorphine may be considered as a dopamine analog (Ernst, 1965). This drug induces constant motor activity in a variety of animals as does morphine and methadone ( see Table VI ) . D. AESOLUTE CONFIGURATION AND PSYCHOMOTOR STIMULATION Dextrorotatory amphetamine is 2 to 3 times as potent a stimulant as its optical antipode. Dexamphetamine has the same configuration as D-( +)-phenylalanine ( Fischer projection), The carboxyl group of phenylalanine corresponds to the a-methyl group of amphetamine (see Table VII ) . The Fischer projection is unambiguous for a-amino acids and sugars for which certain conventions have been adopted (Hartung and Andrako, 1961). For other classes of chemical substances new conventions have to be established. It is therefore advantageous to use the so-called priority sequence rule of Cahn et al. (1956). According to the sequence rule the absolute configuration of dexamphetamine is 2s. The Fischer projection and the absolute configuration of a number of analogous substances are given in Table VII. The priority sequence is based on atomic weight of the substituents of an asymmetric carbon atom I + Br -+ C1+ OH+ N H 2 + CO -, C N -+ C=C+

C-C-,

H

Replacement of a certain substituent without alteration of the absolute configuration therefore may result in a change of R + S or the reverse. So D-phenylalanine has the configuration 2R, whereas exchange of the carboxylic acid group by a methyl group results in dexamphetamine having the same configuration but indicated by the notation 2s. The absolute configuration thus can be indicated suitably by the R : S notation, whereas drawings of the formulas are necessary to indicate whether different drugs have the same configuration with respect to a given asymmetric center. In this paper the four groups of a center of asymmetry are arranged in such a way that the hydrogen atom is below or above the center (see Table VII). The formulas of the various amphetamine-like drugs insofar as the absolute configuration is known is given according to this convention (see Tables I-V). The various potent stereoisomers have identical configuration at

TABLE VII

ABSOLUTE CONFIGWATIONB OF DEXAMPHETAMINE I N RELATION TO

THE

CONFIGURATION OF EPHEDRINE A N D NORADRENALINE~

COOH CH3 I H-F-NHz

H2

It) phenylalanrne

DzFischer projection [ 2 R sequence rule )

6

0 I+)amphetamine

H-C

I+) 2s -amphetamine

I+)2 s amphetamine

sequence rule

CHNHZ I H-C-OH I

I-)eryt hro

1R:2S 0

a-methyl noradrenaline I-)erythro 1R ; 2 S

noradrenaline

I-)1R

norpseudo ephedrine I+)threo ; IS : 2s

norpseudo ephedrine I+)threo' 1 S : Z S

The notation of absolut'e configuration according to the Fischer projection and the priority-sequence rule is indicated.

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

321

the carbon atom adjacent to the amino group as in dexamphetamine. For instance the active isomers of phenmetrazine and phendimetrazine are the threo 1S:2S form (Clarke, 1962; Dvornik and Schilling, 1965). (See Table 11.) Potent isomers do not always have identical configuration to that of dextroamphetamine. The levorotatory isomer of pipradrol is a potent stimulant whereas the dextro-rotatory isomer is inactive (Portoghese et aZ., 1968). It has been found that (-) pipradrol has the 2R configuration which therefore is not stereochemically superimposable upon 2s-dexamphetamine ( Portoghese et al., 1968; Shafiee and Hite, 1969). The configuration of methylphenidate is the more active CNS stimulant antipode is 1R:2R (Shafi'ee et al., 1967; Shafiee and Hite, 1969). (See also Table 11.) The configuration of the more active (+)threo isomer of phacetoperan is likely 1R:2R. For a number of amphetamines, for example, fencamfamin, the configuration of the most potent isomers have not been elucidated. Norephedrine has the same configuration with respect to the second carbon atom as dexamphetamine and the OH group in the 1R configuration as in L-noradrenaline; it is far less potent as a central stimulant than is norpseudoephedrine which also has the 2s configuration with respect to the second carbon atom but the OH group in the opposite position or 1s configuration (Fairchild and Alles, 1967). Norpseudoephedrine is, however, inferior to norephedrine as an alpha sympathomimetic drug. One must conclude that the central stimulant actions of the amphetamines have no relation to the peripheral alpha sympathomimetic action. L-Amphetamine is about 3 times less active as a locomotor stimulant in rats. Methamphetamine with a codguration identical to that of dexamphetamine is about twice as potent as dexamphetamine but about 10 times as potent as its optical antipode. L-Methamphetamine is therefore less potent than L-amphetamine, while the reverse holds true for the dextrorotatory isomers (van Rossum et al., 1970) (Table VIII). The relative central stimulant and anorectic activity of related stereoisomers deserve further study. The psychomotor stimulant ( - )-cocaine has two asymmetry centers with absolute configuration 2R:3s (Fodor, 1957) (Table I). Although cocaine like hyoscyamine is a tropanol derivative, the geometric configuration is quite different. The stereoisomer ( ) -pseudococaine, which is as potent as cocaine with regard to local anesthetic properties, lacks central stimulant anorectic and

+

322

JACQUES M. VAN ROSSUM

TABLE VIII

RELATIONSHIP BETWEEN ABSOLUTE CONFIQURATION AND PSYCHOMOTOR STIMULANT ACTION’ Stimulant

Configuration

Dexamphetamine L-Amphetamine Methamphetamine (-)-Methamphetamine ( +)-Dimethamphetamine ( -)-Dimethamphetamine (+)-No rpseudoephedrine ( -)-Norephedrineb ( -)-Norpseudoephedrine ( +)-Norephedrineb

2s

2R 2s

2R

2s

2R 1s:2s

lR:2S 1R:2R 1S:2R

EDw (@mole/kg)

Relative potency (dexamph. = 100)

3.16 (9.0) 10.0 (38) 1.78 31.6 31.6 316 31.6 (93)

100 (100) 30 (24) 200 10 10 1 10 (‘10) (2) (2 .‘1) (1)

(500)

(385) (1000)

a Unpublished results on locomotor stimulant action in rats. Data between brackets from experiments in mice by Fairchild and Alles, 1967. * Toxic in stimulatory doses.

peripheral sympathomimetic effects ( Gottlieb, 1923; Schmidt et aZ., 1961; Schmidt, 1965; Schmidt and Meisse, 1962). The amino acid L-a-methyl-m-tyrosine ( a-MMT) being enzymatically converted into 3-hydroxydexamphetamine produces the same effects as dexamphetamine (van Rossum, 1963). The central stimulant effect of a-MMT depends on the formation of metabolites 3-hydroxydexamphetamine and eventually also metaraminol. Metaramino1 is the erythro form with the 1R:2S configuration, thus having the hydroxy group in the side chain in the same position as natural L-noradrenaline and ephedrine. With regard to the differences in central stimulant activity of norephedrine ( 1R :2s ) and norpseudoephedrine ( 1s:2s ) , it is unlikely that metaraminol acts as an essential metabolite in the psychomotor stimulant action of a-MMT. Since aromatic decarboxylation is stereospecificfor ],-amino acids (Lovenberg et al., 1962), it can be visualized that dexamphetamine can be formed from a-methylphenylalanine. The lattc,-r compound, however, has no central stimulant activity, presumably because decarboxylation proceeds extremely slowly. Apomorphine has certain stimulant effects in common with dexamphetamine and L-dopa and has identical configuration (2R) at the asymmetry center as dexamphetamine ( 2 s ) (Corrodi and Hardegger, 1955); see Table VI.

ACITON OF PSYCHOMOTOR STIMULANT DRUGS

323

II. Effects of Psychomotor Stimulant Drugs in M a n

The alerting effects of amphetamine in man were soon observed following studies of the antinarcosis effect of amphetamine in animals ( Leake, 1958). A. EFFECTS OF AMPHETAMINESIN THERAPEUTIC DOSES The first clinical application of amphetamine was in the therapy of narcolepsy (Prinzmetal and Bloomberg, 1935). Except for certain applications in some forms of epilepsy, parkinsonism, and depressions, the treatment of narcolepsy is still the only unequivocal indication for psychomotor stimulant drug ( Editorial, 1968). For the treatment of obesity, certain amphetamines may be used, but the specific anorectics are preferable. The possibility exists that certain anorexigenic drugs such as aminorex and cloforex may induce pulmonary hypertension in man (Schwingshackl et al., 1969). Such toxic reactions are apparently unrelated to sympathomimetic effects. The alerting effect or the production of a state of wakefulness accompanied by an increase of all kinds of psychic and motor activity is the most characteristic effect of the psychomotor stimulant drugs in man. Diminished fatigue, a better adjustment toward work, as well as suppression of sleep (Bahnsen et at., 1938) and elevation of mood are the consequences (Nathanson, 1937; Leake, 1958; Connell, 1958; Kalant, 1966). The enhancement of human performance by amphetamines has been proved (see review by Weiss and Laties, 1962). The amphetamines may therefore be used in cases of severe emergency. During World War I1 methamphetamine and dexamphetamine were used extensively ( Bett et al., 1955; Ivy and Krasno, 1941; Ivy and Goetzl, 1943). The psychomotor stimulant effects of amphetamines in man are variable in intensity (Jacobson and Wollstein, 1939) and are experienced as a sense of energy and self-confidence and the occurrence of quicker mentation and decision making (Kalant, 1966). The euphoric effects experienced in a number of individuals is one of the reasons for its misuse by addicts. Following repeated administration of amphetamine, tolerance develops in man (Rosenberg et al., 1963). There is no cross tolerance to LSD in subjects tolerant to amphetamine and there is no cross tolerance to amphetamine in those tolerant to LSD (Rosenberg et al., 1963).Cross tolerance between the hallucinogens LSD,

324

J A C Q W M. VAN ROSSUM

psylocybine, and mescaline occurs (Isbell et d.,1961; Wolbach et al., 1962). Tolerance to the awakening effect of the amphetamines apparently does not occur, because in the treatment of narcolepsy the dose need not be increased (Leake, 1958). The peripheral side effects are of the sympathomimetic type: namely, increase in blood pressure and heart rate, pupillary dilation, and relaxation of the smooth muscle of the gastrointestinal tract ( Kalant, 1966). In higher doses excessive pupillary dilatation, hypertension, and tachycardia prevail. The various psychomotor stimulant drugs differ greatly in their relative potencies of central stimulant and peripheral sympathomimetic effects.

B. Toxrc EFFECTS OF PSYCHOMOTOR STIMULANTSIN MAN After injection of a dose of more than 20 mg dexamphetamine

or intravenous administration of psychomotor stimulants, toxic effects of overstimulation of the central and peripheral sympathetic nervous system may be experienced. Kalant (1966) has given a thorough review of amphetamine intoxication with case reports. Toxic symptoms may include restlessness, hyperactivity, convulsions, tremor, tenseness, irritability, insomnia, confusion, delirium, and anxiety (Leake, 1958; Espelin and Done, 1968). Paranoid psychosis induced by amphetamine with suicidal or homicidal behavior is often encountered, especially after chronic use of intravenous administration ( Connell, 1958; Kalant, 1966). In addition, a number of toxic effects may be observed (due to sympathetic stimulation) such as profuse sweating, rapid breathing, headache, pallor, palpitation, tachycardia, hypertension, and cardiac arrhythmias or circulatory collapse (Leake, 1958). The treatment of amphetamine poisoning should not be symptomatic as with sedatives, but neuroleptic drugs such as chlorpromazine and haloperidol (Espelin and Done, 1968) should be used. The neuroleptics are specific amphetamine antagonists (see later). Chlorpromazine or thioridazine are the drugs of choice for intoxication due to dexamphetamine. Haloperidol is indicated for the treatment of poisoning with pure psychomotor stimulants.

