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Chronic neuroleptic treatment D2 dopamine receptor supersensitivity and striatal glutamatergic transmission.

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Chronic Neuroleptic Treatment:
D2 Dopamine Receptor Supersensitivity
and Striatal Glutamatergic Transmission
Paolo Calabresi, MD, Marco De Murtas, MD, Nicola Biagio Mercuri, MD, and Giorgio Bernardi, M D
We studied the in vitro electrical activity of rat neostriatal neurons following chronic neuroleptic treatment. In
haloperidol-treated rats, unlike naive animals, activation of neostriatal D2 dopamine receptors induced a potent presynaptic inhibition of glutamate-mediated excitatory synaptic potentials. Haloperidol treatment did not affect the intrinsic
membrane properties of the neostriatal neurons. Pre- and postsynaptic physiological responses to direct and indirect
gamma-aminobutyric acid (GABA)-ergic and cholinergic agonists were not affected by chronic haloperidol treatment.
These findings suggest that movement disorders induced by chronic neuroleptic treatment may result, at least in part,
from a hypersensitivity of presynaptic D2 dopamine receptors regulating the release of glutamate.
Calabresi P, De Murtas M, Mercuri NB, Bernardi G. Chronic neuroleptic treatment: I12 dopamine receptor
supersensitivity and striatal glutamatergic transmission. A n n Neural 1902;31:366-37.3
The treatment of schizophrenia with neuroleptics is
one of the major achievements of psychopharmacology
f 13. Although several pharmacological mechanisms and
complex synaptic circuitries may underlie the therapeutic effects of neuroleptics, the antipsychotic potency of these drugs has been usually correlated with
their dopamine (DA) receptor-blocking potency [2].
Long-term neuroleptic therapy may cause several
complications. Tardive dyskinesia (TD)is the most frequent among these complications [3}. TD is characterized by a variety of involuntary movements including
orofacial dyskinesia, chorea, athetosis, tiystonia, and
tics {3, 41. Neuroleptic-induced dyskinesia has also
been observed in rodents and monkeys 141. Although
it has been hypothesized that TD results from a hypersensitivity of neostriatal DA receptors [4],
the pathophysiology of TD is still controversial [ S 1. Several authors previously reported that long-term haloperidol
treatment induces a hypersensitivity of D 2 D A receptors in the neostriatum [6- lo]. Other hypotheses
concerning the mechanisms causing TI> have been
advanced: Alterations of gamma-aminobutyric acid
(GABA)-ergic and cholinergic systems in the basal
ganglia have been postulated [4, 11-13]. For this reason, we investigated the possible physiological changes
induced by chronic neuroleptic treatment on the electrical activity of the neostriatum, a brain structure that
plays a major role in the control of movements [14,
151. In particular, we studied the effects produced by
D2 DA agonists on glutamatergic synaptic potentials
recorded in vitro from neostriatal neurons following
cortical activation both in naive and in hdoperidoltreated rats.
Corticostriatal fibers represent the major p:lutamatergic input to the neostriatum [ 16- 181: An altered
release of excitatory amino acids from these terminals
has been implicated in several motor abnormalities
[ 17-2 11. Considering that biochemical studies have
shown that a consistent proportion of neostriatal D2
DA receptors are located on the axon terminals of
the corticostriatal glutamatergic pathway E22-2 51, we
studied the possible DA modulation of the excitatory
synaptic potentials (EPSPs) recorded from neostriatal
neurons following synaptic activation of cortical fibers.
In addition, we studied the pre- and postsynaptic responses of neostriatal neurons to the application of different concentrations of direct and indirect GABAergic and cholinergic agonists, in order to verify whether
chronic haloperidol treatment induced physiolclgical
and pharmacological changes in the non-DA neuironal
systems in the neostriatum.
From Clinica Neurologica. Dip. Sanita, I1 Universiti degli Studi di
Roma, Rome, Italy.
Address correspondence to D r Calabresl, Clmica Neurologica, Dip.
Saniti, I1 Universiti degli Studi di Roma, Via 0. Raimondo, 00173
Rome’ Italy.
