Differential effects of dopaminergic drugs on anxiety and arousal in healthy volunteers with high and low anxiety

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Neuro-Psycbpharmacd.

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Psychic&

1997. Vol. 2 1. pp. 5X3-590

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DIFFERENTIAL EFFECTS OF DOPAMINERGIC DRUGS ON ANXIETY AND AROUSAL IN HEALTHY VOLUNTEERS WITH HIGH AND LOW ANXIEm YASUSHI MIZUKI, MASATOMO SUETSUGI, ITSUKO USHIJIMA and MICHIO YAMADA Department of Neuropsychiatry, Yamaguchi University School of Medicine, Yamaguchi, Japan

Final form, January iw7)

Abstract

Mizuki, Yasushi, Masatomo Suetsugi, Itsuko Ushijima and Michio Yamada: Differential Effects of Dopaminergic Drugs on Anxiety and Arousal in with LOW Anxiety. Volunteers High and Prog. NeuroHealthy Psychophannacol. & Biol. Psychiat. 1997, I& Pp.573-590. 0 1997ElsevierScienceInc.

1. The appearance of frontal midline theta activity (J?m6),the distinct EEG theta rhythm in the frontal midline area during performance of a mental task, indicates relief from anxiety in humans. 2. The authors examined the effects of bromocriptine and sulpiride on anxiety and arousal in 24 male university students with (Pm0 group, n=12) and without (non-Em9 group, n=12) F'm9. Subjects were given placebo, 2.5 mg bromocriptine and 100 mg sulpiride in a double-blind crossover design. 3. Blood samples were obtained, STAI scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated twice: before and 1 hr after drug administration. 4. Bromocriptine reduced the HVA concentration in both groups; sulpiride caused an increase in both groups. In the Pm9 group, bromocriptine did not alter the appearance time of E'mO, the state anxiety score or the task performance; sulpiride increased the Pm9 amount and reduced the state anxiety but did not affect the task performance. In the non-Em9 group, bromocriptine increased the Pm9 duration and reduced the state anxiety score but did not influence the task performance, while sulpiride reduced F'm9 and increased the state anxiety but had no effect on the task performance. 5. These results suggest that the sensitivity of presynaptic D2 receptors is higher in high-anxiety subjects compared with lowanxiety subjects, and that anxiolytic effects in high-anxiety humans and those in low-anxiety humans may be caused by decreased and increased DA activity, respectively. In addition, the stimulation of DA function may cause anxiogenic effects in high-anxiety individuals. 573

574

Y.

MizukietaL

Kevwords: anxiety, bromocriptine, activity (Fm8), stress, sulpiride

dopamine,

frontal

midline

theta

Abbreviations: cerebrospinal fluid (CSF), decibel (dB), dopamine (DA), electroencephalogram (EEG), frontal midline theta activity (Fme), highperformance liquid chromatography (HPLC), homovanillic acid (EVA), state-trait anxiety inventory (STAI)

Introduction Dopamine (DA) activity is increased in panic disorder (Pitchot et al., 1992), and low doses of neuroleptics are efficacious in the treatment of In animals, various types of

anxiety (Taylor et al., 1983).

stress

(Roth et al., 1988) and administration of anxiogenic drugs such as fi-CCE and FG-7142 (McCullough and Salamone, 1992) can activate DA function. This enhancement of DA function can be partially blocked by diazepam (Coca et

al.,

following direct

1992).

Anxiogenic-like

stimulation

of

DA

also

effects

receptors

are

(Simon et

observed

al.,

1993).

However, administration of bromocriptine, a D2 receptor agonist, or low doses

of

sulpiride,

a

D2

receptor

antagonist,

mediates

anxiolytic

effects during stress tests in rats (Bruhwyler et al., 1991).

At higher

doses, sulpiride has an anxiogenic effect (Simon et al., 1992).