C. ADDICITON TO PSYCHOMOTOR S m m m DRUGS Most adult male inhabitants of the Peruvian mountains are chronic coca chewers. They seldom develop psychotic reactions and they usually abandon their habit when they move to lower altitudes

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

325

( Molina, 1946; Gutierrez-Noriega and Zapata-Ortiz, 1947). The use has spread to the highlands of other countries in South America such as Bolivia and the Salta area of Argentina. Addiction to cocaine with development of tolerance has been described vividly and extensively by Lewin (1893). Abuse of amphetamine, methamphetamine, phenmetrazine, and other drugs is well documented (Morimoto, 1957; Kramer et al., 1967; WHO, 1964). Addiction first occurred on a large scale in Japan and Germany shortly after World War I1 (Morimoto, 1957; Bonhoff and Lewrenz, 1954). In the last few years the abuse appears to be increasing in large cities, where adolescents administer the drugs by intravenous route. Extremely intensive but short-lasting euphoric effects are experienced by the intravenous users (Kramer et aZ., 1967). Many addicts initially use amphetamine orally but they rapidly change to the intravenous route and inject themselves with progressively larger doses of amphetamine. The amount injected generally ranges from 100300 mg per dose but may be as high as 1 gm methamphetamine every 2 hours (Kramer et al., 1967). The users get a sudden generalized overwhelming pleasurable feeling called a “rush.” The mood is euphoric with intense concentration of thoughts and activities which extends to flight of ideas with paranoia and anger (Kramer et aZ., 1967). A review on the abuse of methamphetamine has been given by Hawks et al. ( 1969). The rapid development of tolerance implies that only the very potent and lipophilic psychomotor stimulant drugs are dangerous addictive substances. These are dexamphetamine, methamphetamine, phenmetrazine, and cocaine. Other stimulants listed in Table I1 may be dangerous but presumably less so than the above mentioned. Also, the anorectic agents that have psychomotor stimulant “side” effects may to some extent be addictive stimulants. D. AMPHETAMINEPSYCHOSIS INDUCED BY PSYCHOMOTOR STIMULANT DRUGS Cases of paranoid psychosis due to chronic cocaine abuse have been reviewed as early as 1892 (Lewin, 1893). The cocaine addicts are paranoid, experience persecutory and auditory hallucinations, and eventually may become aggressive against suspected enemies (Lewin, 1893). The occurrence of paranoid psychosis and psychotic states with auditory hallucinations, delusions of persecution, anxiety,

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JACQUES M. VAN ROSSUM

and hostility elicited by chronic or sometimes even by an occasional use of amphetamine is well documented and resembles paranoid schizophrenia ( Connell, 1958; Kalant, 1966; Kosman and Unna, 1968). Amphetamine intoxication in humans is accompanied frequently with stereotyped movements, as, for instance, repeating the same sentences constantly (Tatetsu et aZ., 1956; Bonhoff and Lewrenz, 1954; Connell, 1958; Munkvad et al., 1968). The first indication of amphetamine-induced psychosis has been noticed in the treatment of patients for narcolepsy with amphetamine (Young and Scoville, 1938). Although a number of individuals who show psychotic reactions associated with amphetamine intoxication are abnormal personalities, normal persons may become psychotic following amphetamine abuse (Connell, 1958; GrifEth et d.,1W; Kalant, 1966). Paranoid psychotic reactions are a real danger to society since there is a causal relationship between amphetamine use and crimes of violence and sex offenses ( Walsh, 1964). Drug-induced psychosis is predominantly the case following use of dexamphetamine, methamphetamine, and phenmetrazine ( Askevold, 1959; M. Herman and Nagler, 1954; Bonhoff and L,ewrenz, 1954; Connell, 1958; Marley, 1960).Chronic use of methylphenidate also causes paranoid psychosis ( McCormick and McNeel, 1963), as does amphepramon (Kuenssberg, 1963; Baumer, 1966) and ephedrine (Herridge and a’Brook, 1968). Other stimulants and anorexogenic drugs with stimulating properties may be the cause of psychoses in the future. It has been shown that methyldopa in combination with a monoamine oxidase inhibitor elicits a strong amphetamine-like stimulation in mice (van Rossum and Hurkmans, 1963).These findings suggest that amines related to dopamine might cause psychotic reactions in man. A patient with Huntington’s chorea reacted well to a treatment with methyldopa but became psychotic when the therapy was extended with isocarboxazide ( Korten and Pelckmans, 1968). In male schizophrenics there is apparently an excessive brain stimulation as detected by quantitative EEG (Goldstein and Beck, 1965). Since amphetamine addicts experience a florid paranoid psychosis but do not exhibit the typical dissociated and autistic disorganization of thinking associated with schizophrenia ( Kramer d al., 1967), an amphetamine-like stimulation might be one but not the only etiologic factor in schizophrenia.

327

AClTON OF PSYCHOMOTOR STIMULANT DRUGS

Ill. Effects of Psychomotor Stimulant Drugs in Animals

A. LOCOMOTOR STIMULANTE F F E ~ The amphetamines exert an awakening effect in animals anesthetized by various hypnotics (Tainter et al., 1939). It has been observed that, although certain analogs of amphetamine had little power to hasten awakening from deep narcosis, they exhibited excitation after the animals were aroused (Tainter et al., 1939). This central excitation, characterized by restless coordinated movements, differs from the convulsive seizures that occur from stimulation of medullary centers and the spinal cord, suggesting stimulation of higher centers in the brain (Tainter et al., 1939). Motor stimulation in small laboratory animals may be measured through observation or recorded in a number of ways (Kinnard and Watzman, 1966; Riley and Spinks, 1958). Observations of cats before and after treatment with amphetamine have been recorded (Norton, 1967). Some behavioral patterns, for example, ‘%head down simultaneously with stretching” (which is not seen significantly in controls), occurred with amphetamine. Amphetamine (P. W. Dews, 1953) and other psychomotor stimulant drugs such as pipradrol and cocaine cause a strong increase in locomotion in mice and rats (Schulte et al., 1941; Tainter, 1943; van der Schoot, 1961; van Rossum et al., 1962; C. B. Smith, 1965).

w-1 0964 852 b m 23

t

0964 852c

Cocaine 56.2 p l e / k g i.p.

f Cocaine

I5 min

Cocaine 56.2 pmole/kg oral

k 0964 852 d

if&&

0964 852 e

10 pmole/kg i.v

FIG. 2. Cumulative records of locomotor activity induced by 1-cocaine administered in the mouse via various routes. The onset of action is obviously the most rapid for i.v. injection. The intraperitoneal route is faster than the subcutaneous route. Cocaine is practically devoid of activity when given orally.

328

JACQUES M. VAN ROSSUM

Figure 2 shows cumulative records of locomotor stimulation in mice following administration of cocaine via various routes. A comparison of the action of various psychomotor stimulants in rats is found in Fig. 3. The onset of action and the intensity and duration of locomotor stimulation differs for the various stimulants. The stimulant effects of cocaine and phenmetrazine are fast, intense, and short. The effect of norpseudoephedrine is long lasting. It is probable that cocaine and phenmetrazine have a high addiction liability because of the fast and intense actions, which would be intensified after intravenous administration. Increase of locomotor activity is also obtained with a-methylInterruptiondmin

I00

] A

R2o dexamphetamine 562pnole/kg I P

p

w

ppseudoephedrine.

( t ) nor-

Interruptions/min nterruotions/min

1

H 20

R2a cocaine 31.6pmole/kg i p.

I00 (threo)

(t) methomphetamine

3 16 pmole/kg i.p.

50

Interrupti o n s h i n

R3m

( t ) methamphetamine

3.16 p o l e / kg i.v.

'

j0

6b

90 min

1 '

1

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(t) methamphetamine

3.16 p o l e / k g i.p.

30

60

90

R3m

( t ) methamphetomine

3.16 p o l e / k e p.0.

min

FIG. 3. Records of average locomotor activity per interval, following i.p. administration of various psychomotor stimulant drugs in one rat as well as administration of methamphetamine via various routes in another rat. Cocaine is short acting with a fast onset and high intensity. Norpseudoephedrine is long acting. Methamphetamine is the most potent drug presently available.

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

329

m-tyrosine (van Rossum, 1963) and with dopa in rats pretreated with a monamine oxidase (MAO) inhibitor or a peripheral decarboxylase inhibitor. Even methyldopa in rats pretreated with a MA0 inhibitor exerts after a few hours a strong amphetamine-like effect on locomotor activity. Apomorphine stimulates to some extent, but stereotyped movements predominate over locomotor stimulation. Locomotor stimulation may be considered as a characteristic effect of psychomotor stimulants in mice and rats.

B. PSYCHOMOTOR STIMULANTS ON OPERANT BEHAVIOR Facilitating actions of amphetamine in behavior can be objectively measured by the operant behavioral techniques; rats, cats, monkeys, etc., can be trained to press a lever to obtain food or water (positive reinforcement) or to avoid an electric shock (negative reinforcement). The training can be done on the basis of different schedules of reinforcement ( Ferster and Skinner, 1957). The effect of the amphetamines on operant behavior has been reviewed by P. B. Dews and Morse (1961). In rats working for food on a fixed ratio schedule (FR), amphetamine and related drugs cause cessation of response similar to the behavior of satiated rats (Fig. 4 ) . Eventually they still press the lever but do not eat the food presented. The best example is fencanfamine in rats. Long pauses in food reinforcement in rats on a fixed ratio performance occurs after cocaine administration (Pickens and Thompson, 1968). In rats working for food on a fixed interval schedule (FI) amphetamine increases the rate of responding (Cook and Kelleher, 1962; see also Ray and Bivens, 1966). On a schedule in which animals must wait a certain period in order to obtain the next reinforcement ( differential reinforcement of low rates schedule DRL), amphetamine causes disruption of efficient behavior by shortening of the waiting times (Sidman, 1955; Kelleher et al., 1961; Segal, 1962). The temporal pattern of behavior influenced by amphetamine has been studied by Weiss and Laties (1964). Performance of rats under influence of amphetamine on a multiple schedule has been studied by Clark and Steele (1966). Changes in instrument responding elicited by amphetamine are disturbed to some extent by the inhibitory effects of amphetamine on hunger drives (see Poschel, 1963). Amphetamine and methamphetamine increase the rate of responding of rats conditioned

330

JACQUES M. VAN ROSSUM

0

8

15min

FIG.4. Cumulative records of lever pressing for food of a trained rat on a fixed ratio (FR 30) schedule following injection of saline and increasing doses of dexamphetamine. Pausing normally occurs after lever pressing for Iof an hour but occurs within 10 minutes when dexamphetamine has been given. A 1 mg/kg (5.62 pmole/kg) dose causes response to cease in all rats tested.

to press a lever in order to avoid shocks. Consequently the number of shocks received is decreased ( Verhave, 1958). Amphetamine differentially increases responding on a variable interval schedule and decreases the numbers of shocks accepted by rats in the conflict situation (Geller and Seifter, 1960) (Fig. 5 ) . Behavioral tolerance in response to chronic administration of dexamphetamine has been observed in schedules of reinforcement (FR, DRL, FI) when responses led to a decrease of food reinforcement ( Schuster et d.,1966). However, chronic administration of dexamphetamine led to a uniform increase in rate of responding on scheduled negative reinforcement; as a consequence the rate of shock reinforcement was decreased ( Schuster, 1966). In a test situation in which rats were trained to regulate their environmental temperature by pressing a lever that turned on a heat lamp, it could be shown that amphetamine increased the frequency even though the skin temperature was driven above normal (Weiss and Laties, 1963). Amphetamine reduces freezing behavior and consequently causes improvement of shock avoidance (Krieckhaus et al., 1965). Suppression of freezing may be the reason that psychomotor stimu-

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

331

No drug

J d -Amphetamine 0.5 mg/kg immediately

prior

FIG. 5. Cumulative records of lever pressing of a rat conditioned on a variable interval schedule (VI 2 min) alternating with continuous reinforcement and simultaneous shock (conflict situation). In the absence of a drug the rat does respond to the conflict situation when the shocks are of low intensity (number indicated). After injection of dexamphetamine response in the conflict situation is drastically suppressed. Reproduced after Geller and Seifter (1960) with permission of the authors and Psychophamcologiu.

lants (including pemoline) seem to facilitate learning of instrument responding in an avoidance situation but not in case of a positive reinforcement situation. Amphetamine has a positive influence on performances ( “learning”) in rats which showed consistently low rates of avoidance in a shuttle-box in spite of extensive training ( Rech, 1966). It may be concluded that amphetamine facilitates ongoing operant as well as spontaneous behavior.