Received Apr 30, 1991, and in revised form Jul 1. Accepted for
puhlicarion S t p 2, 1991.
Materials and Methods
Adult (4-6 months old, n = 40) and aged (24-26 months
old, n = 9) Wistar rats were used for the experiments Haloperidol ( 2 mgikg, Serenase, n = 2 8 ) or saline solution (for
controls, n = 21) was injected daily intraperitoneally f x 30
days After a 36-hour, treatment-free, drug-washout period,
Copyright 0 1992 by the American Ncurological Association
the rats were killed by a heavy blow to the chest under ether
anesthesia, which severed major blood vessels. The brain
was quickly removed. Frontal slices (200 pM) including the
neostriatum and cortex were prepared and maintained in
vitro by standard techniques f26-32).
The tissue was completely submerged in a continuously
flowing (2.5 mlimin) solution comprised of (mM): sodium
chloride (NaCl), 126; potassium chloride (KCI), 2.5; monosodium acid phosphate (NaH,PO,), 1.2;magnesium chloride
(MgCI,), 1.3; calcium chloride (CaC12),2.4; glucose, 10; and
sodium bicarbonate (NaHCO,), 26; saturated with 95% oxygen and 5% carbon dioxide at 36°C. Drugs were applied by
changing the superfusion solution to one containing known
concentrationsof drugs; new solutions entered the recording
chamber within 30 seconds. Glutamate was applied by
ejecting a few nanoliters of a 100 mM solution from the tip
of a blunt pipette beneath the surface of the superfusing
solution and just above the tissue slice. Numerical data are
expressed as a mean ? standard deviacion (SD) of the mean.
The statistical significance of the experiments was evaluated
using Student's t test for paired and unpaired observations.
Intracellular recordings from neostriatal neurons were
performed with 2 M KCI electrodes. EPSPs were
evoked by using a bipolar stimulating electrode located
either in the corpus callosum or in the cortical areas
close to the recording electrode. EPSPs were blocked
by kynurenic acid (600 pM), a broad-spectrum antagonist of excitatory amino acids, showing that neostriatal
excitatory transmission is mediated by a glutamate-like
neurotransmitter [3 1, 32). Picrotoxin (30- 100 pM) or
bicuculline (30-100 pM) was added routinely to the
bathing medium to block depolarizing inhibitory potentials [30, 3 l] allowing unambiguous measurements
of the EPSPs. Data were obtained from 64 neurons
recorded from haloperidol-treated rats and 49 cells recorded from naive animals. The intrinsic membrane
properties of cells recorded from haloperidol-treated
rats did not differ from those observed in naive animals. The membrane potential was -80.1 ? 4 mV in
naive rats and - 79.5 5 3 mV in haloperidol-treated
animals. Input resistance was 38 .t 5 MR in naive animals and 39 -t 4 MR in treated rats. A11 the recorded
neurons showed membrane rectification, absence of
spontaneous action potentials, and tonic firing activity
during depolarizing current pulses [26-30).
In haloperidol-treated rats, LY 171555 (0.1-10.0
kM), a D2 DA agonist, produced a large reduction of
the EPSP amplitude (Fig lAa), while in naive animals
these concentrations of LY 17 155 5 did not affect EPSP
amplitude evoked by cortical stimulation (Fig IB). The
reduction of the EPSP was not coupled with changes of
postsynaptic membrane properties such as membrane
potential, input resistance, current-evoked firing frequency, and responses to exogenous glutamate (see Fig
IAb, Ac). These findings suggest that the decrease of
the EPSP amplitude caused by LY 171555 in slices
from haloperidol-treated rats is presynaptically mediated. Figure 2 shows the dose-response curve obtained
for the effects of LY 17 155 5 in naive and in haloperidol-treated rats. Note that in treated animals, the D2
agonist reduced in a dose-dependent manner the EPSP
amplitude while in naive rats LY 171555 caused only
minor effects. As shown in Figure 3A, the presynaptic
inhibitory effect of LY 171555 was antagonized by
(-)-sulpiride (0.3-3.0 pM), a D2 receptor antagonist.
