Effects of d -amphetamine administration on the release of endogenous excitatory amino acids in the rat nucleus accumbens

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EFFECTS OF D-AMPHETAMINE ADMINISTRATION ON THE RELEASE OF ENDOGENOUS EXCITATORY AMINO ACIDS IN THE RAT NUCLEUS ACCUMBENS RODRIGO LABARCAb* MARIA INES GAIARDO’, MARIO SEGUEL*, HERNAN SILVA4, SONIA IEREZ’, AIDA RUIZ4 AND GONZALO BUSTO!? ‘Laboratory of Molecular Psychiatry, CIM, ‘Department of Psychiatry, School of Medicine and ‘Laboratory of BiochemicalPharmacology, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile; YXnica Psiquiatrica Universitaria, University of Chile, Santiago, Chile. (Final form, March 1994) Abstract Labarca, Rodrigo, Maria In& Gajardo, Mario Seguel, Hem&n Silva, Sonia Jetez, Aida Ruiz and Gonzalo Bustos: Effects of D-amphetamine administration on the release of endogenous amino acids in the rat nucleus accumbens. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995. 19(3): 467-473. 1. The effects of acute D-amphetamine administration to rats on the release of endogenous excitatory amino acids from nucleus accumbcns slices were studied. 2. D-amphetamine (5 mg/kg and 10 mg/kg; i.p.) significantly increased the spontaneous release of aspartate and glutamate from nucleus accumbens slices. 3. In contrast, D-amphetamine either produced no change or rather decreased K’ (40 mM)-evoked and N-methyl-D-aspartate (100 pM)-evoked release of aspartate and glutamate from the slices, respectively. 4. When D-amphetamine treated rats were pretreated with haloperidol, the effects of D-amphetamine on the spontaneous release of excitatory amino acids were not produced, whereas its effects on Nmethyl-D-aspartate-evoked release remained unchanged. 5. These data suggest that amphetamine produces changes in excitatory amino acid-mediated transmission in the nucleus accumbens, that may play a role in amphetamine-induced behavioral or psychotomimetic effects. Kev Words: accumbens.

aspartate,

D-amphetamine,

excitatory

amino

acids,

glutamate,

haloperidol,

nucleus

Abbreviations: aspartate (ASP), excitatory amino acids (EAA), glutamate (GLU), high pressure liquid chromatography (HPLC), intraperitoneal (i.p.>, N-methyl-D-aspartate (NMDA), nucelus accumbens (NAc). Introduction Since it was introduced to its euphoric amphetamine

and psychomotor-stimulating

produced

activity, stereotyped resembles to elucidate

for medical use, amphetamine

shizophrenia

properties

a wide variety of behavioral

behaviors,

augmentation

(King and Ellinwood,

the neurobiological

has been a widely abused drug, probably (King

effects,

of aggressiveness,

and Ellinwood,

1992).

In humans,

such as euphoria,

increase

in locomotor

anorexia and a paranoid

psychosis

1992). Animal sudies using self-administration

basis of the reinforcing 467

due

that

paradigms

efficacy and abuse liability of amphetamine,

and

468

R. Labarca

others to explain

its anomctic

on the dopaminergic to be dopamine, is the release

and psychomotor-stimulating

system.

Accordingly,

as amphetamine

and Waldcck,

area and their projections actions of amphetamine

sensitizing

effects

reward efficacy, Mandell,

(Robinson

Preliminary

(1991)

antagonist,

possibility

behavioral

neurobiological

enhancement

by the repeated

to study the effects

of amphetamine

EAA in the nucleus accumbens

properties

effects

Today, neuroplastic

and

(Segal and

adaptations

of the

in the brain may be involved

and

(NMDA)

cocaine.

of methamphetamine

effects

subtype

Moreover, is mediated

1992).

neurotransmission

and the psychotomimetic of amphetamine

that when amphetamine

in

by Karler et al. (1989, 1990) and Wolf and

to amphetamine

administration

are its

to amphetamine.

