愛知学院大学薬学会誌

第１０巻＝総説 1＝
Synaptic transmission in the nucleus tractus solitarius and modes ofaction of central antitussives
Yoshiaki Ohi and Akira Haji*

Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University
Summary
It has been presumed that central antitussives exert their action by inhibiting the so-called ‘cough center’
including the region of nucleus tractus solitarius (NTS) in the brainstem. This review firstly describes synaptictransmission in the second-order NTS neurons that receive peripheral afferents from a variety of visceral
receptors. Next, we summarize modulation of the NTS synaptic transmission by several bioactive substances.
Finally, the possible modes of action of representative central antitussives, codeine and dextromethorphan, on
the excitatory transmission in second-order NTS neurons are proposed.

Keywords: nucleus tractus solitarius, second-order neuron, synaptic transmission, neurotransmitter,neuromodulator, codeine, dextromethorphan
1. Introduction

able to influence reception and/or integration of the

The central nervous system (CNS) controls theperipheral inputs and to modify the autonomic

internal environment of the body by generating

responses.

proper autonomic outputs, which are optimized

Since the second-order neurons in the caudal part

according to the modality and strength of peripheralof NTS are the first cell receiving cardiopulmonary

inputs from a variety of visceral receptors. Suchafferents, this region has been recognized to regulate

peripheral afferents converge through the tractus

cardiorespiratory responses via central neuron

solitarius (TS) on the second-order neurons that

networks (Fig. 1). Especially, the caudal NTS and its

compose the local circuit in the nucleus tractus

neighboring ventrolateral region are considered assolitarius (NTS) of the brainstem1). In addition, the‘cough center’ constituting the cough reflex arc.

second-order

excitatory

andCough is a representative respiratory defensive

generatedbyreflex. The vagal afferent signals from the airway

interconnections between intrinsic neurons and are

rapidly adapting receptors (irritant receptors) andthought to modulate in the NTS network activity are

C-fiber receptors are conducted to the second-orderinhibitory

neurons
inputsreceivethatare* Corresponding author:
Akira Haji, PhD
Tel: +81 52 757 6786, Fax: +81 52 757 6799.
*E-mail address: haji@dpc.agu.ac.jp-1-

NTS neurons

The integrated peripheral

terminal via activation of voltage-dependent Ca2+

information activates the central cough/respiratory

channels and stimulates a core fusion cascade.

network to produce a cough pattern. Finally the

Emerging

generated cough motor drive is conducted to therelease may arise from a vesicle pool that is

respiratory muscles through efferent motor nerves

regulated separately from that for synchronous

6-9).

release 10).

4,

5).

The

evidencesuggeststhat

spontaneous

resultsofimmunocytochemical,

2. Synaptic transmission in second-order neurons ofelectrophysiologicalandneuropharmacologicalthe nucleus tractus solitarius

studies are in agreement, indicating that glutamate

Two modes of transmitter release from axon

is the main excitatory transmitter in both peripheral

terminals to the second-order neurons are postulated

and intrinsic excitatory inputs and GABA mediates

in the NTS; one is spontaneous release and the otherintrinsic inhibitory inputs in the second-order NTS

is synchronous release. The former represents aneurons (Table 1).

spontaneous, stochastic exocytosis from primed
vesicles.

The

latterrepresents

action2-1. Excitatory inputs

potential-induced synchronous vesicle exocytosis.
Action potential allows theCa2+

2-1-1. Glutamate

entry into the-2-It is generally accepted that ionotropic glutamate
receptors

function

inwardcurrent.

Therefore,both

postsynaptic AMPA and NMDA receptors contributeneurotransmission, while metabotoropic glutamate

to the excitatory transmission in the second-order

receptors (mGluRs) coupled with G-protein modify it

NTS neurons and the former plays a pivotal role.

11).

Ionotropic glutamate receptors are roughly

Furthermore, the electron microscopic labeling has

divided into two subtypes, N-methyl-D-aspartate

confirmed that NMDA receptors are localized at the(NMDA)

presynaptic

and

the

an

fast-acting

receptors

ininducesnon-NMDA

receptors

site

in

the

NTS.

