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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.
366
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.
Results
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
shown).
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
A
b
haloperidol-treated
control
3pM L Y
n
i
i
A
wash
A.
100 rns
B
control
naive
3pM L Y
wash
10 ms
60-
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
haloperidol-treated
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
animah.
3uM L Y plus
3 p M sulpiride
LY
control
3pM
control
l O p M DA
1 0 v M DA plus
x
e
t --------control
A
1 0 p M AMPH p l u s
3uM s u l p i r i d e
r-.
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).
Discussion
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
369
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
Baclofen
Naive
Haloperidol-treated
Nipecotic acidh
Naive
Haloperidol-treated
Concentrations
0.3 p M
1.0 yM
2t: i 4 ( n = 5 )
0 . 3 pM
2 9 j : 5 (n = 3 )
60
0 . L mM
19 2 4 (n
0.1 mM
18 2 5 (n
6)
=
5)
0.3 mM
4 8 2 8 ( n = 6)
=
3)
49 2 9 (n
0.3 m M
=
4)
=
3)
1.0 pM
39
-+
9 (n
1 0 yM
Haloperidol-treated
39
Haloperidol-treated
8 (n
=
Muscarine
Naive
Neosrigmine
Naive
?
1.0 p M
58 k 10 ( n = 3)
0.3 p M
12 t 5 (n
2
6 (n
8 (n
=
3)
1.0 pM
24 2 6 (n
1.0 yM
=
3)
25
0 . 3 pM
13
-+
= 3)
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.?
Agonist
Muscimol
Naive
Concentrations
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
8-i3(n
1.0 m M
7F2(n
4
Haloperidol-treated
Nipecotic acid
Naivc
Haloperidol-treatec1
Muscarine
Naive
2-+1(n=3)
0 . 3 mM
2 * l ( n = 3)
10 p M
i ( n = 3)
I0 )*.M
5r,!(n=3)
5*
Neostigmine
Naive
1 0 pM
2 1 (n
3
Haloperidol-treated
=
3)
10 pM
3 t 1 (11 = 3 )
=
4,
=
3)
=
3)
30 p.M
13 t 6 ( n
30 p M
14 t 6 (n
=
6)
=
4)
22 t
I
7
51
(n = 4 )
100 ).Lh.I
8 % 3(n =
100 pM
4)
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
recordings.
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
371
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
OUTPUTS
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-
A
NAfVE
CORrEX
m
ANIMALS
NEOSTRIATUM
_.
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.
B
HALOPERIDOL-TREATED ANIMALS
CORTEX
1. Rifkin A, Siris A. Drug treatment o t acute schizophrenia. Iii
Meltzer HY, ed. Psychopharmacology, the third generation o i
progress. N e w York: Raven Press, 1988: 1095- 1 1 0 1
2. Creese 1, Burt DR, Snyder SH. Dopamine rcwptor Ihiiidiiig
predicts clinical and pharmacologic:il porencies ot anrisc hi70
phrenic drugs. Science 1976;192:481-483
3. Ehadi M, Hama Y. Dopamine, GABA, iholecvstokinin and o p oids in iieuroleptic-induce[l rardive ciyskinesia Neurosci Hiohehav Rev 1988;12:179-187
I
4. Casey DE. Tardive dyskinesia. In: Meltzer HY, c<l,Psychopharmacology, the third generation of progress. New York Kavcii
Press, 1988: 1411-1419
5. Jenner P, Marsden CD. Is the dopamine hypothesis ot rarclive
dyskinesia completely wrong! Trencls Neurosci l980;9:259
6. Seeman P. Brain dopamine receptors. Pharrnacol Rev IOX(J,
r
-
I Presynaptic D2 DA receptors
13
Presynaptic GABAB receptors
5
Presynaptic muscarinic receptors
32:229-313
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
ni-iion of GABA o n r h m output j-tructures. uhich rrill be diJ.in hibited.
Annalc o f NeLirologv
Vol 31
References
ourwrs
NEOSTRIATUM
-
372
-.