The D1 receptor antagonist SCH 23390 (0.3-10.0
pM) failed to antagonize the effect of LY 17 155 5 (not
We also studied the possible inhibitory effects of
exogenous D A on cortically evoked EPSPs. In order
to block postsynaptic inhibitory effects produced by
DA via D1 DA receptors {27, 291, in these experiments slices were perfused with SCH 23390 (1-3
pM), a D1 receptor antagonist. In slices obtained from
haloperidol-treated rats, D A mimicked the presynaptic
inhibitory effect of LY 171555 (Fig 3B). This inhibitory action was dose related (1 pM: - 10 2 5%,, n =
3; 3 pM: -32 & 795, n = 4 ; 10 pM: -49 k 8';?c,n
= 6) and was not coupled with changes of postsynaptic
membrane properties (membrane potential, apparent
input resistance, and postsynaptic responses to exogenous glutamate). Sulpiride (0.3-3.0 pM) prevented or
antagonized (see Fig 3B) the presynaptic inhibitory effect of DA. In naive rats, D A did not produce significant changes of EPSP amplitude (n = 10, not shown).
By utilizing amphetamine, a DA-releasing agent
[29}, we studied the possibility that not only exogenous D A agonists, but also endogenous neostriatal D A
cause presynaptic inhibitory effects on the release of
excitatory amino acids. Also in these experiments,
SCH 23390 was routinely applied during the recordings. In slices obtained from haloperidol-treated Tilts,
amphetamine reduced EPSP amplitude (3 pM: - 1 2
+- 6%, n = 4 ; 10 pM: -48 & 7%', n = 6) without
affecting postsynaptic properties and intrinsic membrane excitability (see Fig 3C). The presynaptic action
of amphetamine, as well as the actions produced by LY
171555 and DA, was prevented by sulpiride (0.3-1.0
FM). In the presence of S C H 23390, amphetamine
did not affect the amplitude of EPSPs recorded from
naive rats. No pharmacological difference in the responses to D A agonists was observed in the different
areas of the neostriatum we studied.
We studied also the possibility that the DA-induced
presynaptic inhibition in haloperidol-treated neurons
was indirectly mediated by endogenous acetylcholine
released by striatal interneurons bearing D2 DA receptors [3 31. In haloperidol-treated rats, the presynaptic
effects induced by LY 171555 were studied in the
presence of scopolamine (3 p.M), a muscarinic antagonist, and of hexamethonium (100 pM), a nicotinic
Calabresi et al: D2 Receptors and Haloperidol 367
3pM L Y
100 rns
3pM L Y
10 ms
LY concentration
( clM 1
antagonist. Under this condition, the dose-response
curve for the LY 1 7 1 5 5 >-induced inhibition of glutamate-mediated EPSPs was similar to that observttd in
control medium for haloperidol-treated rats (n -= 5 ,
data not shown).
Age-related processes cause a decrease in the riumber of D2 D A receptors in the neostriatum of animals
[34, 351 and humans [36).T h e possible effect of aging
o n the DA-induced presynaptic inhibition after chronic
neuroleptic treatment was studied in 10 neurons ob368 Anna15 of Neurology
Vol 3 I
No 4 April 1',192
I naive
Fig 2. Coricentrution dependence o/depre.i.tion of i-orticaffy
eooked ex&tov syiapti(-potential (EPSP, by LY 1 715 5 5
(LY) iii naiiv rats (filled squares) and in halopridol-treuted
atiimah (filled circles). Each point J J ~ I L ~the
J . niem deprm i o n
('lc of control t SDi ohsewed in the numbrr o / ~ i e l l itidiliited.