C. PSYCHOMOTOR STIMULANTS ON SELF-STIMULATION Electrical stimulation in certain areas of the brain are experienced by cats and rats as a reward, and animals learn to press a lever in order to receive an electric stimulus to their brains (Olds, 1956, 1962). Amphetamine increases self-stimulation in cats with electrodes in the lateral hypothalamus or caudate nucleus (Horo-

332

JACQUES M. VAN ROSSUM

Responsesl

I

H

10min

FIG.6. Cumulative records of lever pressing for self-stimulation in a cat with electrodes in the lateral hypothalamus. Amphetamine facilitates selfstimulation, whereas chlorpromazine exerts the opposite effect. Reproduced after Horovitz et a2. (1962a,b) with permission of the authors and Psychopharmacologia. vitz et al., 1962a) and in rats with electrodes in the posterior hypothalamus and midbrain segmentum (Stein and Ray, 1960; Stein, 1964a,b, 1967) (Fig. 6). The facilitating effect is not due to nonspecific augmentation of motor activity since the effect abruptly stops if the electric current is turned off (Horovitz et al., 1962a; Stein, 1964a). Amphetamine facilitates the hypothalamic reward system which may be its mode of action as a stimulant (Stein and Seifter,,1961). The facilitation of self-stimulation is probably due to an amphetamine-induced release of catecholamines in the rewarding system (Stein, 1962a, 1964b). Other psychomotor stimulant drugs do the same. For instance, facilitation of hypothalamic self-stimulation has been observed for methamphetamine and methylphenidate (Stein, 1964b,c). Phenylethylamine, as such, is without effect [Fig. 7( a ) ]

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

333

Phenethylomine hydrochloride ( I mg/kg*) Responses

///)(/)////// AA/+$vl/lA/ Phenethylamine hydrochlorlde ( I rng/kg*) 3 hours after iproniazid phosphate (100m g / k g )

A-

Equimolar with I mg/kg d-Amphetamine sulfate

200 Self stimulations

L

10 min

Q

-methyl-m- tyrosine 300rng/kg

A-

Cont'D

FIG. 7. Cumulative records of lever pressing for self-stimulation on a variable schedule interval in rats with electrodes in the posterior hypothalamus. Dexamphetamine alone and phenylethylamine in combination with a monoamine-oxidase inhibitor both induce a facilitation of self-stimulation. The amino acid a-methyl-rn-tyrosine also facilitates self-stimulation but only after a latency period of 45 minutes. Reproduced after Stein (1964b) with permission of the author and Fed. Proc. Compare with the locomotor stimulant effects of the same treatments in Fig. 1.

334

JACQUES M. VAN ROSSUM

but simulates amphetamine after M A 0 inhibition (Stein, 1964b) [Fig. 7(b)]. The effect of cocaine needs clarification. Low doses that have no facilitating effect of amphetamine on self-stimulation (Stein, 1 9 6 4 ~ )a-Methyl-rn-tyrosine . exerts an amphetamine effect after a latency period of about 45 minutes (Fig. 7) (Stein, 1964b). The time pattern is similar as that for locomotor stimulation (van Rossum, 1963). The facilitating action on hypothalamic self-stimulation may be due to an action on a different brain area such as the reticular formation (Horovitz et al., 1962b). Since the lateral hypothalamus is involved in feeding behavior and since amphetamine is an anorectic drug, it might be expected that amphetamine would inhibit self-stimulation ( Umemoto and Kido, 1967). In relatively high doses Umemoto and Kid0 observed such an inhibition in cats. However, this may have been due to overstimulation. Facilitation of self-stimulation parallels locomotor stimulation to a large extent except for cocaine, which may indicate a different mechanism for cocaine.

D. STEREOTYPED BEHAVIORTHROUGH PSYCHOMOTOR STIMULANTS Amphetamine (0.5-2 mg/kg) hyperactivity has a stereotyped character in mice and rats, such as biting the wires of the cage, backward walking, and self-mutilation (Hohn and Lasagna, 1960; Schulte d al., 1941; Irwin et nl., 1958; Randrup et al., 1963; Janssen, 1961).Furthermore, excessive sniffig over a restricted area of the cage (Randrup et al., 1963), compulsory gnawing ( Janssen, 1961; Janssen et al., 1965), and purposeless searching head movements (Emele et al., 1961) have been observed. Stereotyped movements other than increased locomotion generally occurs with higher doses in rats and mice (Lht, 1965; van Nueten, 1962; Quinton and Halliwell, 1963; Randrup and Munkvad, 1965, 1966a,b, 1967a). Other psychomotor stimulant drugs cause similar stereotype movements. In a number of other animal species this activity appears to be absent, and only stereotyped behavior has been observed. For instance, in cats and monkeys coiitinuous staring and certain head movements occur (Randrup and Munkvad, 1967a) . Apomorphine causes stereotyped movements such as constant snifEng and compulsory gnawing (Harnack, 1874; Amsler, 1923; Ther and Schramm, 1962; Ernst, 1965, 1967; Janssen et al., 1965),

whereas locomotor stimulation is minimal. Apomorphine causes excessive hoarding of ‘‘nonsense food” by golden hamsters (van Rossum and Simons, 1970). Stereotyped behavior is predominant following apomorphine treatment. whrreas with amphetamine increased locomotion suppressrs stcrcotype behavior to some extent.

E. ACTION OF PSYCHOMOTOR STIMULANT DRUGS ON SOCIALBEHAVIOR Rats kept together in a cage. exhibit a number of social interactions such as gnawing, crouching, rearing, crowding in a corner of the cage, agression, and mating. Time spent in these activities decreases under the influence of psychomotor stimulants (Irwin et al., 1958). Mating activity in rats was found to be increased to some extent by low doses of amphetamine, whereas high doses which produce stereotype movements have adverse effects on mating activity ( Bignami, 1966). Amphetamine-treated rats separate from each other and no longer stay together in a corner of the cage. Aggression decreases and exploration drives are exaggerated so that they run around aimlessly (Chance and Silverman, 1964). Behavioral changes resembling aggression and fighting have been observed (Chance, 1947, 1948; Moore, 1963). Fighting between rats after repeated doses, but not after a single dose, has been reported ( Ehrich and Krumbhaar, 1937; Randrup and Munkvad, 1967a,b). Amphetamine in high doses facilitates the attack behavior in cats, which is elicited by electrical stimulation of the lateral hypothalamus as well as the enhancement of facilitation of such attacks by simultaneous stimulation of the midbrain reticular formation ( Sheard, 1967). The psychomotor stimulant methylphenidate but not amphetamine shows inhibition of aggressive behavior in mice (Valzelli et d.,1967). Social interaction in rats is augmented into bizarre forms when amphetamine is given after pretreatment with reserpine ( Morpurgo and Theobald, 1966) or with diethyldithiocarbaniate ( van Rossum and Lammers, 1970). Rats assume positions in pairs standing on their hind legs with their noses and forcyaws in close contact (see Fig. 8a ) . This bizarre behavior resembles aggressive postures but the rats do not fight (Morpurgo and Theobald, 1966). Similar bizarre behavior can be elicited with apomorphine (Schneider, 1968; van Rossum and Simons, 1970).

FIG. 8. Bizarre social behavior of male Wistar rats induced by various treatments. ( a ) Dexamphetamine (5.62 pmole/kg=l mg/kg) in 4 rats pre-

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

337

Apomorphine-injected Wistar rats show excessive sniffing within 5 minutes after injection and bizarre behavior with sound. The rats arrange themselves in pairs when they meet a partner and make rhythmic movements with thcir forepaws (Fig. 8b). It is interesting to note that through a selective increase of dopamine in the brain after injections of L-dopa and a peripheral dopa decarboxylase inhibitor a bizarre social behavior has been observed (Lammers and van Rossum, 1968) (Fig. 8c). This type of behavior is reminiscent of psychosis in humans. It may be concluded that apomorphine as such and amphetamine under certain situations may cause “psychotic” behavior in animals. IV. Kinetics of Absorption, Distribution, a n d Elimination of Amphetamines

The intensity of psychomotor stimulant action depends on the activity of the stimulant and on the concentration at the locus of action, i.e., the concentration in neurons in certain areas of thc brain. The concentration in the brain in turn depends on the plasma concentration of the amphetamines. For the psychomotor stimulant drugs the relationship between brain concentration and plasma concentration has not been studied. In analogy with other drugs, this relation will depend strongly on the physicochemical properties of the stimulants. The rate of absorption, distribution, and elimination also is largely determined by the same physicochemical properties. A. PHYSICOCHEMICAL PROPERTIES OF AMPHETAMINES The amphetamines are weak to moderate-strong organic bases with a pK, value of roughly between 8 and 11.The pK, of amphetamine is 9.8 (Leffler et al., 1951), so at the physiological pH this drug is largely in the ionized form while only a small fraction of treated 15 hours before with reserpine ( 2 mg/kg). The onset of bizarre behavior occurs within 10 minutes after dexamphetamine. ( b ) Apomorphine (3.16 @mole/kg = 1 mg/kg) in 4 rats. The onset of action is within 5 nunutes. ( c ) L-Dopa (316 amole/kg = 63 mg/kg) in 6 rats treated with the peripheral Dopa decarboxylase inhibitor Ro4-4602 ( 316 amole/kg = 52 mg/kg). The onset of bizarre behavior occurs after about 30 minutes, while maximum effect is obtained between 1 and 2 hours after the Dopa injection. Reproduced after Lammers and van Rossum (1968) with permission of the authors of the E. J. P. The effects of the three treatments are qualitatively similar. The bizarre social behavior in treated animals always can be elicited by sounds.

338

JACQUFS M. VAN ROSSUM

this drug is in the neutral form. Passage of drugs through the lipid cell barriers and the blood-brain barrier occurs predominantly in the neutral form. This would imply that amphetamine would act slowly. Cocaine, on the other hand, is a weak base with a pK, of 7.6 with about 40%in the neutral form. The onset of action of cocaine is therefore predictably fast. The pK, value and the fraction of drug in the neutral form of a number of psychomotor stimulant drugs is given in Table IX (Vree et al., 1969). The capacity of the neutral form to pass lipid barriers depends on the lipid solubility of the drug and its affinity for the tissues in the brain that bind the drug. One measure of lipid solubility is the distribution coefficient TABLE I X D~SSOCIATION COXSTANTS AND PARTITIOS COEFPICIENTS OF AMPHETAMINESO Apparent partition True partition neiitral coefficient coefficient at pH 7.4 at pH 7.4 CHCl,/H,O Hept,/H,O CHCla/H20

Percent Ihig

Phenylet,hylamine Dexamphetamine Methamphetamine Et.hylamphetamine Iaopropylamphetamirie Benzylamphet.amine L)imet,hylamphetamine Rlethylethylamphetamine Methylisopropylaniphetamine Benzphetamine Phentermine Mephentermine Chlorphentermine Norephedrine Ephedrine Methylephedrine Norpseudoephedrine Pseudoephedrine Propylhexedrine Phenmetrazine Phendimetrazine

pK.

9.88 0.33 9.90 0.31 10.11 0.19 10.23 0.15 10.14 0.18 7.50 44.1 9.80 0.39 9.80 0.39

0.078 0.48 1.11 2.67 8.09 1000 11.5 19.0

9.4.7 0.88 6.55 87.2 10.11 0.19 10.25 0.13 9.60 0.62 9.5.i 2.80 9.60 0.62 9.30 1.25 9.40 1.00 9.86 0.33 10.74 0.043 8.45 16.8 7 . . 3 44.0

100 1000 1 .oo 1.22 4.00 0.0010 0.0152 1.00 0.001

Aft,er Vree et al. (1969).

0.070 1.11 15.6 1000

0.28 1.88 5.14 38.6 117 110 108 166

20.8 146 565 17!)0 4460 2250

28!)0 47fiO

11300 200 74.8 1400 63.2 514 110.6 806 17.5 797 <0.001 0.035 0.001 2.42 0.91 80.6 0.01 0.1 0.029 20 174 2380 2.1.5 190 8.W 2920

ACTlOh- OF 1'SYCHOhlOTOH

STIMULANT DRUGS

339

between an organic solvent such ;IS chloroform or octanol and water. It is not sufficient to determine the apparent distribution coefficient at pH 7.4 since a more complettl picture is obtained by the distribution coefficient of the neutral bast, at various p H values ( Table IX). It may be concluded that amphetamine-like drugs with a pK,, below 8 and a high distribution coc43kirnt may distribute rapidly within brain tissue and thcreforc. have a rapid onset of action. Stimulants such as cocaine and phcmnctrazine fulfill these requirements. Pemoline is not a base but a wcak acid having completely clifferent physicochemical propertics. From these studies it is likely that pemoline has a distribution pattern different from the amphetamines as well as a different mechanism of action. For the central stimulant action pcr se the configuration is also of importance, while the configuration to some extent also determines physical properties (see Section 1:D).