of GLU (Nash and Yamamoto,

basis of sensitivation

to amphetamine

to its psychotomimetic

that the N-methyl-D-aspartic

amino acid (EAA)-mediated

the effects

exposure

of the psychomotor-stimulating

Work performed

sensitization

concentrations

In view of the above, decided

and intermittent

that other nemotransmitters

effects.

et al.,

for the acute

1986). Thus, it has been described

demonstrated

prevents

that excitatory

uptake (Carlsson

1988).

et al., 1984; Sato et al., 1983).

also suggest

produced

increase in extracellur

agonist, the result of which

of dopamine

the limbic and frontal cortex are required

arc thought to mediate sensitization

have recently

MK-801,

neurotoxicity

and Becker,

actions seems

of the ventral

of the repeated

there is a progressive

evidence

amphetamine-induced Khansa

towards

exclusively

neurons

and there might even occur sensitization

system

modulator of amphetamine

and the blockade

(Koob and Bloom,

effects

1974; Woolverton

dopaminergic

have focused almost

1966). At the cellular level, dopamine-containing

tegmental

is used intermittently,

the nemobiological

dopamine

reinforcing

One of the most striking

properties,

is able to act as an indirect dopaminergic

of newly synthesized

1965; Carlsson

et al.

receptor dopamine

by a delayed

These evidences

raise the

may also be involved

in the

to amphetamine.

on the release of EAA in the brain, the authors

administration

on the spontaneous

and evoked

release of

(NAc) of the rat.

Methods

D-amphetamine solution

was obtained from Laboratorio Chile (Santiago, Chile). NMDA and salts

were obtained

Amnhetamine

from Sigma Chemical

KRP

Administration

Male Sprague-Dawley

rats, weighing

(i.p.), at 09:OO AM and sacrificed necessary,

used in

Co. (St. Louis, MO., U.S.A.).

rats

were

pretreated

200-250 g, were administered Control

2 hrs after. with

haloperidol,

animals

1 mg/kg

D-amphetamine, received

(i.p.),

saline

30 min

5 and 10 mg/kg solution.

before

When

amphetamine

administration. Release of Excitatory Release

experiments

Amino Acids were performed

according

to Bustos and Roth (1972) and Fiedler

and Bustos

Effect of b4mphetamine (1991).

Briefly,

in superfusion

tissue with Krebs-Ringer-Phosphate 1 mYmin.

Aliquots

to the stimulus

of Excitatory

1991).

Routine

of the

to 37” C, at a constant

rate of

of 1 min each were collected

the tissue was stimulated

(Asencio

superfusion

to determine

the

with K+ (40 mM) or NMDA (100

every minute and kept at -20°C for amino acid determination subtracting

the mean of the three min previous

during the stimulus and thereafter.

Amino Acids

(ASP) and glutamate

by HPLC chromatography

described

a continous

and prewarmed

release was calculated

to the values obtained

Determination Aspartate

were collected

Net-evoked

which permitted

three samples

(basal) release, and thereafter

by HPLC analysis.

chambers

(KRP), oxygenated

After 60 min of incubation,

PM) for 2 min.

469

8 to 10 slices (1 mg prot each) from NAc, prepared as previously

et al., 1991). were incubated

spontaneous

on the Release of EAA in the Rat NAC

(GLU) were determined

coupled to fluorimetric

limits of detection

according

to Lindroth

detection as previously

were 0.6 pmoles per injection

and

described

Mopper

(1979)

(Fiedler and Bustos,

for both ASP and GLU.

Data Analysis Statistical

analysis

was performed

using the non-parametric

U test analysis

of Mann-Withney.