Note that LY 171353 produced u large inhibzton uc-tiopt O H
EPSP amplitude in treated rut.r. but orill mitior e1fict.l in m i i v
3uM L Y plus
3 p M sulpiride
l O p M DA
1 0 v M DA plus
t --------control
1 0 p M AMPH p l u s
3uM s u l p i r i d e
10 ms
Fig 3 . in dices obtained from haloperidol-treated vats. d p i r i d e
antagonizes the reduction of the excitatoy synaptic potential
(EPSP) amplitude induced by LY I71555 (LY), dopamine
(DA), and amphetamine (AMPH). (A,The EPSP amplitude
recorded in control condition (at was reduc-ed by LY 171555
ibt: thiJ inhihitor), rf;/rct u*a.iantagonized bj sulpiride ic,.
i B ) I n aiiothrv cell the amplitude oJ the EPSP obsewed in control cunditiut?(a1 'was decreased bj DA ibt: .idpiride rer*er.ted
the inhibitor) t@rt of D A ( ( I . ( C I In thzj experiment. the amplitude of miitrul EPSP la) was dewmrd b.y amphetamine tb,:
alto i n th2.l czse scilpiride verwsed the irihibitoty dfect ici.
iB. C I SCH 23390 at a conc-entratio?2of 3 . 0
u'as present
thmiighrmt all the rxperitnents to block possible rlectrophysiological e f l k t ~ niediated h j D 1 DA r*ei'eptovactizariun. Resting nienibsutie potrwtiah irr A. B. and C were. sespectirely. 80 niV.
-8.3 NIV. and -81 tnV.
tained from 5 aged rats. After haloperidol treatment,
in cells from aged rats, the dose-response curve for the
LY 17155 5-induced inhibition of glutamate-mediated
EPSPs was similar to that observed in adult rats (data
not shown). In 7 neurons recorded from naive aged
rats (n = 4),LY 171555 did not produce significant
presynaptic action.
Since changes of the GABAergic and cholinergic
striatal systems have also been postulated in the pathophysiology of neuroleptic-induced TD 14, 11-13], we
studied the effects of direct and indirect GABAergic and cholinergic agonists on neostriatal neurons recorded from naive and haloperidol-treated rats. Endogenous GABA and GABAergic agonists produce
both pre- and postsynaptic actions on neostriatal neurons [31, 37). The presynaptic effect is mediated by
GABA, receptors located on the terminals of glutamatergic fibers [31, 37). Table 1 shows data on the
presynapric inhibition of glutamate-mediated EPSPs
caused by different concentrations of baclofen (a
GABA, selective agonist) in naive and in haloperidoltreated rats. Baclofen (0.3-3.0 pM) did not alter the
intrinsic membrane properties of the recorded cells,
but it induced a dose-dependent decrease of glutamate-mediated EPSPs {31, 37). There was no significant difference between the effects induced by baclofen in naive and in haloperidol-treated rats. The pre-
synaptic effects of endogenous GABA in these two
groups were studied by using nipecotic acid (0.1-1.0
mM), a GABA-uptake blocker C31, 37), in the presence of bicuculline (30-100 p M to avoid postsynaptic
effects induced by GABA, receptor activation). The
inhibitory presynaptic effect of nipecotic acid was not
significantly different in these two groups of neurons
(see Table 1).
Table 2 shows data on the postsynaptic membrane
responses induced by GABA, receptor activation in
haloperidol-treated rats and in naive animals. Both
muscimol (0.3-3.0 pM), a GABA, receptor agonist,
and nipecotic acid (0.3-3.0 mM) induced dosedependent membrane depolarizations. The membrane
depolarization caused by the GABA, receptor activation is caused by the opening of C1- channels, which
under our experimental conditions (very negative resting membrane potentials and KCI-recording electrodes) produces a depolarizing driving force {3 1, 37).
No significant difference was observed in the postsynaptic action of muscimol and of nipecotic acid in the
two groups of cells (see Table 2).
Also, the activation of muscarinic receptors produces both pre- and postsynaptic actions on neostriatal
neurons {38). We studied the effects of direct and indirect cholinergic agonists in naive and in haloperidoltreated rats. Low concentrations of muscarine, a direct
muscarinic agonist, reduced in a dose-dependent manner the EPSP amplitude of glutamate-mediated EPSPs
without affecting postsynaptic membrane properties.