Activationofincludingpresynaptic NMDA receptors exerts an inhibitory

-amino-3-hydroxy-5-methylisoxazole-4-propioniceffect on TS-evoked release of glutamate but aacid hydrobromide (AMPA) receptors and kinate

facilitatory

receptors.

Following

evidencesuggests

glutamateprimarily

mediates

the

that

glutamateeffect14).

onspontaneous

releaseof

The mGluRs are suggested to be

excitatory

involved in the synaptic transmission in the NTS.

synaptic transmission from both peripheral afferent

Function of Group I mGluRs is inconsistent between

fibers and intrinsic sources to the second-order NTS

animal species. While activation of Group I mGluRs

neurons 12, 13). AMPA induces an inward current infails to alter the glutamatergic transmission in thethe postsynaptic membrane. An antagonist of AMPA

rat NTS neurons

receptors markedly blocks both TS-evoked andfacilitates the release of glutamate from intrinsic

spontaneous

currents

terminals in the guinea pig NTS neurons through the(EPSCs). When the membrane is depolarized topresumably activation of Gq protein and increase inremoveMg2+

excitatory

postsynaptic

block from NMDA receptors, NMDA

15),

the mGluR1 mechanism

Ca2+ concentration 16). Group II and III mGluRs play-3-

an inhibitory regulation of glutamate release fromthe signal transmission from sensory afferents to theintrinsic

NTS neurons via postsynaptic nicotinic receptors 23).

interneurons

andperipheral

afferent

terminals in the rat 15) and guinea pig 16).
2-2. Inhibitory inputs
2-1-2. Substance P

2-2-1. GABA

The intermediate and caudal NTS are enrichedwith substance P-containing axon terminals

In addition to the excitatory synaptic inputs, the17),

NTS neurons receive inhibitory inputs from intrinsic

vagal

sources. A balance of these two mechanisms controls

afferent C fibers and terminals with cell bodies

the net activity of neurons. Spontaneous inhibitory

originating within the NTS and higher brain centers.

postsynaptic currents (IPSCs) in the second-order

Depletion of substance P in the vagus nerve blocks

NTS neurons are reversed at the membrane

rapid shallow breathing and apnea induced bypotential similar to an equilibrium potential of Cl-

pulmonary congestion

Local application ofand markedly blocked by GABAA antagonists 2).

substance P 19) or a selective neurokinin 1 receptor

These results indicate that GABA mediates theagonist 20) depolarizes the NTS neurons, suggesting

intrinsic inhibitory transmission in the second-orderthe postsynaptic excitatory action of substance P.

NTS neurons by activating the postsynaptic GABAA

Moreover, it has been demonstrated that substance P

receptors.

decreases both TS-evoked EPSCs with an increase inrelease from the afferent terminals via GABAB

the

of

receptorsthemodulated by glutamate through mGluRs 25). Thiswhich

emanatefrompaired-pulse

spontaneous

ratio,

andcapsaicin-sensitive

18).

and

the

miniature

frequency

EPSCs

in

Moreover,24),

GABA inhibits

glutamateand conversely, GABA release issecond-order NTS neurons 21). This proposes a newheterosynapticrole of substance P, which is a presynaptic depression

glutamatergic and GABAergic terminals are in close

of

the

proximity. In mechanically isolated NTS neurons, thesecond-order

spontaneous EPSC frequency is increased by GABAA

glutamatergic

broncho-pulmonarytransmission
afferents

betweenandneurons.

modulation

impliesthatthereceptor agonists, but decreased by GABAB receptor
agonists. The antagonists of GABAA and GABAB

2-1-3. Acetylcholine
Acetylcholine

receptors exert opposite effects. Either Na+-K+-Cl-

(ACh)

is

broadly

distributed

co-transporter type 1 antagonist or Na+/Ca2+ channel

throughout the CNS and contributes to central

inhibitorautonomic

regulation.

Cholinergic

systems

receptor-mediated release of glutamate, indicating

identifiedbypresence

of

the

are

cholineblocksGABAA-mediatedfacilitation
presynaptic

of

the

GABAA

depolarization

26).

acetyltransferase, ACh esterase and ACh in the NTS

Thus, tonically released GABA activates GABAA and

22). Microinjection of ACh or nicotine into

GABAB receptors to modulate

the NTSrelease of

elicits hypotension and bradycardia similarly to

glutamate.