Re.SllltS The administration spontaneous

release

of D-amphetamine of endogenous

GLU, Table 1). In contrast, (40 mM) or NMDA administration. treatment,

i.p.) resulted

in a significant

Whereas

increase

in the

ASP and GLU from rat NAc slices (p c 0.03 for both ASP and

the release of ASP and GLU from NAc slices evoked either by high K+

(100 PM) was found not to change or to be reduced following

NMDA-evoked

amphetamine

(5 mg!kg;

i.p. D-amphetamine

K+-evoked release of ASP and GLU was not modified release

of ASP, but not of GLU, decreased

quite

by D-amphetamine

substantially

after D-

(p < 0.03, Table 2).

Table 1 The effects

Experimental

of D-Amphetamine

Condition

on the Spontaneous Acids.

ASP

AMPH Wallis:

= D-Amphetamine. Results * p < 0.03 vs saline.

1.27 3.22 0.98 2.26 1.15 1.37

Amino

GLU (pmoles/mg

Saline AMPH (5 mg) Saline AMPH (10 mg) Saline AMPH (10 mg) + Haloperidol

Release of Excitatory

f f + f f *

0.18 0.13* 0.18 0.22* 0.1 0.17

prot/min)

1.40 3.28 1.15 2.62 1.55 1.63

f + f + f f

are the mean + S.E.M. of four different

0.19 0.62* 0.15 0.33 0.18 0.11 experiments.

Kruskal-

R. Labarca et al.

470

Amphetamine,

at 10 mg/kg, also markedly augmented the spontaneous

(p < 0.03, Table significance.

1); spontaneous

In addition,

release of ASP from NAc slices

release of GLU was also increased

NMDA-evoked

release of ASP decreased

but without

reaching

statistical

after 10 mg/kg of D-amphetamine

(p c 0.05, Table 2). as it was the case in the experiment

with 5 mg/kg of amphetamine.

NMDA-

evoked

was reduced,

to reach

release

of GLU following

statistical significance. amphetamine action.

10 mg/kg amphetamine

Since amphetamine

effects on spontaneous

releases newly-synthesized

and evoked-release

For this purpose, rats were pretreated

mg/kg of amphetamine. in the spontaneous

dopamine,

with haloperidol,

decrease

of NMDA-evoked

receptor-mediated

30 min before the administration completely

of ASP and GLU, evoked by amphetamne.

effect on amphetamine-induced

it was studied whether

of EAA involved a dopamine

As it is shown in Table 1. haloperidol

release

but not the extent

abolished

However,

of 10

the augmentation haloperidol

had no

release of ASP (Table 2).

Table 2 Effects Experimental

of D-Amphetamine

Condition

on Net-Evoked

Release of Excitatory

Stimulus

ASP

GLU (pmoles/mg

Saline AMPH (5 mg) Saline AMPH (5 mg) Saline AMPH (10 mg) Saline AMPH (10 mg) + Haloperidol

Amino Acids.

K+ (40 mM) K+ (40 mM) NMDA (100 PM) NMDA (100 pM) NMDA (100 pM) NMDA (100 pM) NMDA (100 pM) NMDA (100 pM)

9.66 8.51 6.90 1.85 4.0 0.96 7.82 2.23

+ * + f f + + *

prot/min)

27.15 21.81 12.19 10.53 4.48 2.84 6.50 2.60

2.30 0.9 1.40 0.55* 1.0 0.3** 2.2 0.98*

AMPH= D-Amphetamine. Results are the mean + S.E.M. of four different -Wallis: * p < 0.03 vs control; ** p < 0.05 vs control.

experiments.

+ + + f f * f f

4.0 2.6 4.6 4.2 0.48 0.76 1.4 0.99

Kruskal

Discussion As it was shown by Nash and Yamamoto at 5 and 10 mg/kg, increased results further

add that this phenomenon

since haloperidol

completely

between

dopaminergic

NMDA

receptor

may be through the activation

dopamine

evoked the release of recently taken up ‘H-dopamine

and/or aspartergic

afferents

in NAc.

system,

release

Recent reports have suggested

in the rat NAc, as L-GLU

through an effect that was completely

by Mg2’ (Marien et al., 1983) or by the NMDA-receptor et al., 1987). and the sensitivity

of the dopaminergic

These data support to a greater extent an interaction

nerve terminals

might modulate

in the striatum, amphetamine,

release of ASP and GLU from NAc slices; the present

blocked the effect.

and glutamatergic

activation

(1992) for methamphetamine

the spontaneous

or NMDA antagonized

antagonist 2-Amino-5-phosphonovalerate

of which seems to be determined,

that

(Jones

at least in part, by glutamatergic

from the frontal cortex (Asencio et al., 1991).