A distinct electroencephalogram midline area during performance

(EEG) theta rhythm from the of

a

mental

task

Ishihara and Yoshii (1972) and named Fm8 (Fig. 1).

was

frontal

identified by

The appearance of Fm8

differs among individuals (Mizuki et al., 1980).

It is more marked in subjects who are less neurotic and less anxious, while more neurotic and

more anxious subjects display less or no Fm8 When anxiolytic drugs

such

without Fm8, the authors

as

diazepam

were

to

normal

1984). humans

found a significant correlation between the

appearance of FmO and a decrease in anxiety 1983).

(Mizuki et al., given scores

(Mizuki et

al.,

Thus, the appearance of Fm0 may coincide with a decrease in

anxiety, hence Fm8 could be a useful tool in predicting the clinical effects of anxiolytic drugs.

The plasma homovanillic acid central turnover of DA

(HVA) is regarded as an index of the

(Bacopoulos et al.,

1979).

Blood and plasma

levels of DA metabolites have been found to be highly correlated with cerebrospinal .fluid (CSF) levels and to (Heninger et al., 1979).

reflect

central

DA

activity

In the present study, the effects of bromo-

criptine and sulpiride on anxiety and arousal in healthy male university

Anxiety.dopamineandFm6l

575

students with and without FM3 were examined by monitoring the plasma HVA concentration, the

F'm0 amount, and the state-trait

anxiety

inventory

(STAI) score.

Methods

Subjects

On 3 consecutive days, 50 male university students had an EEG recorded for 5 min during the performance of an arithmetic addition test in order Students in whom the F'meappeared

to determine which students had a Fm8.

on the second or third day were excluded.

The study group consisted of

12 subjects who exhibited FmO on all 3 days, and 12 subjects in whom Fmf3 did not appear on any of the 3 days.

The former was termed the E'me

group and the latter the non-Fmf3group.

Subjects ranged in age from 20

to 25 (mean age: 23.2) years, and their resting EEGs were normal.

All

subjects were screened, and those who had any type of medical disorder or who were taking any medication were excluded.

Prior to the study,

informed consent was obtained from all subjects.

Druqs

Two drugs, 2.5 mg bromocriptine and 100 mg sulpiride, and placebo were used.

Capsules containing the drugs and their placebos, were prepared.

Drug doses were determined from data obtained in human studies (Seeman, 1995) and from minimal effective doses in clinical use (EPIC, 1995).

Experimental Procedure

Subjects were evaluated on the STAI-11 (trait anxiety) at lo:30 hr, and then ate lunch at 11:00 hr. subjects rested Blood

samples

in a quiet were

drawn

Scalp electrodes were attached, and the room reading a newspaper from

the

antecubital

vein

or at

a magazine. 13:00

hr.

Subjects then completed the STAI-I (state anxiety), and rested for 3 min with their eyes closed.

They performed the arithmetic addition task for

5 min as rapidly and accurately as possible.

Thereafter, the subjects were administered one of the active drugs or the placebo according to a double-blind, crossover, randomized design. hr following drug

administration.

between administrations.

The tests were repeated 1

There was

a l-day washout

period

EEGs were continuously recorded throughout the

576

Y.

entire

procedure,

except

Mizukietal

during

vein

puncture

and

the

60-min

rest

period.

Assessments Mental Task

The subjects performed the Uchida-Kraepelin test, a test

of continuous arithmetic addition (Kuraishi et al., 1957), as a mental task.

The subject adds horizontally arranged sequential pairs of single

digits aligned vertically.

He writes the last digit of the sum of each

pair in a space just below each pair.

Formerly, the numbers on the test

sheet were written in a manner such that the subject changed to a new line of numbers every minute.

In the present study, the test paper was

lengthened to a band-paper 4 cm high and 240 cm wide on which 8 lines containing 464 numerals each were printed.

Continuous addition could

thus be performed without changing lines.

Psychological Testinq

The STAI

(Spielberger et al.,

1970) used in

this study consists of separate self-report scales for measuring two distinct anxiety

concepts,

state

anxiety

(STAI-I) and

trait

anxiety

(STAI-II). The higher the score on each scale, the greater the anxiety level.