No 4
April 1992
7. Staunton DA, Magistretti PJ, Kooh GF, et ‘11. Dopaminergi<
supersensitivity induced by denervation and chronic receptor
blockade is additive. Nature 19XL;LO9.~Z-’ri
8. Reches A, Wagner R H , Jackson V, et ‘11 Doparnine receptor\
in the denervated striatum: further supersensitivity b y chroiii(
haloperidol treatment. Brain Res 1981;L75:183- 185
9. Lappalain J, Hietala J, Koulu M, et al. Chronic treatment with
SCH 23 390 and haloperidol: effects o n clopaniinergic a i d serotoninergic mechanisms i n rat brain. J Pharrnacol Exp ’I‘hci1990;252:845-852
10. Debonnel G, Gaudreau P, Quirion K, D e Montigny C. Effect>
of long-term haloperidol treatmenr on the responsiveness ot
accumbens neurons to cholecystokinin and cl<>pamme:electrophysiological and radioligand binding studies in the rat. .I N C Y rosci 1990; 10:469-478
11. Fibigcr H C , Lloyd KG. Neurohiological substr‘ites oi t‘irdivc,
dyskinesia: the GABA hypothesis. Trends Neurosci 1084; 1 ?.
462-464
12. Gunne LM, Haggstrom J-E, Spquisc B. Association with persistent neuroleptic-induced ciyskinesia
GABA synthesis. Nature 1984;109
13. Thdker GK, Tammina GA, Alphs LD, et al. Brain y-aminobutyric acid abnormality in tardive dyskinesia. Arch Gen Psychiatry
1087;44:522-528
14. Groves PM. A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement.
Brain Res 1983;5:109-132
15. Mercuri NB, Calabresi P, Bernardi G. Physiology and pharmacology of dopamine D,-receptors. their implications in dopamine-substitute therapy for Parkinson’s disease. Neurology
1989;39:1106-1 108
16. Spencer HJ. Antagonism of cortical excitation of striatal neurons
by glutamic acid diethyl ester: evidence for glutamic acid as an
excitatory transmitter in the rat striatum. Brain Res 1976;102:
91-101
17. Divac I, Fonnum E, Storm-Mathisen J. High affinity uptake of
glutamate in terminals of corticostriatal axons. Nature 1977;
266: 377-378
18. Reubi JC, Cuenod M. Glutamate release in vitro from corticostriatal terminals. Brain Res 1979;176: 185-188
19. McGeer EG, McGeer PL. Duplication of biochemical changes
of Hunrington’s chorea by intrastriatal injections of glutamic
acid and kainic acid. Nature 1976;263:517-519
20. Greenamyre JT, Penney JB, Young AB, et al. Alterations in
L-[’H) glutamate binding in Alzheimer’s and Huntington’s diseases. Science 1985;227:1496-1490
21. Young AB, Greenamyre JT, Hollingsworth 2, et al. NMDA
receptor losses in putamen from patients with Huntington’s disease. Science 1988;241:981-983
22. Garau L, Govoni S, Stefanini E, et al. Dopamine receptors:
pharmacological and anatomical evidences indicate that two distinct populations are present in rat striatum. Life Sci 1978;23:
1745-1750
23. Schwdrcz R, Creese I, Coyle JT, Snyder SH. Dopamine receptors localized o n cerebral cortical afferents to rat corpus striarum. Nature 1978;271:766-768
24. Theodorou A, Reavill C, Jenner R, Marsden CD. Kainic acid
lesions of striatum and decortication reduce specific {’HI sulpiride binding in rats, so D-2 receptors exist postsynaptically on
cortico-striate afferents and striatal neurons. J Pharm Pharmacol
1981;33:439-444
25. Maura G, Giardi A, Raiteri M. Release-regulating D-2 dopamine receptors are located on striatal glutamatergic nerve terminals. J Pharmacol Exp Ther 1988;247:680-684
26. Calabresi P, Misgeld U, Dodt H U . Intrinsic membrane properties of neostriatal neurons can account for their low level of
spontaneous activity. Neuroscience 1987;20:293-303
2 7 . Calabresi P, Mercuri N , Stanzione P, et al. Intracellular studies
on the dopamine-induced firing inhibition of neostriatal neurons
in vitro: evidence for D l receptor involvement. Neuroscience
1987;20:’57-77 I
28. Calabresi P, Benedetri M, Mercuri NB, Bernardi G. Depletion
of carecholamines reveals inhibitory effects of bromocriptine
and lysuride on neostriatal neurones recorded intracellularly in
vitro. Neuropharmdcology 1988;27:579-587
20. Calabresi P, Benedetti M, Mercuri NB, Bernardi G. Endogenous dopamine and dopaminergic agonists modulate synaptic
excitation in neostriatum: intracellular studies from naive and
catrcholamine-depleted rats. Neuroscience 1988;27: 145- 157
30. Calabresi P, Mercuri NB, Bernardi G. Synaptic and intrinsic
control of membrane excitability of neostriatal neurons. 11. An
in vitro analysis. J Neurophysiol 1990;63:663-675
31. Calabresi P, Mercuri NB, De Murtas M, Bernardi G. Endogenous GABA mediates presynaptic inhibition of spontaneous and
evoked excitatory synaptic potentials in the rat neostriatum.