No significant difference was observed between naive
and haloperidol-treated rats (see Table 1).The presynaptic action of endogenous acetylcholine was studied
by using neostigmine, an inhibitor of acetylcholinesterase. The effects of neostigmine (0.3-3.0 pM), as well
as those produced by muscarine (0.3-3.0 kM), were
similar in the two groups of cells (see Table 1).
The postsynaptic membrane depolarization induced
by activation of muscarinic receptors in neostriatum is
known to be due to the decrease of potassium conductance [38]. This effect, however, was only observed
after application of high concentrations of muscarinic
agonists C38). The membrane depolarizations induced
by muscarine (10-100 kM) and neostigmine (10-100
kM) were studied in naive and in haloperidol-treated
rats. No significant difference was observed in these
two groups (see Table 2).
We studied the effect of chronic neuroleptic treatment
on the physiological and pharmacological responses
of presumed medium spiny neurons that are sttiatal
GABAergic cells projecting to the output structures
of the basal ganglia (globus pallidus and substantia nigra
pars reticulata) [14). Although we did not attempt intracellular staining of these neurons in this study, it is
probable that most impaled cells were medium spiny
Calabresi et ai: D2 Receptors and Haloperidol
Tab/r 1 . Prr.cynaptiz Eflects (Excitatq Sjnaj)tii-Potential {EPSP] Redzdoti)
of GABAt:t*girand Cholinergir Agonists in ICai7.e and Haloperidol-Tveuted Rut.iL
Ago n is t
Nipecotic acidh
0.3 p M
1.0 yM
2t: i 4 ( n = 5 )
0 . 3 pM
2 9 j : 5 (n = 3 )
0 . L mM
19 2 4 (n
0.1 mM
18 2 5 (n
0.3 mM
4 8 2 8 ( n = 6)
49 2 9 (n
0.3 m M
1.0 pM
9 (n
1 0 yM
8 (n
1.0 p M
58 k 10 ( n = 3)
0.3 p M
12 t 5 (n
6 (n
8 (n
1.0 pM
24 2 6 (n
1.0 yM
0 . 3 pM
= 3)
* 5 ( n = 3)
3 0 pM
53 ? 9 ( n = 4 )
1.0 pM
5 5 t- 8 ( n = 4 )
"Values are given as mean 2 SD of V of inhibition of the EPSP amplitude recorded before the drug application. n = the nuniher of cells
recorded in each experimental condition. Note that haloperidol treatment did not cause any statistically significant ( I test. p :
, 0 . 0 5 ) change o f
the drug-induced inhibition of the synapric potenrial.
these experiments nipecotic acid was applied in the presence of 30-100 p M bicuculline t o avoid interactions of endogenous G A B A w r h
postsynaptic GABA, receptors.
Table 2. PoA-tsjlnapticEffectJ (Meribrune Depolurizutionl of GABArrgic
arid Cholinergir Agonists in Naiue and Haloperidol-Treated Rat.?
0.3 ~ L M
t 2 I'n = 4 )
0 . 3 ILM
4 2 2 ( n = 3)
1.0 p M
15 t 3 (n = 5 )
3 0 yM
21 i 'I (n
1.o +M
14 5 4 ( n
3.0 p M
0 . 3 rnhl
1.0 mM
1.0 m M
Nipecotic acid
0 . 3 mM
2 * l ( n = 3)
10 p M
i ( n = 3)
I0 )*.M
1 0 pM
2 1 (n
10 pM
3 t 1 (11 = 3 )
30 p.M
13 t 6 ( n
30 p M
14 t 6 (n
22 t
(n = 4 )
100 ).Lh.I
8 % 3(n =
100 pM
8 2 i ( n = 3)
"Values are expressed as mean f SD of the membrane depolarization (mV) induced, at resting level, during the application o f the clrug. n =
the number of the cells recorded in each experimental condition. Note that haloperidol treatment did not cause any statistically significc1.nt( I
test, p > 0.05) change of the drug-induced membrane liepolarizations.