Laboratory Instruments

EEGs

These were

recorded

not

only

directly

on

paper

for visual

analysis but also simultaneously on an analog tape recorder for further computerized automatic analysis before and during the task performance. Disc electrodes were reference.

placed at Fpz, Fz, and Cz, using Al+AZ as

The recording conditions were as follows: paper speed of 1.5

cm/set, time constant of 0.1 set, and sensitivity of 10 pV/mm. high-cut filter was spectra

the

requirements

Transformation.

The

used. by

a

resting EEG was

digital

computer

analyzed using

A 60-HZ

for power

Fast

Fourier

Each lo-set epoch was analyzed with 102.4 points/set,

which permitted the analysis of frequencies up to 50 Hz.

Time samples

of 60 set were analyzed.

EEGs during the task were evaluated by computer analysis, and only the theta rhythm recorded from the Fz electrode was detected by the interval histogram method

(Kuwahara et al.,

1988).

performed for the final evaluation of Fm8.

Visual analysis was also The theta rhythm selection

Anxiety,dopamineandFmO

577

algorithm employed a criterion which specified whether the signal slope following a peak

or trough was

sufficiently negative or positive to

qualify the peak or trough as a theta rhythm.

The criteria

for Fm9

were: continuity of more than 4 consecutive waves, frequency of 5.0-7.5 Hz, and amplitude of more than 20 pV, for computer analysis; rhythmical sinusoidal configuration,

markedly

higher

amplitude

as

compared with

background activity, duration exceeding 1 set, and frequency of 5.0-7.5 Hz, for visual analysis. Artifact segments containing eye blinking and eye movement were excluded from analysis, but there were few of these episodes as shown in Fig. 1.

Biochemical Determination

Ten-ml blood samples were collected on two occasions with heparinized syringes and transferred into siliconized tubes containing 0.1 ml of 10% Na2-EDTA.

The blood was

mixed,

immediately placed on

centrifuged at 3000 rpm for 10 min at 4°C.

ice, and then

The top layer of platelet-

rich plasma was transferred to pipette tubes and stored at -80 "C.

RVA

concentrations in 2-ml plasma samples were measured by high-performance liquid chromatography (HPLC) with electrochemical detection according to the technique of Sailer and Salama

(1984) with

slight modifications.

HVA values were obtained from a single assay.

Fig 1. A sample of EEG during performance of the Uchida-Kraepelin test. Fm8 is underlined.

Statistical Analysis

Resting EEG, plasma WA

concentration, appearance time of Fm8, STAI-I

578 and

Y.Mizukieta1 STAI-II scores,

number of

performed

tasks,

and

number

of

errors

before the drug and placebo administration were averaged and used as the The

control values.

values

obtained

following drug

or

placebo

in-

gestion were averaged and compared with controls except for the STAI-II scores.

The control and treatment values in the Fm0 group were also

compared with

the

corresponding

values

in

the

non-Fm0

group.

The

comparison of resting EEG between the two groups and between the control EEG and the EEG following drug administration in both groups was analyzed by the Student's t-test and the paired t-test, respectively.

The

comparison of remaining items between the groups was analyzed by the Ftest for equal variance, and a probability level of 0.05 was set for statistical significance.

The Student's t-test was

used .for further

post-hoc analysis in the case of Fz2.82 (PgO.05); the Aspin-Welch t-test was adopted at Fp2.82

(P~0.05).

As

for the

comparison

between

control and experimental values following drug administration

the

in both

groups, the chi-square test for goodness of fit was employed for normality, and a probability level of 0.05 was required for statistical significance.

The

paired t-test was

used when x223.84 (PgO.05); the

Wilcoxon signed-ranks test was adopted when x2>3.84 (PCO.05).

Results

Restinq EEGs

In the frontal area (Fig. 2), the power values of the control EEG were greater at the whole bands in the Fm8 group as compared to the non-Fm8 group.