B. KINETICSOF ABSORPTIONOF AMPHETAMINES The amphetamines are in most cases administered orally as hydrochlorides or other salts. Thcy are readily absorbed from mucous membranes of the small intestine. The average peak of plasma concentration for ph"iiii'.trazinc, was found to occur 2 hours after administration, although indivicluwl variation occurs ( Quinn et al., 1967). The peak level following a 75 mg dose has been found to vary from 0.10 to 0.25 mgllitcr (Quinn et al., 1967). The rate of absorption may be characterizcd by a half value time of roughly 30 minutes to 1 hour (Beckett et d., 1968a; Wilkinson and Beckett. 1968a,b ). Human subjects given 10-15 mg of dexamphetamine sulfate had maximum blood l e \ ~ l sof 0.04-0.05 nig/liter after 1.5-2 hours, falling to 0.002 mglliter after 8-10 hours (Campbell, 1969). By using a very sensitive gas chromatographic technique it is possible to follow blood levels of amphetamine in man (Rowland. 1969). The maximum blood concentration following an oral dose of 10 mg dexamphetamine was found to be about 35 pg/litcJr ( Rowland, 1969). The apparent volume of distribution of dexamphetamine and phenmetrazinc) may bc calculated from the above figures to be roughly 200-700 liters. Since plasma levels of amphetamine are low and the potent drugs are administered in low doses it is difficult to estimatc plasma levels. The rate of renal excretion is proportional to the plasma l e \ ~ l so , from the curves of the renal

340

TACQUEs M. VAN ROSSUM

'oil plasma conc. 1pg/11

21,

2.2

2.0 1.8

log

I-"

b

subj. P

l o

c\

1.1,

i

o

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Phenrnetrazine p.0. 75mg

Phenflurarnine p 0. 60 mg

0 .L

1.1,

2

I

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6

,

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---- subject A

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100

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FIG.9. Plasma levels as well as renal excretion curves of some psychomotorstimulant drugs in man following oral administration. (Upper left) Following intake of 75 mg phenmetrazine HC1 in two human subjects. After Quinn et al. (1967). (Upper right) Following intake of 60 mg of phenfluraniine HC1 in man. After Bruce and Maynard (1968). (Lower left) Following intake of 10 mg dexamphetamine sulfate in man. The solid circles refer to blood levels and the open circles to renal excretion data. I t may he concluded that the kinetics can be described with a single open compartment system. Reproduced after Rowland (1969) with permission of the author and the J. Pharm. Sci. (Lower right) Renal excretion rate following intake of fenfluramine in the same subjects as those in upper right graph.

ACXIOA' OF PSYCHOMOTOR STIMULANT DRUGS

341

excretion rate as a function of time after administration certain features of absorption and elimination can be obtained (see Fig. 9 which is from an experiment for fenfluramine) (Bruce and Maynard, 1968). The maximal excretion rate coincides with the peak in the plasma concentration. Absorption curves of amphetamine, methamphetamine, and related drugs have been studied by following urinary excretion rates (Fig. 9 ) (Beckett and Rowland, 1965a,b,c; Beckett, 1966; Reckett and Brookes, 1967; Rowland, 1969). Absorption of various amphetamines from buccal membranes is fast and is pH-dependent (Beckett et al., 1968a,b; Beckett and Triggs, 1967). Absorption of amphetamine, methamphetamine, mephentermine, ephedrine, and pseudoephedrine is negligible at pH 5.0 but 10-23% at pH 7.5. However, the buccal absorption of benzphetamine, fenfluramine, phenmetrazine, and dimethamphetamine is substantial at pH 5.0 (Brckett and Triggs, 1967; Beckett et al., 1968a). The absorption rate depends on the particular stimulant, the pharmacological formulation, and the route of administration. Absorption may be retarded when food has been ingested recently or when higher doses are given of stimulants that have sympathomimetic properties which consequently cause intestinal muscle relaxation. OF AMPHETAMINES C. KINETICSOF DISTRIBUTION

From studies of 14C-labeled amphetamine by total body autoradiography, it is evident that methamphetamine passes rapidly from blood to brain (Fig. 10). The brain concentration is far in excess of the blood even within 20 seconds after intravenous injection when the drug has only reached the large vessels of the liver. A strong accumulation of methamphetamine and related compounds signifies that the appiirent volume of distribution will be large. Using ,'H-laheled dexaniphc+amine in rats it was found that absorption following intrapcritoneal administration was rapid. Maximum plasma levels were achieved in 30 minutes (Maickel et al., 1966). Plasma levels declined in a biphasic exponential curve ( tl,- = 30 minutes the first 2 hours and about t,,? = 3 hours during 2-24 hours). Dexamphetaminc was taken up rapidly and bound to tissues except fat. Tissuc/pl;isma ratios were found maximal within

342

JACQUES M. VAN ROSSUM

FIG. 10. Total body autoradiograms of N-methyl-"C-labeled methylamphetamine in mice following I.V. injection of 5pCurie radioactive compound. Sections from different mice killed 2, 16, and 32 minutes after injection of the label. Within 2 minutes after injection a high amount of label is already seen in the brain, especially in the cortex, thalamus, and infundibular area. There is a large amount in the stomach indicating secretion into the lumen. The salivary glands are strongly labeled, but the blood contains a small amount of label. This suggests a rapid distribution and accumulation in various parts of the body. After longer survival times the thymus gland becomes labeled while the liver and the kidney show a high intensity. The stomach continues to have a high level of radioactivity. There is obviously not a uniform pattern of distribution for methamphetamine.

the first half hour: brain 9, liver 1, kidney > 30, heart 4,arid fat 1. Tissue levels fell at the same rate as plasma levels (Maickel et d., 1W9). The distribution of pemoline in rat brain is not uniform; higher levels are found in the cerebellum (Brink and Stein, 1968). From the curves of Fig. 9 a rough estimate of fictive volume can be made by dividing the dose by the maximum p l a s m con-

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

343

centration, under the assumption that the drugs have been absorbed. A fictive volume of 200-700 liters for normal man is obtained. The fictive volume of distribution of dexaniphetamine in human subjects was found to be 250-290 liters ( Rowland, 1969). This figure is of the same order of magnitude as the fictive volume of the highly lipid-soluble drug thiopental ( Riegelman et al., 1968). Since the amphetamines are relative strongly lipid soluble in the form of the free base, the ratc of penetration of various drugs will be dependent on the pK, value. No studies have been made in this regard, but the onset of stimulant effect may serve as an indication of rate of penetration into the brain. Phenmetrazine acts rapidly, while the onset of action of norpseudoephedrine is rather slow (see Fig. 3). Information on the distribution pattern in man can only indirectly be obtained from plasma concentration curves while few such curves have been determined as yet. D. KINETICSOF METABOLISM OF

AMPHETAMINES

Amphetamine is eliminated partly by renal excretion and partly by biotransfonnation. Para hydroxylation followed by conjugation and oxidation to benzoic acid takes place in man. In various animal species and with analogs, different biotransformation processes take place. In the rat, ring hydroxylation is the predominant step but in the rabbit, dealkylation ( Axelrod, 1954, 1955). Metabolism of amphetamine in the dog and monkey resembles biotransformation in man, whereas rats and rabbits metabolize via different routes (Dring et al., 1966; Ellison et nl., 1965) (Table X ) . There are slight differences in metabolism for the dextro and lev0 forms (Dring et al., 1966; Gunne and Galland, 1967). From blood level curves of amphetamine studied by Rowland (1969), it may be calculated that the total clearance of dexamphetamine in man is 260 ml/minute, the renal clearance 125 ml/minute, and the metabolic clearance 130 ml/minute. The biologic half-life is about 12 hours. If metabolism only was responsible for elimination, the biologic half-life would be about 25 hours. If renal clearance were maximal as is the case for acid urine (Beckett et al., 1969), the total clearance would be about 6 hours. Methamphetamine is demethylated to amphetamine while both compounds are excreted in the urine at the same rate (Beckett and Rowland, 1 9 6 5 ~ ) In . dimethylamphetamine the first methyl group

344

JACQUES M. VAN ROSSUM

TABLE X ELIMINATION OF VAR~OUS METABOLITES OF RACEMIC AMPHETAMINE SIJLFATEIN MANAND OTHERM A M M A L S ~ . ~ Metabolites found in urine in percentage of dose Amphetamine p-Hydroxyamphetamine Berizylmethyl ket,one l-Phenylpropan-2-01 Benzoic acid Total of above metabolites “C output total in urine after 2 days total in urine after 3 days total in feces after 3 days total eliminated

Rabbit

Man

Dog

Rat

4 7

30

38 7 2 .5 2 32 82

60 0 0 3 76

8 27 68

3 3 0 20 56

81 92

66 91

7 99

91

22

89 91.5 91.5

13

84 86 5 .5 !3 I

From Dring et al., 1966. Isotope dilution was carried out on urine collected for 2 days after dosing i n the rat, and one day for the other species. a

is removed rapidly with the formauon of methamphetamine (Fig. 11).From the urine excretion rate curves it may be concluded that methamphetamine is the metabolite that is responsible for the stimulant action of dimethylamphetamine in man. The same is true for rats, as the locomotor stimulant action of dimethamphetamine is largely abolished by proadifen (SKF-525A) (van Rossum et al., 1970). Benzphetamine is metabolized mainly into methamphetamine and excreted in the urine as such (Beckett et al., 1967). In rats treated with SKF 525A the benzphetamine dealkylation is prevented, and consequently the intensity of action is diminished but the duration is tremendously increased (van Rossum et al., 1970). Methylephedrine also is rapidly demethylated into ephedrine, while further demethylation appears to occur slowly ( Wilkinson and Beckett, 1968a,b). Although there is still a lack of information on the metabolism of most of the psychomotor stimulant drugs, it is likely that there are enormous differences among the individual drugs. Simultaneous administration of other drugs with amphetamines may result in interaction at the level of the receptors or also at the level of metabolic degradation. Desipramine potentiates the am-

Urine ml/rnin Dimethylamphetarnine HCL 10 rng.8 19 mg free base

Subject T.V

a 0.5 70

501

12 24 36 Renal excretion ( g/min log scale

60

48 Hours

72

I

04

6

r

I.o

,.... . .. !

:

01 Amphetamine

i

001

0005

12

24

36

Cumulative renal excretion (mg base) 2.0

48 Hours

60

72

84

-

96

Cumulative renal excretion (% 1 ;e)

20

1.5 1.0

.A

Dtmethylarn@etarnine

10

0.5 o-.-.o-.-'

12

24

o-

36

Amphetamine 0

48

o-.-.O-.~-.-.-.Q-.-.-.-oO-.-.-.-

60

72

84

Hours

FIG.11. Kinetics of renal excretion of ( + ) dimethylamphetamine in man following oral administration of the hydrochloride salt obtained from analysis of fractionally collected urine. Average urine production per fradion ( a ) ; urine pH of each fraction ( b ) ; renal excretion rate of the parent compound and the two metabolites dexamphetamine and methamphetamine ( c ) ; cumulative renal excretion of the parent compound and its two metabolites ( a ) ; dimethylamphetamine is rapidly converted into methamphetamine, which in turn is more slowly converted into amphetamine. The major fraction is excreted as methamphetamine.

346

JACQUES M. VAN ROSSUM

phetainine action in rats probably by impairment of the hydroxylation of amphetamine to parahydroxyamphetamine ( Consolo et a?., 1967). E. KINETICSOF ELIMINATION OF AMPHETAMINES Amphetamines and related compounds are to some extent excreted unchanged via the kidney (Beckett and Rowland, 1965a,b,c; Beckett and Brookes, 1967; Bruce and Maynard, 1968). In addition to glomerular filtration there is tubular secretion since a renal clearance of 400-500 ml/minute has been found for dexamphetamine in case of acid urine ( Beckett et al., 1969). Tubular reabsorption is substantial but dependent on the urinary pH. Since, at the pH of the blood, amphetamine and methamphetamine are largely in the ionized form, tubular reabsorption following glomerular filtration is incomplete. Lowering of the pH of the urine results in a still smaller fraction of neutral base, which results in a greater renal clearance (Beckett et al., 1967; Asatoor et al., 1965) (see Fig. 12). It is anticipated that amphetamine-like drugs with pK, value lower than 7.5 are sparsely excreted by the kidney even at the lower end of the possible pH scale. This is the case for cocaine and Cumulative renol excretion (mg)

-

Dexamphetarnine I I mg

:-.-.-.-

Alkaline Uncontrolled

4

8 Hours

12

4

8

12

Hours

FIG. 12. Cumulative renal excretion of dexamphetamine and methamphetamine in man under conditions of production of uncontrolled acid ( p H 5-6) or alkaline (pH 7-8) urine. After Beckett et al. ( 1966; Rowland and Beckett, 1966).