370 Annals of NeLirology Vol 3 1 No 4
April 1992
neurons since other studies reported that the majority
of intracellularly stained cells in the neostriatum were
of this type [39, 40). Our findings suggest that chronic
haloperidol treatment does not alter the intrinsic membrane properties of these cells [26-301; thus, no
significant difference of resting membrane potential,
apparent input resistance, and firing properties was observed in cells recorded from naive rats compared to
those obtained from haloperidol-treated rats. We did,
however, find that in haloperidol-treated animals, unlike naive rats, activation of D 2 DA receptors reduces
the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. Since this effect
was not coupled with significant changes of postsynaptic membrane properties and with modifications of the
postsynaptic sensitivity to exogenously applied glutamate, we argue that this action is presynaptically mediated. Our data suggest that chronic haloperidol treatment induces a hypersensitivity of presynaptic D2 D A
receptors located on the axon terminals of the corticostriatal pathway and controlling the release of glutamate in the striatum {23-251. Activation of these
hypersensitive receptors by exogenous and/or endogenous DA would reduce the release of glutamate in
the neostriatum and alter the output signals from the
neostriatum to the other structures of the basal ganglia
E 141.
However, an alternative explanation must be considered. It is possible that corticostriatal excitatory synapses responsible for the EPSPs were electronically remote from the somatic recording site; consequently,
changes in the postsynaptic neurons at the synaptic site
occurred. but were not detected with the intrasomatic
In contrast with biochemical studies 123-251, receptor autoradiographic studies do suggest that few or no
D2 receptors exist on corticostriatal fibers 141, 42).
The recent in situ studies for localizing D2 messenger
RNA (mRNA) gave mixed results. Two groups of investigators reported low levels of 0 2 mRNA in a deep
layer of the cortex [43, 441, but Mengold and colleagues reported no detectable levels of D 2 mRNA in
the cortex {453. Thus, the data regarding localization
to corticostriatal fibers are still controversial. Our data
provide some functional information about this complex issue. We suggest that receptor supersensitivity
caused by either chronic neuroleptic treatment or DA
denervation [28, 291 reveals a presynaptic inhibitory
effect on glutamatergic terminals mediated by D2 receptors. This idea is supported by most of the studies
that directly measured D2 receptor density after repeated haloperidol administration [46-48). The lack
of changes of postsynaptic membrane properties and
postsynaptic sensitivity to glutamate is consistent with
the evidence that striatal glutamic acid decarboxylase
(GAD) activity is not altered after haloperidol treat-
ment for 1 to 3 months [49].However, although we
chose an experimental paradigm similar to those utilized in previous behavioral and biochemical studies, it
is possible that lower or higher doses of haloperidol or
different durations of treatment might give a different
response 149).
Biochemical studies have shown that the activation
of D2 DA receptors located on striatal cholinergic interneurons reduces the release of acetylcholine in the
striatum C33). The possible involvement of these cholinergic interneurons in the presynaptic effect of D2
DA receptor agonists on glutamatergic potentials was
ruled out by the finding that the action of LY 17 1555
in haloperidol-treated rats persisted even in the presence of muscarinic and nicotinic antagonists.
Since it has been shown that the plasticity of D 2 DA
receptors in the striatum decreases with age 134-363,
while the incidence of TD seems to increase with age
13, 41, we studied whether the haloperidol-induced
supersensitivity of presynaptic D 2 DA receptors was
changed in aged animals in comparison to adult animals. Our data show that age-related processes do
not affect the presynaptic inhibition induced by LY
17 155 5 in haloperidol-treated animals. This finding can
be explained either by assuming that supersensitivity of
presynaptic D2 DA receptors located on glutamatergic
terminals does not decrease with age or by considering
that in aged animals, factors other than D2 DA receptor supersensitivity contribute to maintain the DA-mediated presynaptic inhibitory effect.
The possible involvement of non-DA neurotransmitter systems in the functional changes induced by
chronic neuroleptic treatment was further investigated
by measuring the pre- and postsynaptic electrophysiological responses during activation of GABAergic
and cholinergic receptors in naive and in haloperidoltreated neurons. It is interesting to note that we failed
to demonstrate any significant difference between
these two groups of cells not only regarding the effects
of direct receptor agonists (such as muscarine, baclofen, and muscimol), but also concerning the electrophysiological effects produced by indirect agonists
such as nipecotic acid (an inhibitor of GABA uptake)
and neostigmine (an inhibitor of acetylcholinesterase)
which increase, respectively, the endogenous GABAergic and cholinergic tone in the striatum 131, 37, 38).