Following administration of placebo, the power values in the Fm8

group were higher at 10, 11, 14-17 and 29-32 Hz but lower at 40 and 41 Hz compared to the non-Fm8 group.

Following administration of 2.5 mg

bromocriptine, the power values in the Fm8 group were higher at 3, 5, 6 and

39-42

Hz

but

lower

at

22

Hz

compared

to

the

non-Fm8

group.

Following administration of 100 mg sulpiride, the power values in the Fm0 group were

higher at 4-6 and

12 Hz but lower at

38 and

41 Hz

compared to the non-Fm0 group. Placebo was associated with an increase in the power at 12, 16 and 32 Hz and a decrease at 41 Hz in the Fm8 group, but an increase at 6 and 8 Hz and a decrease at 24,

33-36 and 45 Hz in the

compared with the respective control values

non-Fm8 group, as

(Fig. 3).

Bromocriptine decreased the power at 6 and 7 Hz and increased the power at 21 and 23 Hz in the Fm8 group, but decreased the power at

3, 5 and

6 HZ

and

Anxiety, dopamineand Fm8

579

(dB)

Fig. 2: Resting EEGs at the frontal area in the Fm8 group and the non-Fm8 group. The figures represent the EEG power spectra in the Fm8 and nonThe power values during control conditions and following Fm8 groups. placebo, bromocriptine and sulpiride administration are shown from the upper to lower rows. The values of EEG frequency during control conditions and following drug administration from the Fm8 group were The compared with the corresponding values from the non-Fme group. solid line shows the Fm8 group [Fm8 (+)I, and the dotted line the non-Fm8 Ordinate: logarithmic power values (dB); abscissa: group tFm8 (-)I. frequency of EEG (Hz). A: PcO.10; *: PCO.05; **: P
increased the power at 12 and 22-25 Hz in the non-Fm8 group compared with the control values.

Sulpiride reduced the power at 4, 6 and I Hz

and increased the power at 13, 18, 29-32 and 38-41 Hz in the Fm8 group, but reduced the power at 5 and 6 Hz and increased the power at 25-28 and 39

Hz

in the non-Fm8 group compared with the control values.

580

Y.Mizuki etal

FmO(+)

(de)

Fme( -)

(dBJ

I 0

10

20

30

40

50(HZ)

-10

(dB)

10

20

10

20

30

40

50 (Hz)

40

50 (HZ)

(dE)

I

-’ 0

10

20

30

40

1 -10

50 (HZ)

(dB)

I -’ 0

30

(dB)

10

20

30

40

AW)

-1M

SO(HZ)

Fig. 3: Resting ERGS at the frontal area during control conditions and The following placebo, bromocriptine and sulpiride administration. figures represent the power spectra of EEGs before and after drug The power values during administration in the Fm0 and non-I%@ groups. control conditions are respectively compared with those following The left side of placebo, bromocriptine and sulpiride administration. the figure: the FmB group [Fme (+)I; the right side: the non-Fm0 group [FmB (-)I. The solid line indicates the control, and the dotted line placebo (PL), bromocriptine (BRC) and sulpiride (SLR), respectively. The details are given in the legend for Fig. 2.

Plasma HVA Concentration

The HVA concentration was lower at baseline and following sulpiride administration in the FmO group compared with the non-Fm0 group, but there were no significant differences in the HVA concentration following bromocriptine and placebo ingestion between the groups (Table 1). The increased by sulpiride compared with the control values in both groups. Placebo had

HVA

concentration

was

decreased

by

bromocriptine

and

no effect on the HVA concentration in either group.

Appearance Time Of Fme The appearance time of Fm(!l was greater in the Fmtl group than in the non-Fm0 group at any time (Table 1).