347

ACTIOX OF PSYCHOAIOTOR STIMULANT DRUGS

Psychomotc) r stimulant or anorexic drng

I'ercwiiagr of

Dexamphetamiriea~ Methamphetaminea Dimethamphetaminec Bensphetamineo Phenmetrasined Phenterminec Chlorphenterminec Fenfluraminee

dose excTf.letl

Biological h slf -1 if e

Illlc.hallyed

(hours)

20-60 20-50 .5-20 0..i-l 90-1 00 80-90 10-30

Apparent fictive volume of distribution (liters)

6-8 6-8 3 4

200-700

6-8

200-300

15-20 3.i-40 2-4

200-300

Beckett et uZ. (1967).

* Beyer and Skinner

(1940).

Vree et al., 1969. Quinn et a!. (1967). e Bruce arid Maynard (1968).

benzphetamine. Such stimulants would have a prolonged action if they were not metabolized. At the normal pH of the urine in man about 2050%of amphetamine is excreted by the kidney in the unchanged form (Beckett et (il., 1967). The biological half-life of amphetamine is 6-12 hours. (See Table XI for t,,? values of related drugs. ) Analogs of amphetamine with stronger lipophilic properties (for example, benzphetamine) are excreted unchanged in small amounts (Beckett et al., 1967). Metabolically stable amphetamines such as phentermine and chlorphentermine are completely excreted in the urine (Vree and van Rossum, 1970). The lipid solubility of chlorphentermine is greater than for phentermine, while the pK, value is slightly lower. The low rate of excretion of the chloro analog is in accordance with physicochemical properties (Vree et al., 1969). V. Antagonism of Amphetamine Action and Interaction with Other Drugs

A dissociation of the various components in the psychomotor action can be obtained by studying structural analogs. By the use of selective antagonists and other drugs that interfere with, or

348

TACQIJES M. VAN ROSSUM

stimulate, amphetamine actions, further information on the various components of amphetamine action can be obtained. Interaction of amphetamine with selectively acting drugs may provide evidence for its mechanisms of action.

A. ANTAGONISM WITH NEUROLEPTICS The neuroleptic phenothiazines, such as chlorpromazine and trifluperazine, and butyrophenones such as haloperidol and pimozide, are useful in the treatment of psychomotor agitation in psychotics. They reduce aggressive behavior in man and lessen psychotic symptoms such as paranoia. The neuroleptics cause behavioral inhibition, ptosis, and catalepsy, and they suppress avoidance behavior in rats and other animals (Janssen et al., 1965). On various behavioral features the neuroleptics exhibit an effect op-

?dl-rn-Tyroslne316~ole/kg I p

1265 6 I O c Pretreated wlth

Spiramide 056pmole/kg

J

t

dl-m-Tyroslne

316pmole/kg I P

Ip

t

dl-m-Tyrosine

1000 pmole/kg

IP

/-

FIG. 13. Antagonism of dexamphetamine and m-tyrosine by the neuroleptic drug spiramide tested on locomotor activity in mice. The antagonism is surmountable since a higher dose of the stimulant can break through the blockade produced by the antagonist. Reproduced after van Rossum (1967) with permission of the proceedings of the CINP meeting.

ACTIOK OF PSYCHOhlOTOR STIMULANT DRUGS

349

posite to the amphetamines. For instance, they inhibit self-stimulation in cats and rats, whereas amphetamine produces facilitation (Horovitz, 1962b) (see also Fig. 6 ) . The neuroleptic drugs are selective and potent antagonists of amphetamine. Dexamphetamine locomotor activity is reduced to a normal or subnormal level by an adequate dose of chlorpromazine or haloperidol (Fig. 13). The antagonism is surmountable as higher doses of amphetamine break the antagonism indicating competition (van Rossum, 1967). Increasing locomotor activity induced by other psychomotor stimulant drugs is antagonized by similar doses of the neuroleptics. Therefore, the effect of methamphetamine, norpseudoephedrine, and cocaine, as well as the stimulant effect of L-dopa and m-tyrosine, is efficiently blocked by neuroleptics. The chlorpromazine-amphetamine antagonism has also been studied in pigeons conditioned for food reinforcement on a fixed ratio schedule (Davis, 1965). Pigeons injected with amphetamine in a dose that completely stops operant behavior exhibit trained behavior when amphetamine is combined with chlorpromazine. Rats conditioned on a FR or DRL schedule also behave normally on a combination of spiramide and cocaine. Simultaneous registration of motor activity shows that motor activity is more susceptible than operant behavior to the action of amphetamine and the neuroleptic (Fig. 14) (van Rossum, unpublished observations, 1966). Stereotyped behavior induced by amphetamine or apomorphine is also completely blocked by neuroleptics but not by ataractics such as meprobamate and diazepam (Randrup et al., 1963; Randrup and Munkvad, 1965; Z. S. Herman, 1967); thymoleptics, however, increase stereotyped movements ( Lapin, 1966). The increase in motor activity by low doses of chlorpromazine (Sulser, 1968) and amphetamine, which facilitated self-stimulation in rats, is probably due to a thymoleptic action of certain neuroleptic agents. The antagonism of dexamphetamine on apomorphine-induced motor agitation and compulsive gnawing and sniffing is used as a routine procedure for the evaluation of neuroleptics (Janssen et al., 1960, 1%7; van Neuten, 1962). From profiles of antagonism of a large number of neuroleptics it may be concluded that agitation and compulsive chewing are different entities, which may be antagonized to a different degree by the various neuroleptics (Janssen et al., 1967). In low doses certain neuroleptics may inhibit stereotyped activity preferentially over locomotor activity. Thus

350

TACQUES M. VAN ROSSUM

)566 Rat 51

[ / J & Z & 0

8

0 5 6 6 Rat 51 DRL 10" ss 28

1 Cocaine 31.6pmole/kg

15 min

--

i.p.

t

0 5 6 6 Rat 51

t

Spiramide 0.56 mole/kg i.p Cocaine 31.6pmole/kg i.p.

t FIG. 14. Simultaneous records of lever pressing for food on a differential low rate schedule (DHL 10 sec) and locomotor activity in rats. Reinforcements are indicated by oblique pip7 on the record. (Top) the control session ( 2 7 ) while the control session 29 is omitted; (middle) following administrrition of cocaine (28), lever pressing is increased but the number of reinforcements decreases, while locomotor activity strongly increases; (bottom) the neuroleptic spiramide counteracts the stimulant effects of cocaine with respect to both locomotor activity and lever pre-sing. The rat now receives many reinforcements.

perphenazine inhibits the stereotyped movements induced by amphetamine but simultaneously increases grooming and locomotor activity (Kandrup and Munkvad, 1965). Profiles of neuroleptic activity of chlorpromazine, haloperidol, and pimozide in various animal species reveal that the amphetamine

ACI'ION OF PSYCHOMOI'OH STIMULANT DRUGS

35 1

and aponiorphine antagonism is a general feature of neuroleptic drugs (Janssen et al., 1968). Bizarre social behavior elicited by amphetamine in reserpinized rats, or by apomorphine alone or by dopa (in Ro 4.4602 treated rats) is completely abolished by low doses of neuroleptic drugs (Lammcm and van Rossum, 1968; van Rossum et al., 1970). B. AMPHETAMINE ACTIONIS RESERPINIZED ANIMALS Reserpine causes a release of biogenic amines, dopamine, noradrenaline, and 5-hydroxytryptamine (5-HT), both in the peripheral and central nervous system (Pletscher et al., 1956). The peripheral sympathomimetic effects of amphetamine and phenylethylamine are prevented by reserpine treatment, suggesting that amphetamine acts as an indirect sympathomimetic by releasing noradrenaline (Burn and Rand, 1958). Reserpine in doses of 1-5 mg/kg causes behavioral inhibition in animals. Typical symptoms are reduction of locomotor activity and a hunched-back posture. In trained animals reserpine causes a reduction of avoidance responses in low doses, while in higher doses the escape responses are impaired ( Hanson, 1965 ) . Amphcxtamine counteracts the behavioral inhibition elicited by reserpine ( K . Tripod et al., 1954; Kobinger, 1958; Everett and Toman, 1959). Adequate doses of reserpine that cause catecholamine and 5-HT depletion in the central nervous system do not abolish the central locomotor stimulant effects of amphetamine (Everett et al., 1957; Everett and Toman, 1959; Everett, 1961; K. Tripod et al., 1954; Stein and Seifter, 1960; C. B. Smith, 1963; van Rossum et al., 1962). In some studies a reduction of the locomotor stimulant effects of amphetamine occiirs in reserpinized animals, but by increasing the dose of amphetamine it is always possible to restore maximal stimulant action (Rowe et al., 1961; van Rossum et al., 1962; C. B. Smith, 1963). In most studies the peak effect of amphetamine is enhanced by the reserpiue treatment (C. B. Smith, 1963; Quinton and Halliwell, 1963) (Fig. 15). Enhancement or suppression of the amphetamine effect depends on the time interval between dosage of the two drugs. Time studies as well as doseresponse studies show that shortly after reserpine the amphetamine effect is diminished, but that more than 8 hours after reserpine the amphetamine action is enhancwl (C. B. Smith, 1963; Stolk and Rech, 1967). In a study of the locomotor stimulant action of amphetamine

352

JACQUFS M. VAN ROSSUM

p E 7 i 7

m 14:m 64 (reserpinized)

FIG. 15. Interaction of reserpine with dexamphetamine and cocaine on locomotor activity in mice. The cocaine effect is fully abolished by the reserpine treatment, whereas the amphetamine effect remains virtually unchanged. Reproduced after van Rossum and Hurkmans (1964) with permission of Intern. J . Neuropharm.

and cocaine in the same animals, it has been shown that while the amphetamine or methamphetamine effect is not altered by reserpine pretreatment the cocaine action is completely abolished (van Rossum et a/., 1962; Schmidt and Meisse, 1962; J. Tripod et al., 1954; Kobinger, 1958) (Fig. 15). Pipradol (C. B. Smith, 1963) and benzylamphetamine (van Rossum et al., 1962) is affected by reserpine treatment in the same way as cocaine. By analogy with the peripheral effects of amphetamine, it has been concluded that amphetamine might act directly on receptors for catecholamines in the brain (van Rossum et al., 1962; C. B. Smith, 1963, 1965; Everett and Toman, 1959). Conditioned avoidance behavior is decreased by reserpine, while amphetamine treatment thereafter restores the conditioned avoidance response in cats ( Hanson, 1965). The facilitation of amphetamine on self-stimulation in the posterior

ACTIOS OF FSYCIIOMOTOR STIMULANT DRUGS

353

hypothalamus ( medial forebrain bundle) is completely abolished by reserpine treatment (Stein, 1964a). From these data it has been concluded that amphetamine might act by a release of noradrenaline (Stein, 1964b). The stereotyped behavior of high doses of amphetamine is not changed by reserpine pretreatment (Janssen et al.. 1965; Randrup and Munkvad, 1965, 1967a,b). Reserpine treatment changes certain components of thc amphetamine action and leaves others unchanged while stereotyped movements are exaggerated. It is obvious that it is not justified to draw general conclusions from amphetamine-reserpine intcractions with regard to amphetamine, since depletion of brain amine stores does not necessarily mean impairment of transmitter function. L-Dopa and related amino acids such as rn-tyrosine also counteract reserpine behavioral inhibition (Carlsson et al., 1957; Blaschko and Chrusciel, 1960; Everett and Wiegand, 1962). 5-Hydroxytryptophan (5-HTP), however, is without effect (Kobinger, 1958; Everett and Wiegand, 1962; van Rossum et al., 1962; C. B. Smith, 1965). These findings suggest a specific function of brain catecholamines in psychomotor stimulation and amphetamine effects. OF MONOAMINE OXIDASEINHIBITORS WITH C. INTERACTION AMPHETAMINES

M A 0 inhibitors such as iproniazid, nialamide, and pargyline cause a rise in the brain monoamines noradrenaline, dopamine, and serotonin. They do not have strong behavioral effects in normal rats and other animals. There are differences, however, among the various MA0 inhibitors; for example, tranylcypramine exerts an amphetamine-like effect in addition. Also, nialamide has a locomotor stimulant action about 3 hours after intraperitoneal injection which continues for several hours. M A 0 inhibitors strongly potentiate psychomotor stimulant effects of phenylethylamine, which amine is also metabolized by the M A 0 enzyme (Blaschko, 1952; Mantegazza and Riva, 1963; Stein, 196413) (see Figs. 1 and 7 ) . However, M A 0 inhibitors also potentiate amphetamine-induced locomotor increase (van Rossum and Hurkmans, 1964), self-stimulation (Stein, 1964b), positive and negative reinforcement, and oprrant behavior ( Carlton, 1961). The central stimulant effect of cocainc. is not potentiated by MA0 inhibition (van Rossum and Hurkmans, 1964). M A 0 inhibitors such as pargyline prevent the metabolism of the metabolites of dopa, and