These

stimulation of the arterial baroreceptors. Nicotinic

mechanisms

ofreceptors are also involved in tachypnea induced byintegration of peripheral visceral afferent signals in

thethe NTS.

peripheral

chemoreceptor

activation.

AChfindings

theheterosynaptic

providecellular

GABA-glutamate

modulates the activity of sympathetic nerve andphrenic nerve via nicotinic receptors. Iontophoresis

2-2-2. Glycineof ACh causes excitation of NTS neurons. Nicotine

Glycine is one of the two major inhibitory

induces an inward current, and this effect is blockedneurotransmitters in the CNS. Mixed GABA-glycine

by hexamethonium. Together, ACh mediates, in part,axon terminals are located at the lateral part of NTS-4-

within subnuclei surrounding the TS. Pure glycine

This thermally driven glutamate release persists

axon terminals are rare in the lateral part and hardly

when Ca2+ entry through voltage-dependent Ca2+

detected in the medial part. Electrophysiologicalchannels is blocked. TRPV1 channels play a key role

experiments have demonstrated existence of a dual

in neonatal respiratory regulation

inhibition involving the co-release of GABA andtemperature shifts within the NTS.

with small

glycine, and confirmed predominance of GABAOn the other hand, endocannabinoids activate

inhibition in the NTS. Glycine receptors are expressedcannabinoid type 1 (CB1) receptors and broadly

postsynaptically in the NTS together with GABAA

inhibit cardiovascular and gastrointestinal functions

receptors. Glycine induces inhibitory responses of the31). Activation of CB1 receptors decreases TS-evoked

NTS neurons

Furthermore, glycine is mostly

synchronous release of glutamate in the second-order

GABA withinterminals,

NTS neurons, while it has no effect on thesuggesting the possibility of a dynamic regulation of

spontaneous release 32). CB1 receptors and TRPV1

GABA/glycine release at the presynaptic level 28).

channels differently regulate glutamate releaseassociated

27).

with

axon

despite co-existence in the same terminations. This
3. Modulation of the synaptic transmission in

two-poolsecond-order neurons

opposite modulation of glutamate release by single

The NTS is extremely rich in receptors for many
endogenous

bioactive

substances,

and

lipid

arrangement

metabolites.

allowsindependent

Therefore,

the

and

synaptic

theirtransmission from TS afferents with TRPV1+ oractivation strongly influences the signal processing

TRPV1− serves as a unique model to assess CB1in this region (Table 1).

receptors/TRPV1 channels interactions in the releaseof

3-1. Endocannabinoidergic mechanisms
Endocannabinoids

arederivedglutamate.

Additionally,

activation

of

CB1

receptors expresses long-term depression thorough
from

lipid

stimulating the presynaptic NMDA receptors in themetabolites. They closely resemble the chemical

NTS.

structure of vanilloid agonists and can activatetransient receptor potential vanilloid 1 (TRPV1), a

3-2. Serotonergic mechanisms

nonselective cation channel, which is sensitive to

The NTS neurons are innervated by serotonergic

high temperature (> 43ºC), protons and chemical(5-HTergic) terminals from the raphe nuclei 33) andsubstances. The afferent terminal fields within thevagal afferents 34). Immunohistochemical and mRNANTS appear strongly immunoreactive for TRPV1

analyses have revealed the existence of 5-HT1A,

channels. Second-order NTS neurons receive the TS

5-HT2, 5-HT3, 5-HT5A and 5-HT7 receptors in theafferent inputs that either express TRPV1 channels

NTS. 5-HT is suggested to modify cardiorespiratory(TRPV1+) or not (TRPV1-) 29). TS-evoked synchronous

functions including related reflexes. Activation of

release of glutamate is indistinguishable between

5-HT2 and 5-HT3 receptors causes apnea and that of

TRPV1+ and TRPV1- afferent terminals, while

5-HT1A receptors inhibits cough reflex in animal

TRPV1+

afferents display 10-fold higher rate ofmodels. Stimulation of 5-HT3 receptors within the

TRPV1-NTS results in a rise in blood pressure and inhibitionafferents. Activation of TRPV1 channels by capsaicinof bradycardia evoked by chemoreceptor activation.

inhibits TS-evoked EPSCs but increases spontaneous

The 5-HT2A mechanism facilitates the baroreceptor

spontaneous release of glutamate than

EPSCs

30).