Sulpiride increased the FmO amount

in the FmO group compared with the control value, but bromocriptine and

FmB(+)

Fm8(-)

2.33*0.29

2.18kO.20

360.33k5.47

Fm8(-)

me(+)

46.26&O-86

Fme(+)

361.17*5.35

42.6720.82 **

Fm8(-)

mef-b

42.52kO.88

me(+)

FmBf-)

2.00zt0.27

2.03iO.25

362.88k5.34

362.69r5.45

40.39AO.87

37.69kO.92 *

1.52i0.38 C

0.46*0.10

me(+)

39.38kO.99 *

9.92kO.68 10.79i1.70 ***

10.7Ok1.32 ***

8.59kO.59

10.09iO.62

8.38*0.50 *

Fm8(-)

m(+)

Placebo

1.82kO.29

1.65kO.26

363.19k5.23

363.55i4.86

39.55kO.98 C

41.70*0.90

1.75~0.48 C

10.3523.84 *

7.50*0.70 c

6.89AO.45 C

Bromocriptine

2.84kO.31

2.71kO.27

365.95k5.43

364.3225.53

45.42i1.03 C

35.32kO.82 B ***

0.20*0.07 C

17.93e2.02 B ***

11.85i0.52 C

10.06*0.61 c *

Sulpiride

The values for the control and those following placebo, bromocriptine or sulpiride administration are shown as actual measurements (meaniS.E.M.). The BVA values are expressed in ng/ml, and Fm8 amounts in sec. Fm8(+): the Fm8 group; Fme(-): the non-Fm8 group. Statistically significant differences between the groups *: PCO.05; **: P
Error

Task

STAI-11

STAI-I

FmB

EVA

Control

Effects of Placebo, Bromocriptine and Sulpiride on the BVA Concentration, Appearance Time of Fm8, STAI Scores, the Number of Performed Tasks and the Number of Errors.

Table 1

$

1

9

582

Y.Mizukiet&.

placebo had no effect.

In the non-Fm8 group, bromocriptine and placebo

increased the Fin0 amount compared

with

the

control,

while

sulpiride

and

following

caused a decrease.

STAI Scores

The

state

anxiety

scores

lower

were

at

baseline

sulpiride and placebo administration in the Fm8 group as compared to the There were no significant differences between

non-Fm8 group (Table 1).

the groups following bromocriptine administration. the state anxiety scores

Sulpiride reduced

in the Fm8 group compared with

values, but bromocriptine and placebo had no effect.

the control

In the

group, bromocriptine decreased the state anxiety scores, sulpiride caused an increase and placebo had no effect.

non-FmH whereas

The trait anxiety scores were lower at baseline in the Fm8 group than in the non-Fm8 group.

Number of Performed Tasks and Number of Errors

There were no significant differences in the task performance and the number

of

errors

at

any

time

between

the

groups

(Table

1).

No

significant change in the task performance level or the number of errors was noted in either

group when

compared with

the respective control

values.

Discussion

Bioloqical Aspects of DA Function

The

mental

established

arithmetic as

a

task

stressor

used

in

the

present

(Gorman

et

al.,

1987).

study The

has been stressful

manipulations activate mesolimbic and mesocortical DA neurons (Moore and Lookingland, 1995) and stress clearly changes the DA metabolism in the ventral striatum as well as in the frontal cortex (Le Moal and Simon, 1991).

A specific increase in DA turnover is observed in the nucleus

accumbens 1 hr after stress (D'Angio et al., 1987), and the increased DA utilization

under

the

stressful

condition

is

a

general

phenomenon

Anxiety. dopamineand FmB related to various types of anxiety

583 This

(Le Moal and Simon, 1991).

anxiogenic-like effect is also observed following the stimulation of DA receptors (Simon et al., 1993). both

and

pre-

Although D2 receptors are those

post-synaptically,

located

at

localized

presynaptic

nerve

terminals function as autoreceptors controlling the release of DA in the nigrostriatal

and

mesolimbic

DA

systems

(Roth and

Elsworth,

1995).

Acute administration of bromocriptine decreases DA synthesis and release by stimulating presynaptic D2 receptors, while that of sulpiride increases DA synthesis and release by blocking presynaptic D2 receptors (Roth and Elsworth, 1995).