354

JACQUES M. VAN ROSSUM

consequently the brain levels of dopamine are increased 10-fold and a strong amphctamine-like central excitation ensues ( Everett and Toman, 1959; Everett and Wiegand, 1962). The combination of dopa and pargyline only slightly increases brain noradrenaline and brain serotonin levels, indicating a predominant role of dopamine in central excitation ( Everett and Wiegand, 1962; Bertler, 1961). Dopa and also other tyrosine analogs exert a central stimulant effect following M A 0 inhibition (Blaschko and Chrusciel, 1960; van Rossum and Hurkmans, 1964). M A 0 inhibition has no influence on compulsory chewing induced by apomorphine ( Ernst, 1967). The augmentation of amphetamine effects by pretreatment with MA0 inhibitors is in accordance with a possible releasing effect of amphetamine on brain monoamines. OF THYMOLEPTICS WITH AMPHETAMINES D. INTERACTION

The thymoleptic drugs imipramine, desipramine, protriptyline, etc., are used to elevate depressive states. The thymoleptics exaggerate certain components of the central stimulant action of amphetamine-like drugs. Desipramine augments the locomotor stimulant effects of amphetamine, but the locomotor stimulant effect of cocaine is not potentiated by desipramine. However, the stimulant effects of cocaine on continuous avoidance behavior in rats is potentiated by various thymoleptics ( Scheckel and Boff. 1964). Desipramine does not potentiate amphetamine-induced stereotyped behavior but predominantly augments the increase in locomotor activity (van Rossum et al., unpublished), When a thymoleptic is combined with an MA0 inhibitor a pure rage reaction results in rats not accompanied by stereotyped activity ( Fog, 1969). The antidepressant drugs imipramine, amitryptyline, and protryptyline, while having a slight effect on evoked cortical responses in the rabbit by themselves, significantly potentiate the increase in amplitude of cortical evoked responses produced by methamphetamint: ( Plotnikoff and Everett, 1965). Imipramine strongly potentiated the facilitating effect of methamphetamine on the self-stimulating rat with electrodes in the hypothalamic or midbrain reward system (Stein, 1962b, 1964a,b,c, 1967). Imipramine alone also facilitates self-stimulation in cats with electrodes in the lateral hypothalamus, but not when electrodes were placed in the caudate nucleus (Horovitz et al., 1962a,b). The thymoleptics act by inhibiting re-uptake of noradrenaline released as a result of nervous activity or by other

ACTION OF PSYCE-IOhIOTOR STIMULANT DRUGS

355

means (Iversen, 1965). Cocainc- also inhibits re-uptake of noradrenaline and exhibits, as well, a psychomotor stimulant action. This implies that cocaine, in addition to its imipramine-like effect, also is able to release catecholamines in the brain or has the capacity to inhibit re-uptake of dopaminc. The potentiation of the amphetamine effects by re-uptake inhibitors suggest that amphetamine may cause a release of noradrenaline as far as locomotor activity and self-stimulation is concerned. OF AMPHETAMINESWITH SYMPATHOLYTIC DRUGS E. INTERACTION

Alpha sympatholytic drugs inhibit to some extent the central stimulant effects of amphetamines. The analeptic effect of amphetamine measured on EEG was found to be inhibited by irreversible acting drugs such as dibenamine and phenoxybenzamine as well as by chlorpromazine but not significantly by the classic alpha sympatholytics phentolamine and dihydroergotamine ( Mufioz and Goldstein, 1961 ) . The beta sympatholytic dichloroisoproterenol was without any effect in this test. Propranolol has been found to antagonize stereotyped movements to some extent (Z. s. Herman, 1967) but was found to be ineffective in other experiments (Randrup et ale, 1963). Chlorpromazine and a number of other neuroleptics exhibit sympatholytic effects ( Janssen et al., 1965). Certain potent neuroleptics such as haloperidol, perphenazine, and spiramide are extremely weak sympatholytics. There is no correlation between the selective antiamphetamine and antiaponiorphine effects of the neuroleptics and the antiadrenergic effects (Janssen et al., 1965; van Rossum, 1967). Alpha receptors do not play a role in amphetamine-induced stereotyped behavior and bizarre social behavior and only a minor role in locomotor stimulation. F. INTERACTION OF AMPHETAMINE WITH CHOLINOLYTIC AND OTHER DRUGS

Amphetamine-induced increase of locomotor activity is potentiated by cholinolytic drugs (J. Tripod, 1952). The stimulant effect of amphetamine in an operant shock avoidance situation is augmented by atropine ( Carlton and Didamo, 1961 ) . Also, scopolamine has been found to exert such a potentiation. Atropine, scopolamine, and trihexyphenidyl produce a slight potentiation of the increase of

356

JACQUES M. VAN ROSSUM

responding of rats in a continuous avoidance schedule, but they markedly potentiate the stimulant effects of cocaine (Scheckel and Boff, 1964). The cholinolytics also potentiate amphetamine-induced stereotyped behavior ( Arnfred and Randrup, 1968; Schelkunov, 1964). Tranquillizers such as meprobamate and chlordiazepoxide have no antagonistic effect on the amphetamine action in doses that do not cause significant motor incoordination (Z. S. Herman, 1967; Randrup and Munkvad, 1965; Lammers and van Rossum, 1968). Although the amphetamines have an awakening effect in animals and man depressed with barbiturates and other hypnotic drugs (Tainter et al., 1939), other forms of interactions may be encountered. Barbiturates may exaggerate amphetamine-induced central stimulation in certain doses and cause inhibition in higher doses (Steinberg et al., 1961; Rushton and Steinberg, 1963). Cholinolytics and a number of other drugs may antagonize or facilitate, in an unspecific manner, certain components of amphetamine-induced central excitation. Such interactions have provided little information on the mechanism of action of amphetamine.

VI.

Psychornotor Stimulant Action and Brain Catecholamines

Since amphetamine and all other psychomotor stimulant drugs except cocaine have in common with the catecholamines the phenylethylamine structure, it is reasonable to assume that receptors for catecholamines in the brain play a role in psychomotor stimulant action. The significance of brain monoamines for psychomotor stimulant action has been critically reviewed recently by Beauvallet ( 19SS). Much evidence has accumulated indicating a predominant function of brain dopamine and noradrenaline but an insignificant role of 5-hydroxytryptamine in the central stimulant effects of amphetamine.

A. EFFEC~S OF AMPHETAMINEON BRAINMONOAMINES Extremely high doses of amphetamine (10-30 mg/kg) cause a diminution of brain noradrenaline levels ( McLean and McCartney, 1961; Moore and Lariviere, 1963; Sanan and Vogt, 1962; Beauvallet et aZ., 1963). With the same treatment serotonin levels are slightly increased ( McLean and McCartney, 196l), while dopamine levels remain unchanged (Baird and Lewis, 1964). The use of a normal

ACTION OF PSYCHOXIOTOR STIMULANT DRUGS

357

dose of amphetamine showed that brain dopamine levels increased significantly ( C. B. Smith, 1965; Littleton, 1967). Dexamphetamine and tetrahydronaphthylamine lowered the noradrenaline content of hypothalamic brain areas (but not that of striatal dopamine) while they increased homovanillic acid levels ( Laverty and Sharman, 1965). By simultaneous inhibition of the biosynthesis of cathecholamines it has been found that dexamphetamine in normal doses ( 2 mg/ kg ) counteracts the catecholamine lowering effect of the inhibition of biosynthesis ( Littleton, 1967). In studying various psychomotor stimulant drugs such as phenmetrazine, methamphetamine, and cocaine, it became evident that d-phenmetrazine is a more potent psychomotor stimulant than l-phenmetrazine, whereas the latter has a stronger effect in lowering brain noradrenaline than the former ( Baird and Lewis, 1964). Furthermore, the doses used were high with regard to the central stimulant actions. The possible influence of amphetamines on brain monoamine levels has probably no relation to their psychomotor stimulant action. This conclusion is not in contradiction with a possible catecholamine releasing effect of amphetamines in the brain. With the fluorescence microscope technique it could be shown that again extremely high doses of amphetamine (15-60 mg/kg) cause a marked decrease in number and intensity of noradrenaline neuron terminals in the neocortex, gyrus cinguli, and reticular formation, while dopamine and 5-hydroxytryptamine terminals exhibited normal appearance. In reserpinized animals treated with nialamide and L-dopa, amphetamine (5 mg/kg) causes a decrease of dopamine and an increase in 3-methyldopamine indicating a release of dopamine ( Carlsson et al., 1965). Amphetamine in relatively low doses (0.1-0.5 mg/kg) partially blocked dopa-induced accumulation of noradrenaline in various parts of the brain, whereas dopamine accumulation was not reduced but rather augmented (Carlsson et al., 1966a,b). In these experiments the reduction of noradrenaline accumulation appeared to be most sensitive to the action of amphetamine. OF SYNTHESISOF CATECHOLAMINES B. INHIBITION AND PSYCHOMOTOR STIMULANT ACTION

Tyrosine hydroxylase is the rate-limiting step in the biosynthesis of catecholamines from L-tyrosine via L-dopa (Levitt et al., 1965).

358

JACQUES M. VAN ROSSUM

The a-methyl analog of L-tyrosine (a-MPT) is a potent inhibitor of mammalian tyrosine hydroxylase ( Nagatsu et al., 1964). Inhibition of the biosynthesis of catecholamine by a-MPT leads to a severe reduction of noradrenaline and dopamine levels in brain and other tissues ( Spector et al., 1965). In a dose of 100300 mg/kg, a-MPT causes a reduction of spontaneous locomotor activity in rats and mice (van Rossum, 1963; Rech, 1966), operant behavior (Rech et al., 1966), and self-stimulation (Stein, 1968) simultaneously with a selective depression of catecholamine levels (Rech et al., 1966). In man following chronic a-MPT medication only minimal behavioral depression has been observed (Gershon et al., 1967). This is comparable with the development of tolerance to a-MPT found in rats (Moore and Rech, 1967a) . Maximum reduction in catecholamine levels correlates well with behavior depression which occurs 4-8 hours after wMPT (Hanson, 1965; Moore, 1967b; Pirch and Rech, 1967). Treatment with a-MPT blocks the central stimulant action of amphetamine with regard to locomotor activity ( Weissman et al., 1966; Dingell et al., 1967), conditioned avoidance behavior in rats (Weissman et al., 1966; Weissnian and Koe, 1965) and in cats (Hanson, 1965), and stereotyped movement ( Randrup and Munkvad, 1966a). These experiments strongly suggest that amphetamine acts by releasing catecholamines. In studying the influence of drugs on self-stimulation in rats, Poschel and Ninteman (1966) found that methamphetamine antagonized the suppression of self-stimula. tion caused by a-MPT. Also, the finding that dexamphetamine restores to a large extent the a-MPT depressed behavior in a conditioned avoidance situation is not in contradiction with this postulation (Moore and Rech, 1967b), since depletion of catecholamines by a-MPT is not complete unless high doses are used. Since a-MPT blocks biosynthesis of catecholamines the extent and the rate at which brain levels are reduced depends on the rate of release of neurotransmitters. Inhibition of re-uptake of noradrenaline by desipramine accelerates depletion ( Neff and Costa, 1967). A severe and persistent depletion occurs if reserpine and a-MPT are combined (Hanson, 1967a) (Fig. 16). The dependence of catecholamine levels on the action of nmphetamine is stressed by the observation that the amphetamine action is reported after a-MPT treatment by L-dopa with regard to stereotyped movements (Randmp and Munkvad, 1966b; Emst, 1967),

359

ACTION OF PSYCIIOMOTOR STIMULANT DRUGS

a

b

Group

100 80

60 LO

20 Reserpine 0.1 mg/kg aMPT ester 200 mg/kg [+)-Amphetamine 2 m g / kg

0

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FIG. 16. Conditioned avoidance ( hatched columns ) and escape response (open colunins) in percent in untreated cats and in cats that received various treatments inducing changes in brain catecholamine levels. Reserpine and the combined treatment with reserpine and tyrosine methylester (aMPT) Completely blocks avoidance responding. Dexamphetamine does not reverse conditioned avoidance responding whereas subsequent administration of L-dopa does result in complete reversal of avoidance responding. Reproduced after Hanson ( 1967a,b) with permission of the author and Psychophurmacologia.

locomotor activity, and conditioned avoidance behavior ( Hanson, 1967a,b) (Fig. 16). The behavioral action of apomorphine is not changed by treatment after a-MPT (Weissman and Koe, 1965; Ernst, 1967). Apomorphine-induced bizarre social behavior is not changed following inhibition of synthesis of a-MPT ( van Rossum and Simons, 1970). If, however, a-MPT is preceded by a low dose of reserpine, ensuring selective depletion of catecholamines, apomorphine action on bizarre social behavior is increased and modified in the sense that vigorous biting also occiirs (van Kossum and Simons, 1970). Selective depletion of brain catecholamines, dopamine, and noradrenaline with sufficiently high doses of a-MPT or with the combined treatment of a-MPT and reserpine blocks the various components of central stimulant action of amphetamine. It may be concluded that the presence of noradrenaline and/or dopamine is required for psychomotor stimulant action and that amphetamines

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TACQUES M . VAN ROSSUM

release these amines. The distinct role of noradrenaline and dopamine will be discussed later.