Most TS afferents are

TRPV1+ andthereflexbyfunctional

interaction

with

NMDA

rate of spontaneous transmitter release depends

receptors co-expressed in the same neuron. Various

closely on temperature in the physiological range.

effects of 5-HT on the NTS neuron activity or-5-synaptic transmission have been demonstrated. The

concentration in the NTS. This increase in DA

spontaneous activity is inhibited by 5-HT2 andcontent is eliminated by section of the carotid sinus

5-HT1D mechanisms, but enhanced by 5-HT1B andnerve. DA decreases TS-evoked EPSCs together with

5-HT7 mechanisms. 5-HT inhibits TS-evoked EPSCs

an increase in the paired-pulse ratio, but had neither

in the second-order NTS neurons via presynaptic

effect on the EPSC decay nor input resistance of the

5-HT2 receptors while facilitates spontaneous EPSCs

membrane 38). Similar results are obtained by a D2

via presynaptic 5-HT3 receptors 35). Furthermore,

receptor agonist but not by a D1 receptor agonist. DA

5-HT2C receptors at the postsynaptic membrane aredecreases the frequency of miniature EPSCs andrelated to facilitation of excitatory transmission from

sulpiride, a D2 receptor antagonist, has an opposite

both TS afferent and intrinsic inputs 36).

effect. DA also inhibits spontaneous IPSCs throughD2 receptors 39). Immunohistochemical study shows

3-3. Adrenergic mechanisms

co-localization of D2 receptors with synaptophysin.

Noradrenaline is a neurotransmitter in central

Together, DA tonically modulates synaptic activity

autonomic regulation. Peripheral

chemoreceptor

between the afferent sensory fibers and second-orderstimulation

noradrenergic

NTS neurons via presynaptic D2 receptors.

activates

centralstructures. Phenylephrine, an 1 receptor agonist,
decreases the amplitude of TS-evoked EPSCs in the

3-5. L-dopaergic mechanisms

caudal NTS neurons and this effect is blocked by

L-dopa, the metabolic precursor of DA, isprazosin, an 1 receptor antagonist. Phenylephrine issuggested to be one of neuromodulators of baroreflex

without effect on the basal current, input resistancepathways in the NTS, since stimulation of the aortic

and current-voltage relationship. The frequency ofdepressor nerve causes release of L-dopa in parallel

miniature IPSCs is increased by phenylephrine, butwith induction of hypotension and bradycardia.

that of miniature EPSCs is decreased. These resultsMoreover, L-dopa functions to stimulate the caudal

suggest that activation of 1 receptors reduces

ventrolateral medulla (CVLM) that is a depressor

excitatory inputs and enhances inhibitory inputs insite receiving inputs from the NTS 40). Lesion of thethe second-order NTS neurons via presynaptic

NTS selectively decreases the tissue content of

mechanisms 37). It is suggested that noradrenaline

L-dopa in the ipsilateral CVLM. The gene product ofplays an inhibitory role in the synaptic transmission

ocular albinism 1 (OA1), which is coupled within the NTS via 1 receptors and modulates the

Gq-protein, possesses L-dopa-binding activity and isautonomic responses to hypoxia.

expressed in the NTS. OA1 knockdown suppresses
the depressor and bradycardiac responses to L-dopa,

3-4. Dopaminergic mechanisms

indicating that OA1 is a functional receptor for

Dopamine (DA) is presented in the chemoreceptor

L-dopa in the NTS 41). In the second-order NTS

afferent fibers synapsing to the second-order NTS

neurons, L-dopa decreases both the frequency ofneuronsinminiature EPSCs and TS-evoked EPSCs together

D2 receptors and/orwith an increase in the paired-pulse ratio. ThesemRNA are found in the vagal afferent neurons andeffects are blocked by an OA1 antagonist and also by

NTS, while D1 receptors are not yet. Microinjectiona D2 antagonist. Furthermore, the L-dopa’s effects

of DA into the NTS produces either pressor effectare completely abolished in reserpine-pretreated rats.

with

and

plays

an

cardiorespiratory reflexes

tachycardia

with

These results propose a possibility that L-dopa may

occurrenceof

release DA via OA1 receptors located at the DA axon

respiratory depression coincides with a rise in DA

terminals and the released DA decreases theDuringdepressor

stepeffectbradycardia.