Pharmaco-EEG of Bromocriptine and Sulpiride

In the present study, bromocriptine reduced the power of 0 activity and

increased

the

power

of

low-fast

$

activity

in

both

Bromocriptine also decreased S activity in the non-Fm8 group.

groups. Sulpiride

reduced the power of 8 activity and increased middle- and high-fast @ activity in both groups. activities

in

the

Sulpiride also increased fast a and low-fast fi EEG

F'm8 group.

profiles

following

the

acute

administration of 2.5 mg bromocriptine in humans are characterized by a decrease in slow (6 and 8) waves and an increase in fast a, low- and 'middle-fast fi activities

(Suitsu, 1992).

On

the

other

hand,

acute

administration of 400 mg sulpiride in normal volunteers has been found to increase the proportion of slow wave activity as well as decrease CI and fl activities

(McClelland et al.,

(1982) have reported that

three

1990).

types

of

However,

EEG

changes

Saito were

et

al.

observed

following the administration of 200 mg sulpiride in normal subjects: i) increased slow wave and fiactivity associated with decreased CI activity (thymo-leptic type), ii) increased slow wave

and decreased fl activity

(neuroleptic type), iii)and decreased slow wave and increased p activity (psychostimulant

type).

Therefore,

the

present

EEG

findings

are

consistent with the results of previous studies and suggest that the EEG effects of 2.5 mg bromocriptine and those 1992),

of

nootropic

and

vigilance

psychostimulants,

100 mg

enhancers, such

as

sulpiride are similar to

such

as

amphetamine

piracetam

(Suitsu,

(Herrmann,

1982),

respectively.

Stress, Anxietv and DA Turnover In the present study, the control values of BVA concentration in the

584

Y MizukietaI_

Fm8 group were lower than in the non-Fm8 group. decreased and

sulpiride

increased WA

However, bromocriptine

concentration

in

both

groups.

Furthermore, the sulpiride-induced HVA decrease was greater in the nonFm8 group than in the Fm8 group. is increased by psychological

Although DA turnover in normal humans

stress, subjects with

a high

level of

anxiety exhibit an increased DA turnover in both relaxed and stressful situations compared with subjects with

low anxiety levels

(Mizuki et

Increased DA turnover correlates with the probability of

al., 1992).

panic attacks, and this elevation has been associated with

increased

Fm8 is more marked in subjects who

anxiety (Roy-Byrne et al., 1986).

are less neurotic and less anxious; subjects who are more neurotic and more anxious show a reduced or absent Fm8 (Mizuki et al., 1984). administration

of

bromocriptine

reduces

DA

function

by

Acute

stimulating

presynaptic D2 receptors, while that of sulpiride increases DA function by blocking presynaptic

D2 receptors

(Roth and Elsworth,

1995).

In

addition, the sensitivity of DA receptors is increased in patients with Therefore, data on HVA levels

panic disorders (Pitchot et al., 1992).

after sulpiride administration in the present

study

suggest

that D2

receptor sensitivity may be higher in individuals with high levels of anxiety compared with those with low levels of anxiety. bromocriptine

for

D2

receptors

is

greater

(Billard et al., 1984; Creese, 1987). groups are

normal

humans

in

the

than

The affinity of

that

of

sulpiride

Furthermore, the subjects in both

present

study.

Therefore,

it

is

possible that the strong affinity of bromocriptine for D2 receptors may mask

the

slight

differences

in D2

receptor

sensitivity

between

the

groups.

Anxiety and D2 Recenters Bromocriptine and sulpiride had different effects on Fmf3 amount and state anxiety scores in Fm8 and non-Fm8 subjects in the present study. The

appearance of

Fm8

is

negatively

correlated

with

a

decrease

in

anxiety and is closely related to the personality of subjects (Mizuki et al., 1984). The present results suggest that bromocriptine produced an anxiolytic effect but sulpiride caused the opposite effect in highanxiety subjects under stressful conditions, only sulpiride reduced the anxiety

level

of

low-anxiety

subjects

in

a

stressful

situation.