This finding seems to indicate that in the striaturn,
chronic neuroleptic treatment alters neither the sensitivity of GABAergic and cholinergic receptors nor the
ability of GABAergic and cholinergic synapses to release amounts of transmitters sufficient to activate preand postsynaptic receptors. However, our study does
not rule out the possibility that chronic neuroleptic
treatment causes changes of striatal GABAergic and
cholinergic systems that are not detectable with our
technique. In addition, alterations of extrastriatal sys-
Calabresi et al: D2 Receptors and Haloperidol
sion in the striatum; under this condition, the excitatory inputs are mainly controlled by muscarinic [ i X I
and GABA, C31, 37) receptors (see Fig 4A). However, chronic neuroleptic treatment induces superserisitivity of these presynaptic D 2 DA receptors probably
by increasing the number of these receptors, rather
than by altering their affinity [46-48).Activation of
these supersensitive receptors will cause a further reduction of glutamatergic inputs to the striatum (see
Fig 4B). The reduction of the excitatory inputs to the
striatum will cause a decrease in the release of GABA
in the output structures of the basal ganglia (globus
pallidus and substantia nigra pars reticulata) [ 141. As a
consequence of the reduced GABAergic inputs from
the striatum, these structures will be disinhibited. For
I 1 this reason, an altered DA control of the corticostriatal
transmission will ultimately result in a more general
imbalance of the functional activity of the basal ganglia.
terns and of striatal peptidergic modulation [SO1 may
contribute to the motor and behavioral effects produced by chronic neuroleptic treatment.
Although o u r data d o not provide a full explanation
of the physiopathology of T D , we propose a possible
mechanism that may underlie some of the functional
changes observed in the basal ganglia after chronic neuroleptic treatment (Fig 4). W e suggest that under control conditions, presynaptic D2 D A receptors d o not
play a major role in regulating the excitatory transniis-
This work was supported by a Consiglio N;lzion.ile dellc Ricerehe
(CNR) grant “Prog. Fin. Chimica Fine 11” (to G . U.1and Consiglio
Nazionale delle Riccrchc grants 890347
and 90(J3187 ( 7’0.4 ( t o
P. C.).
We thank G. Gattoni and M. Tolu for their excellent technicd A
tance and D r A. Constanti for critically reading the manuscript.
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I Presynaptic D2 DA receptors
Presynaptic GABAB receptors
Presynaptic muscarinic receptors
F i g 4.Sr.hnNe q/ the pwJ.snuptic- c-ontrof of glutamate refeu.Fr in
the ilroJtriatiirn q/ n a i arid
~ hnloperidol-treated rats. (A,Under u control ~ ~ ~ d i t i the
o i i release
of glutamate from corticostriatal.fiber.1 iJ- iiihibited by the ac-titJationof GABA, (white symbols) nnd ? u u ~ - c a ~ i(gray
i i i ~ symbols) pre~:ynapticreceptors: iti
m p t i i - D.? dopamitie ( D A ) rec.eptors (black
syinbuls) e.vert oii!]. u viinvr rdr i t 1 the c-owtro/ of-c.urtii-o.rt~iui/nl
glutairintergii.transmission. IBi Chronic haloperidol treatnirrit
itiditm hypprrseii.ritii,it.r of pmynaptic D.2 D A receptors. Note
the iric-rra.rt.rl tiitnibrr o{ D2 DA rerepton located on gfutamarevgic trrniinalr. These veieptorJ. udl exert a stronger inhibitoyi
cvntrol o n the releaje cjgfittamate in the neo.rtriatum. The re-du(2d escitatoty itiput~t o t h e GABAergic-neostriatal neurwu
prqjectitig t o the globus pallidu (GP) uiid to the substantia nigra pars retiiulta (SNr) wili came a decrease qf- the inhibitiq
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