On the other hand, it appears

Effect of u-Amphetamine that dopamine

receptor

blockade,

the atypical neuroleptic

clozapine,

et al., 1992). Whether

the effects

consequences

chronic administration

of amphetamine

treatment

and evocked

the K+-or NMDA-evoked release

suggesting

NMDA receptor

coupled

EAA-containing

neuronal

psychotic

reactions

PCP antagonizes,

1990).

to EAA release in the NAc.

the glutamatergic

i.e. the hypofunction

effects

Perhaps,

distinct

ASP, through amphetamine

since hypofunction of psychosis

a possible

in

(PCP), in which

by NMDA (Wong et al.,

system hypofunctional.

in this manuscript

of the glutamatergic

of

1964) have been described.

effects mediated

or aspartergic

of the

and Nowak,

If this is correct,

of amphetamine

or aspartergic

on EAA-

neuronal systems,

might

on the spontaneous

explanation

and evoked-release

to this phenomenon

of EAA are difficult to

resides in the existence

of an overactive

system which may at the same time enhance the release of EAA, and on the other hand

the release

structures

expression

psychosis.

of amphetamine

induce the desensitization regulate

or fuctional

(Luby et al., 1959; Domino,

that the particular effect described

transmission,

dopaminergic

or even decreased. of 5 and 10 mg/kg

who abuse phencyclydine

manner, the excitatory

amphetamine

binds near or within the ion channel of the NMDA receptor (McDonald

relate to amphetamine-induce

interpret.

unaltered

after the injection

This might be interesting,

1987). This is the case for individuals

Thus, PCP tenders

The opposite

EAA remained

following

in the brain have been related to the appeamnce

very similar to schizophrenia

it may be speculated mediated

remain to be determined.

release of ASP and GLU was increased

release of endogenous

in a noncompetitive

1988), and possibly

or

in the NAc has any behavioral

that this drug may induce a lower sensitivity

systems

such as haloperidol

et al., 1987; Csemansky

of amphetamine,

of ASP was reduced quite substantially

of amphetamine,

human beings (Olney,

on EAA release

manifestations

471

release of EAA

Despite the fact that the spontaneous

NMDA-evoked

NAC

of a typical neuroleptic

increase GLU levels in the NAc (Lindefors

or has any role in the behavioral

Amphetamine

treatment,

on the Release of EAA in the Rat

of putative NMDA autoreceptors

of ASP and GLU. from co&o-accumbens

trans-synaptic

mechanisms

Another

(Martin et al., 1991; Bustos et al., 1992) that

possibility

terminals,

is that NMDA receptors,

might indirectly

modify

located in NAc

the release of GLU and

(Bustos et al., 1992). which in turn may be desensitized

by

administration.

Conclusions The acute spontaneous

administration

of D-amphetamine

to rats was found

release of EAA and a decrease in NMDA-evoked-release

in the spontaneous

release of EAA induced by amphetamine

to suggest that these changes

may be related to amphetamine

to produce

an increase

of EAA in the NAc.

was blocked by haloperidol. behavioral

in the

The increase It is tempting

and psychotomimetic

effects.

Acknowledgements Supported

by a grant from Fondo National

de Desarrollo

Cientffico

y Tecnol6gico

(FONDECYT

No

R. Labarca et al.

472 0672/91).

D-amphetamine

was a gift from Laboratorio

Chile S.A. Ms. Lucy Chacoff

did the editorial

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