(1991) have reported that bromocriptine demonstrated

Bruhwyler et al.

anxiolytic effects at moderate doses but had no effects on anxiety at high

doses

in

administration

the of

open-field

bromocriptine

test may

for treat

rats. anxiety

Clinically, in

the

acute cocaine

Anxiety.dopam~neandF& withdrawal syndrome caused by (Markou and

Koob,

activation of DAergic neurotransmission

In

1992).

585

low doses

addition,

of

sulpiride

effective in preventing anxiety induced by the conflict test

are

in rats

(Pith and Samanin, 1986), and clinical efficacy for sulpiride has also been established in patients with anxiety (Peselow and Stanley, 1982). Therefore, the previous studies on the anxiolytic effects of the two drugs coincide well with

the present data on bromocriptine

in high-

However, it

anxiety subjects and sulpiride in low-anxiety subjects.

recently has been reported that sulpiride can exhibit an anxiogenic-like effect in the two-compartment exploratory test for mice 1992).

In

addition,

individuals with

high

increased anxiety

DA

turnover

compared with

(Simon et al.,

has

been

observed

those

with

low

in

anxiety

(Mizuki et al., 1992), and the present results of HVA levels suggest that

the

sensitivity

individuals than

in

of

D2

receptors

low-anxiety

is

higher

in

high-anxiety

Therefore,

individuals.

anxiolytic

effects in high-anxiety humans may be caused by decreased DA activity (stimulation of presynaptic D2 receptors), while those

in low-anxiety

humans may be caused by increased DA function (inhibition of presynaptic D2 receptors).

Arousal and D2 Receptors

No significant differences were found in the task performance or the number of errors between groups in the present study, no were there significant changes in these parameters in either group when compared with the respective control values.

Performance of an arithmetic task

reflects the level of arousal rather than the level of attention, and the number of errors is correlated with major changes in the arousal level but

is not affected by

small changes

(Mixuki, 1987).

In the present study, no drug had an effect on arousal in either high-anxiety or

low-anxiety

subjects.

Recently,

it

has

been

reported

that

stimulation of Dl receptors led to some desynchronization in baseline EEG and a general decrease usually regarded as 1993).

in EEG power

spectra,

signs of arousal in rats

results which

are

(Kropf and Kuschinsky,

The probable mechanism of this phenomenon is that increased DA

in the synaptic cleft activates Dl receptors that stimulate release of acetylcholine, which

initiates the arousal response

(Yoshida et

al.,

1993).

On the other hand, a characteristic increase of power in the slow a activity is apparently due to activation of postsynaptic D2 receptors (Kropf and Kuschinsky, 1991, 1993). that pre-synaptic autoreceptors mediate

However, the hypothesis an increase in the EEG power

following a low dose of a DA receptor agonist is doubtful

(Kropf and

586

Y.Mizuki etal.

Kuschinsky, 1993).

In the present study, the doses of bromocriptine and

sulpiride were small, acute administration of the drugs was used, and it was

hypothesized

these

drugs

autoreceptors predominantly. ther bromocriptine

nor

had

an

influence

on

presynaptic

Therefore, it is not surprising that nei-

sulpiride

affected

the

arousal

level

of

the

subjects in both groups.

Conclusions

The present results suggest that the sensitivity of pre-synaptic D2 receptors was higher in high-anxiety subjects compared with low-anxiety subjects. anxiety

Our results also suggested that anxiolytic effects in high-

humans

decreased DA addition,

the

and

those

activity

and

stimulation

in

low-anxiety

increased DA of

DA

humans

function,

transmission

may

may

be

caused

respectively. cause

by In

anxiogenic

effects in high-anxiety individuals.

Acknowledgment

A part of this research was supported by a grant-in-aid for scientific research from the Ministry of Education, Science and Culture, Japan (No. 60480262).

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