Neurosci Lett 1990;l 18:99-102
32. Calabresi P, De Murtas M, Mercuri NB, Bernardi G. Kainic
acid on neostriatal neurons intracellularly recorded in vitro: elec-
trophysiological evidence for differential neuronal sensitivlty. J
Neurosci 1990;10:3960-3969
33. Lehmann J, Langer SZ. The striatal cholinergic interneuron. synaptic target of dopaminergic terminals. Neuroscience 1083;10:
1105-1120
34. Memo M, Lucchi L, Spano PF, Trabucchi M. Aging process
affects a single class of dopamine receptors. Brain Res 1980;
202:488-492
35. Morgan D G , Finch CE. Dopaminergic changes in the basal ganglia: a generalized phenomenon of aging in mammals. Ann N Y
Acad Sci 1988;515:145-160
36. Wong DF, Wagner HN, Dannals RF, et al. Effects of age on
dopamine and serotonin receptors measured by positron emission tomography in the living human brain. Science 1984;226:
1393-1396
37. Calabresi P, D e Murtas M, Mercuri NB, Bernardi G. Involvement of GABA systems in the feedback regulation of glutamate
and GABA-mediated synaptic potentials in the rat neostriatum.
J Physiol 1991;440:581-599
38. Misgeld U, Calabresi P, Dodt U. Muscarinic modulation in the
neostriatum: possible involvement of calcium. Exp Brain Res
1986;S14:176-184
39. Bishop GA, Chang HT, Kitai ST. Morphological and physiological properties of neostriatal neurons: an intracellular
horseradish peroxidase study in the rat. Neuroscience 1982;
7: 1 79- 191
40. Misgeld U, Frotscher M, Wagner A. Identification of projecting
neurons in rat neostriatal slices. Brain Res 1984;299:367-370
41. Trugman JM, Geary WA, Wooten GF. Localization of D-2 dopamine receptors to intrinsic striatal neurones by quantitative
autoradiography. Nature 1986;323:267-269
42. Joyce J N , Marshall JF. Quantitative autoradiography of dopamine D2 sites in rat caudate-putamen: localization to intrinsic
neurons and not neocortical afferents. Neuroscience 1987;20:
773-795
43. Mansour A, Meador-Woodruff JH, Bunzow JR, et al. Localitation of dopamine D1 receptor mRNA and D , and Dz receptor
binding in the rat brain and pituitary: an in situ hybridizationreceptor autoradiographic analysis. J Neurosci 1090;10:25872600
44. Weiner DM, Levey AI, Sunahara RK, et al. D, and D Ldopamine
receptor mRNA in rat brain. Proc Natl Acad Sci USA
199 I;88:1859-1863
45. Mengold G , Martinez-Mir MI, Vilaro MT, Palacios JM. Localization of the mRNA for the dopamine D, receptor in the rat
brain by in situ hybridization hisrochemistry. Proc Natl Acad
Sci USA 1989;86:8560-8564
46. Mac Lennan J, Atmadja S, Lee N , Fibiger HC. Chronic haloperido1 administration increases the density of D, dopamiiie receptors in the medial prefrontal cortex of the rat. Psychopharmacology 1988;95:255-257
47. Kazawa T, Mikuni M, Higuchi T, et al. Characterization of
sulpiride-displaceable ’H-YM-0915 1-2 binding sites in rat frontal cortex and the effects of subchronic treatment with haloperido1 o n cortical D-2 dopamine receptors. Life Sci 1990;47:
531-537
48. ODell SD, La Hoste GJ, Widmark CB, e t al. Chronic treatment
with clozapine or haloperidol differentially regulates dopamine
and serotonin receptors in rat brain. Synapse 199O;6:146-153
49. Rupniak NMJ, Prestwich SA, Horton RW, et al. Alterations
in cerebral glutamic acid decarboxylase and ’H-flunltrazepam
binding during continuous treatment of rats for up to 1 year
with haloperidol, sulpiride and clozapine. J Neural Transm
1987;68:113-125
50. Gerfen CR, Engber TM, Mahan LC, et al. D, and DLdopamine
receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990;250:1429-1432
Calabresi er al: D2 Receptors and Haioperidol
373
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