C. INHIBITION OF SYNTHESIS OF NORADRENALINE AND PSYCHOMOTOR STIMULANTACTION The synthesis of noradrenaline takes place in the storage granules of noradrenergic neurons. Reserpine abolishes catecholamine storage and as a consequence impairs noradrenaline synthesis (Stjiirne, 1966). Evidence has been obtained that reserpine does not effect dopamine synthesis since the brain levels of dopamine metabolites such as dioxyphenylacetic acid and homovanillic acid are not decreased in reserpinized animals (AndCn et al., 1964). Both the locomotor stimulant action and other behavioral symptoms of central excitation such as stereotyped movements are normally present following amphetamine administration in reserpinized animals (C. B. Smith, 1963; van Rossum et al., 1962), indicating the importance of dopamine in psychomotor stimulant action. The biosynthesis of noradrenaline from dopamine can be blocked to some extent with disulfuram and diethyldithiocarbamate (Goldstein and Nakajima, 1966). In reserpinized animals treated with dopa and diethyldithio carbamate, the level and turnover of noradrenaline is low ( Schcel-Kriiger and Randrup, 1967a) while only dopamine is present in sufficient amounts. Under such conditions amphetamine still elicits stereotyped movements but lacks any locomotor stimulation. These experiments indicate the involvement of dopamine in stereotyped behavior and suggest that noradrenaline would be needed for locomotion ( Scheel-Kriiger and Randrup, 1967a). Diethyldithiocarbamate is given in such high doses that locomotion may be impaired by toxic effects. In rats, nialamide (100 pmole/kg) causes a strong increase of locomotor activity after a latency period of 2-3 hours, and a subsequent intraperitoneal injection of diethyldithiocarbamate at the peak effect of nialamide immediately reduces motor activity. Inhibition of biosynthesis of noradrenaline in such a situation would imply reduction of motor activity only after a latency period. D. INHIBITION OF SYNTHESIS OF BRAINSEROTONIN AND PSYCHOMOTOR STIMULANT ACTION

It has been suggested that aniphetarnine-induced central stimulant effects may be due to an interaction at the level of serotonin or tryptamine receptors (Vane, 1961).

ACTION OF PSYCHOMOIOR STIMULANT DRUGS

361

Parachlorphenylalanine causes a selective inhibition of 5-HT synthesis (Weisman et al., 1966). Inhibition of the synthesis of 5-HT, however, does not influence the effects of amphetamine on locomotor activity and operant behavior on a DRL or FR schedule of food reinforcement ( Martens and van Rossum, 1970). These experiments provide further cvidence that 5-HT does not play a role in the psychomotor stimulant effects of amphetamine. In agreement with this thesis is the fact that the behavioral inhibition caused by reserpine treatment cannot be restored by injection of 5-hydroxytryptophan (Kobinger, 1958; van Rossum et al., 1962; C. B. Smith and Dews, 1962). Furthermore, 5-hydroxytryptophan given to animals after an M A 0 inhibitor induces a behavioral inhibition (Aprison and Ferster, 1961). The same precursor of 5-HT given in combination with a peripheral decarboxylase inhibitor does not produce an increase in locomotor activity or stereotyped behavior but a decrease in activity (van Hossum, unpublished data). VII. Mechanism of Action of Psychomotor Stimulant Drugs

Although amphetamine is one of the simplest chemical structures that has profound psychotropic actions, various components in the psychomotor stimulant action of amphetamines can be distinguished. The mechanism of action of amphetamine may therefore be multifactorial with regard to both the different neurotransmitters involved and the action on different structures of the brain. However, the neurotransmitters dopamine and noradrenaline fulfill a major role in the central stimulant effects of amphetamine, and brain structures in which dopamine and/or noradrenalinecontaining neurons are present may be of importance for the locus of action of psychomotor stimulant drugs. A. SIGNIFICANCE OF BRAINNORADRENALINE RECEPTORS

Since amphetamine is an indirect sympathomimetic drug that acts by a release of noradrenaline from sympathetic nerve endings it is reasonable to assume that, in the central nervous system also, a release of noradrenaline could take place. Indeed there is ample evidence that amphetamine causes a release of noradrenaline from adrenergic neuron terminals in the neocortex and the hypothalamus ( Carlsson et al., 1966a; Glowinski and Baldessarini, 1966). A number of psychomotor stimulant drugs, for example, phenmetrazine and zylofuramine, show weak or no sympathomimetic

362

JACQUES M. VAN ROSSUM

actions so that a relationship between peripheral and central effects of amphetamine-like compounds and noradrenaline release need not both occur. Blockade of the amphetamine pressor effect by reserpine pretreatment serves as the major argument for an indirect action in the peripheral nervous system. However, reserpine does not block the central effects of amphetamine although the various components in the action are relatively changed in intensity (see Section V,B ) . In contrast, cu-hIFT blocks practically all amphetamine effects even before brain levels fall below 50%of the control values (Dingell et al., 1967). The antiamphetamine effect of a-MPT clearly cannot be related to the degree of noradrenaline depletion. After inhibition of biosynthesis of noradrenaline with a-MPT the synthesis of dopamine is also blocked. It depends on the relative turnover rates of brain noradrenaline and dopamine as to which neurotransmitter is first depleted. The turnover rate of noradrenaline is about two times slower than that of dopamine ( t l I ndopamine 2-2.5 hours, t,,. noradrenaline 3.5-4 hours) (Udenfriend and Zaltzman-Nirenberg, 1963; Costa and Neff, 1966). The amphetamine-induced central simulation is thus either due to brain dopamine or in certain components (locomotor stimulation) the amphetamine action may depend on the availability of newly synthetized noradrenaline ( Dingell et al., 1967). The cocaine-induced locomotor stimulation is blocked by reserpinization (Fig. 15). Administration of dopa does restore the cocaine central stimulant effect (van Rossum et al., 1962) (Fig. 17). However, the immediate precursor of natural noradrenaline Lthreo-deoxyphenylserine ( L-threo-dops) given as the racemate (only the L form is decarboxylated) is not able to restore the reserpine abolished cocaine stimulation ( van Rossum and Hurkmans, 1964). These experiments suggest that noradrenaline plays only a minor role in the locomotor activity increasing effect of psychomotor stimulant drugs. Intraventicular injection of noradrenaline does not result in an increase in locomotor activity but rather in a decrease, whereas dopamine induces an increase (Bogdanove and Nir, 1965). threodops in rats induced an increase in sleep over control rats as measured by the EEG (Havlicek, 1967). Disulfuram or diethyldithiocarbamate causes a selective although not complete inhibition of synthesis of noradrenaline at the level of the dopamine p-hydroxylase enzyme. Pretreatment with disulfuram reduced the

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

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FIG. 17. Reversal of reserpine-induced suppression of cocaine-induced stimulation of locomotor activity by L-dopa. The cocaine effect is blocked in reserpine-treated mice. L-dopa in a dose that exhibits no effect of its own restores the cocaine effect within 30 minutes. This suggests the involvement of brain dopamine. The intermediate precursor amino acid threo-dioxyphenylserine (threo-dops) does not restore cocaine action under the same circumstances, suggesting that noradrenaline does not play a role.

amphetamine-induced hyperactivity in mice and rats (Maj and Przegalinski, 1967). Also the locomotor stimulation induced by 100 pmole/kg nialamide occurring after a latency period of 2-3 hours is antagonized by diethyldithiocarbamate ( van Rossum, unpub-

364

JACQUES M. VAN ROSSUM

lished ) . Dopa-induced “rage” but not stereotyped behavior is blocked by inhibition of dopamine P-hydroxylase (Scheel Kruger and Randrup, 1967a,b) . Disulfuram attenuated the L-dopa reversal of reserpine-induced suppression of the conditioned avoidance response but spontaneous activity did not seem to be affected (Seiden and Peterson, 1968). Amphetamine reverses the reserpine-induced suppression of conditioned avoidance behavior but is ineffective if a-MPT also has been given (Hanson, 1967a,b) (see Fig. 16). The activity of amphetamine can be restored by dopa ( Hanson, 1967a,b) (see Fig. 16). These experiments suggest the importance of dopamine rather than noradrenaline in conditioned avoidance behavior. Evidence has been obtained with the help of histochemical fluorescence methods that mainly noradrenaline neurons increase their activity during conditioned avoidance behavior, suggesting an important role of noradrenaline nerve terminals in the neocortex for arousal essential for performance of behavioral activity (Fuxe and Hanson, 1967). It seems likely that both noradrenaline and dopamine are involved in conditioned avoidance behavior. Reserpine strongly reduces the stimulating effect of amphetamine on self-stimulation in rats with electrodes in the posterior hypothalamus or midbrain segmentum (Stein, 196413). Treatment with a-MPT diminishes the rate of self-stimulation, but methamphetamine causes a reversal (Poschel and Ninteman, 1966). M A 0 inhibitors such as iproniazid and inhibitors of noradrenaline reuptake such as desipramine potentiate the facilitating action of amphetamine on self-stimulation (Stein, 1962a,b, 1964b,c). The facilitating effect of amphetamine on self-stimulation is therefore most probably due to a release of brain noradrenaline, It has recently been shown that self-stimulation in rats with electrodes in the medical forebrain bundle is suppressed by disiilfiram (Wise and Stein, 1969). Reversal of this suppression-occurred with intraventicular injection of levonoradrenaline but not with dopamine (Wise and Stein, 1969; Stein, 1968). Certain components of the central stimulant action such as facilitation of self-stimulation are due mainly to brain noradrenaline. Others depend on both noradrenaline and dopamine, for example, effects on conditioned avoidance responses, while again other components such as stereotyped behavior depend mainly on brain dopamine.

ACTION OF PSYCIIOXIOI'OH STIhlULAST DRUGS

365

R. SIGNIFICANCE OF BRAIND O P A ~ ~RECEPTORS INE

The R configuration of the ,8-hydroxy group in noradrenaline is of great importance for its effect. The optical antipode (+)-noradrenaline is about 30 times less potent. Dopamine lacks this O H group as does amphetamine. It is therefore conceivable that amphetamine exhibits dopamine-like c4fccts ( van Rossum and Hurkmans, 1964). Dopamine is located in distinct areas of the brain, predominantly the neostriatum and the nucleus accuinbens ( Fuxe, 1965). Administration of dopa-"C in combination with an extraneuronal decarboxylase inhibitor to rats followed by autoradiography shows a predominant localization in these areas and in certain nuclei of the septum (van Rossum et ul., 1970) (Fig. 18 ) . Also, the tuberculum olfactorium and a number of structures outside the brain such as the hair follicles are labeled. A critical review of the role of brain dopamine has recently been gi~7enby Hornykiewicz (1966). L-Dopa causes reversal of rcserpinc-induced inhibition of locomotor activity (Holtz et al., 1957; Carlsson et al., 1957; Everett and Toman, 1959; Blaschko and Chrusciel, 1960; van Rossum et d., 1962; C . B. Smith and Dews, 1962). Administration of dopa alone or in combination with MA0 inhibitor causes a rise in brain dopamine content, the level of which correlates with the degree of behavioral excitation (Everett and Wiegand, 1962). Dopa infused into one lingual artery of a cat caused EEG arousal on the side of infusion, while dopamine levels increase twofold, and noradrenaline levels in the brain remain unchanged (Dagirmanjian et al., 1963) . Locomotor stimulation as induced by cocaine is blocked by reserpine (Kobinger, 1958; van Rossum et al., 1962). Dopa restores the reserpine-induced suppression; also, m-tyrosine had the same effect, but DOPS was ineffective (van Rossum and Hurkmans, 1964) (see Fig. 17). Under such conditions a-methyldopa abolishes the stimulant action of cocaine, and also when animals are reserpinized. If L-dopa is administered 30 minutes after cocaine a locomotor stimulation is observed (Fig. 19). This effect is not observed in reserpinized animals in which b-methyldopa is omitted. The explanation might be that a-methyldopamine metabolites block the storage of dopamine formed from dopa while cocaine blocked re-uptake in the neuron.

366

FIG.18. Total body autoradiograms of a Mongolian gerbil injected with the peripheral dopa decarboxylase inhibitor RO 4-4602 followed by dopa-"C labeled in the 2 position. ( a ) Two hours after injection of labeled dopa there is a high amount of radio activity in the neostriatum, the tuberculum olfactorium, the pancreas, the epidydimus, and the hair follicles. ( b ) Radioactivity in the brain coincides with areas containing a large amount of dopamine nerve terminals. Reproduced after van Rossum et al. (1969), with permission of the Europeaii Journal of Pharmacology.

368

JACQUES M. VAN ROSSUM

0964 834 c

\ \ t

I - - M e dopa 1000 prnole/kg

I

p

FIG. 19. Locomotor activity induced by a low dose of L-dopa in a rat treated with a-methyldopa causing a depletion of brain catecholamines and a prevention of storage. In addition, cocaine causes an inhibition of intraneuronal reuptake of noradrenaline and possibly also dopamine. The dopamine formed by decarboxylation of dopa under these conditions cannot be stored, and once released outside the neuron terminal probably cannot be taken up again. Su5cient dopamine may then react with the postsynaptic dopamine receptors to produce stimulation of motor activity.

The behavioral effects of dopa alone in combination with a peripheral decarboxylase inhibitor or in combination with an M A 0 inhibitor appeared to be quantitatively different from amphetamine stimulation ( see Sections III,E and V,C) . High dopamine levels elicit behavioral effects similar to the stereotyped and bizarre social behavior components of the amphetamine spectrum of action and to the effects of apomorphine. In rats treated with a-MPT, stereotyped behavior induced under normal conditions with amphetamine are blocked, but they can be restored after administration of dopa ( Randrup and Munkvad, 196613). In rats pretreated with a-MPT and injected with dopa and diethyldithiocarbamate, amphetamine-induced locomotor activity is reduced but stereotyped behavior (licking, sniffing, and gnawing) is of normal intensity, although movements may be slow (Randrup and Munkvad, 196713).

ACTION OF PSYCHOhIOTOR STIhfULANT DRUGS

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Rats treated with reserpine (3.16 pmolc,/kg) and 16 hours later given 516 pmole/kg (U-MPTdo not give any of the behavioral stimulant actions of amphetamine, Administration of 3.16 pmolelkg catapresan simultaneously with L-dopa did restore motor activity in this situation almost completely (van Rossum et al., 1970). In reserpinized animals dopa causes stereotypy and a “rage” reaction. If, in addition, diethyldithiocarbaniate was given, only stereotypy is left ( Scheel-Kruger and Randrup, 1967a,b). All these experiments suggest that brain dopaminc>levels alone are sufficient to guarantee amphetamine-indiicctl stereotypy but that for locomotor stimulation noradrenaline is necessary in addition. The apomorphine stereotyped movcmcnts and bizarre social behavior is not iiifluenced by (U-MPT(Ernst, 1967) h i t is to some extent by reserpine plus wMPT (van Rossum and Simons, 1970). Apomorphine therefore may directly interact with dopamine receptors (Ernst, 1967). It has been shown that the combination of apomorphine ( a dopamine receptor activator in thc brain) and catapresan ( a noradrenaline receptor activator i n thr~brain) can counteract the reserpine-induced behavioral dcprcssioii ( motor activity) in a similar way to dopa or aniphetaminc: ( A n d i ~ i1970). , Neither catapresan nor apomorphinc does this. Tlicse data suggest the importance of both noradrenalinc and dopaininc receptors in the psychomotor stimulant action of amphetaminc ( AndPn, 1970). The neuroleptic drugs are potent antagonists of dopamine ( van Rossum, 1967) and of apomorphine and various components of the amphetamine effect (Jaiissen et al., 1965, 1967). From the data presented above it may be concluded that dopamine receptors play an important role in various aspects of amphetamine-induced bchavioral cxcitation. In stereotyped and bizarre social behavior dopamine has the predominant role. In locomotor activity dopamine rcccptors are involved, but also noradrenaline receptors have some function.

c. THE MIDBRAINKETICULAR STIMULANTACTIOX

F o R n i A T I o h - AKD

PSYCHOMOTOR

Amphetamine induccs activation of the EEG similar to stimulation of the reticular formation ( Imigo and Silvestrini, 1957; Hiebel et al., 1957; Bradley and Elkes, 1957; van Meter and Ayala, 1961). With low doses ( u p to 0.5 mg/kg) a disappearance of slow waves

370

JACQUES M. VAN ROSSUM

and spindles is observed; furthermore, waves of the subconvulsive type occurred in the occipital recording. With larger doses ( u p to 3 mg/ kg ) there is activation, especially in the frontal recordings ( Longo and Silvestrini, 1957). In addition, amphetamine lowers the threshold for behavioral and EEG arousal following stimulation of the midbrain reticular formation (Bradley and Elkes, 1957; Bradley and Key, 1958). Amphetamine-induced EEG activation is obtained in cats with a section at the c1 level (encbphalc isolk) but not in cats with a section at a higher level (cerveau isolk). From such data it has been concluded that the locus of action of amphetamine is in the midbrain reticular formation (Bradley and Key, 1958). The acetylcholine output in the cerebral cortex is increased by amphetamine as well as by electrical stimulation of the reticular formation ( Pepeu and Bartolini, 1967). The increase caused by amphetamine was found to be blocked by chlorpromazine, not influenced by pentobarbital, and facilitated by imipraminc, whereas the increasc caused by reticular formation stimulation was blocked by pentobarbital, reduced by chlorpromazine, and not influenced by pentobarbital ( Pepeu and Bartolini, 1968). Amphetamine affects the firing rate of cortical neurons in different ways. The majority show increased discharge frequency, whereas a few are inhibited or not affected by amphetamine (Herz and Fuster, 1964). Neurons with relatively high spontaneous activity ( >3/sec) are further activated by amphetamine, while slower units ( < 3 / s e c ) are not affected or inhibited (Herz and Fuster, 1964). Under influence of methamphetamine, resting alpha motoneurons of the tonic extensors start to fire while already active neurons show an increase in firing frequency. As a consequence, the monosynaptic reflex amplitude increases, and activation of the tonic alphamotoneurons occurs (Haase and Tan, 1965). It has heen concluded that the interneurons of the tonic systems are activated by methamphetamine. It may be concluded that, as far as the awakening effect had increased locomotion is concerned, amphetamine may act directly in the midbrain reticular formation as well as in the cerebral cortex and, at a lower lever, in the spinal cord.

D. THENEOSTRIATUM AND PSYCHOMOTOR STIMULANT ACTION Convincing evidence has accumulated that brain dopamine is involved in the psychomotor stimulant action of amphetamine and related drugs (van Rossum and Hurkmans, 1964).

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

371

In the central nervous system dopamine is found mainly in the nucleus caudatus, putamen, tuberculum olfactorium, nucleus accumbens, nuclei interstitialis striae terminalis and eminentia mediana (Fuxe, 1965). Of these areas the neostriatum and nucleus accumbens at first seem to be of primary importance. Furthermore only certain components in the central effects such as stereotyped and bizarre social behavior are related to brain dopamine. When the locomotor stimulant effect of amphetamine is studied in rats with chronic brain lesions, it is observed that the sensitivity to amphetamine is increased in rats with lesions in the frontal or posterior cortex but not in rats with lesions in the caudate nucleus (Adler, 1961). These data suggest that the caudate nucleus is not an important area for amphetamine-induced locomotor stimulation. Apomorphine exerts only the stereotyped and bizarre social behavioral effects of amphetamines. After ablation of the striatum in guinea pig and rats the apomorphine-induced gnawing was abolished ( Amsler, 1923) . Also amphetamine-induced stereotyped behavior is prevented in rats with lesions in the caudate nucleus. Microinjections of apomorphine or dopamine in the striatum induces stereotyped behavior (Ernst and Smelik, 1966; Fog et al., 1967; Fog, 1967). In cats with cannulae in the head of the caudate nucleus, dopamine and dexamphetamine produce similar effects in behavior registered on ethograms, whereas noradrenaline injections produce totally different effects ( Cools and van Rossum, 1970). Furthermore, the behavioral effects of stereotactically administered dopamine and amphetamine were abolished by low doses of a neuroleptic drug such as haloperidol while the blockade could be surmounted by increasing the dose of amphetamine or dopamine (Cools and van Rossum, 1970). The neuroleptic drugs are selective dopamine antagonists (van Rossum, 1967). Rats with unilateral lesions in the nigrostriatal system turned to the homolateral side following systemic dopa injections and to the heterolateral side to the lesion following administration of a neuroleptic drug (And6n et al., 1966). Microinjection of quaternized neuroleptics directly into the neostriatum antagonized also the amphetamine-induced stereotyped behavior (Fog et al., 1968). The neuroleptic drugs that are selective amphetamine antagonists are also dopamine antagonists presumably at the level of the caudate nucleus. They increase turnover of striatal dopamine as evidenced by increased levels of metabolites of dopamine such

372

JACQUES M. VAN ROSSUM

as homovanillic acid and dioxyphenylacetic acid (Roos, 1965; Sharman, 1966). Dexamphetaminc acts in the striatum and other structures containing dopamine nerve terminals by release of dopamine. Perfusion through a push-pull cannula with dexamphetamine has been found to result in a significant increase in dopamine output from the caudate nucleus ( McKenzic and Szerb, 1968). Evidence was obtained that the aniphetamine-induced dopamine [Fig. 20( a ) ] release occurred from a nondiffusible bound form. The metabolite dioxyphenylacetic acid [Fig. 20 ( b ) ] was found to be increased by amphetamine and, as anticipated, reduced by an M A 0 inhibitor (McKenzic and Szerb, 1968) with an elegant in vitro preparation, it has been shown that low doses of amphetamine 0 Locke ( 4 ) 0 Pheniprazine ( 3 )

I

Q Dextroamphetamine ( 8 ) Dextroamphetamine (4)

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40 -

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FIG.20. Release of dopainine and its metabolite dioxyphenylacetic acid by perfusion of the caudate nucleus with dexarnphetamine and other dnigs through a push-pull cannula system. Dexamphetamine causes a strong increase of dopamine (left) and dopac (right) in the effluent in untreated cats and even inore in cats treated with d o p a . The monoamine oxiclase inhibitor pheniprazine has little effect on the release of dopainine but as anticipated suppresses the oxydation of dopamine to dopac. Reproduced after McKcnzie and Szerb (1968) with permission of the authors and J. Phamacol uncl Exptl. Therap.

ACTION OF PSYCHOMOTOR STIMULANT DRUGS

373

induced a release of newly synthcsizcd dopamine (Besson et al., 1969) . The effect of amphetaiiiinc at the level of the striatal neurons is probably indirect by rclease of dopamine which in turn acts as an inhibitory transmitter. It has heen found that firing of neurons of the caudate nucleus and putamen cither spontaneously or following stimulation of the mcdial thalnmus is inhibited by microelectrophoretically applied dopaminc (Herz and Zieglggnsberger, 1966; Bloom et al., 1965). From experiments with a-methyldopa on histochemical fluorescence in rat brain, evidence is provided which suggests that dexamphetaminc cmi also release a-methyldopamine present in dopamine nervc’ terminals after administration of amethyldopa ( Carlsson et NL., 1967). I t is questionable whetlicsr thc dcxainphctamine effects in man at therapeutic doses 1ia1.e much in common with a dopainine release in the basal ganglia. It is more likely that chronic toxic effects, especially amphetanrinc-induccd psychosis, is due to effects in the dopamine containing titiclei. The relationship between amphetamine-induced psychosc~s and certain forins of schizophrenic psychosis in the light of thc prcwnt knowledge of amphetamine action on dopamine neurons m a y suggest the importance of dopamine in the pathogenesis of schizophrenia (see also the review by Munkvad et al., 1968).

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The author is indebted to Dr. P. A. J. Janssen, Beerse for valuable suggestions and to Miss J. Th. A. M. Hurkmans for her help in compiling the list of references and correction of the proofs.