or

1).

importanthypoxia,-6-glutamate

transmission

through

activationofwithin the TS. EM-1 decreases the amplitude ofpresynaptic D2 receptors 42).
3-6. Purinergic mechanisms

TS-evoked

EPSCs

with

an

paired-pulse

ratio,

butdoes

increaseinthe

not affect input

resistance. EM-1 decreased spontaneous EPSCs andPurinergic receptors in the caudal NTS are

IPSCs in frequency but not in amplitude. These

43).

results suggest that EM-1 acts at presynaptic

andμ-receptors to inhibit the peripheral inputs and the

adenosine 5-triphosphate (ATP), are the primary

intrinsic inputs from local synaptic circuitry in the

mediators signaling emergency changes in the

NTS

internal environment in the CNS. Expression of

DAMGO inhibits the TS-evoked and spontaneous

adenosine transporter, A1 receptors and adenosine

EPSCs in the NTS neurons 51, 52).

required for normal cardiovascular reflexes
Extracellular purines,

such

as

adenosine

50).

Similarly, activation of -receptors bydeaminase in the NTS suggests roles of purinergic
signaling in the NTS. The afferent terminal fields in

3-8. Prostaglandin E2-mediated mechanisms

the NTS appear strongly immunoreactive for P2X

Prostaglandin E2 (PGE2) exerts profound effects on

receptor subtypes and their mRNA. P2X3 receptors

various physiological functions such as temperature

are localized at presynaptic terminals containing

regulation, circulation and nociception by acting theglutamate
receptors

44).

on

ATP activates
the

axon

presynaptic P2X

terminalsofneural networks. PGE2 receptors are rich in the

intrinsic

medial part of NTS 53). PGE2 enhances chemical andexcitatory NTS neurons facilitating spontaneous

mechanical sensitivities of C fibers. PGE2 potentiates

release of glutamate and also presynaptic adenosine

tetrodotoxin-resistantA1 receptors, after being hydrolysed to adenosine,

capsaicin-sensitive pulmonary sensory neurons andreducing evoked release of glutamate from theperipheral

primary afferent terminals. Thus, ATP modulates

voltage-dependent Ca2+ currents in the NTS neurons.

excitatory synaptic inputs arising from distinct

The effects of PGE2 on synaptic transmission inorigins and converging on single postsynaptic neuron

second-order NTS neurons are still controversial;in opposite directions through activation of distinct

either excitatory, inhibitory or no effect. For instance,

presynaptic purinoceptors 45, 46). ATP also induces aPGE2 increases the amplitude of TS-evoked EPSCs infast inward current in a subset of acutely isolated

NTS neurons 54) or decreases it via presynaptic EP3

NTS neurons, suggesting a postsynaptic mechanism

receptors coupled with G-proteins linked to adenylyl

47).

cyclase and protein kinase A activity 55, 56). PGE2
increases

3-7. Opioidergic mechanisms
Opioid receptors including three subtypes (-, -

nerve

the

Na+

currents

terminals,

frequency

spontaneous

EPSCs

mechanism

different

56)

of

while

it

miniaturethroughfromaininhibits

54)

andpresynaptic

EP1-4

receptorand -receptors) are present on the NTS dendrites

mechanisms. On the contrary, there is a report thatand the vagal afferent terminals 48). Endomorphine 1

PGE2 decreases the frequency and amplitude ofand 2 (EM-1 and EM-2) are endogenous opioidergic

spontaneous and miniature EPSCs

peptides with high affinity and selectivity for the

PGE2 interacts with TRPV1 channels and 5-HT3

-receptor in mammals

receptors 57).

49).

Immunohistochemical

55).

Moreover,studies have shown that EM-1 staining is found incell bodies and terminal fields within the NTS, and is

3-9.

closely related to the staining of -receptors. EM-2

mechanisms

staining is located at varicose fibers, and perhaps

Platelet-derived

growthfactor-mediatedPlatelet-derived growth factor (PDGF)-BB is-7-released in the NTS during hypoxia together withcough center and is postulated to be the site of action

glutamate from chemoreceptor afferents. Hypoxicof central antitussives.

ventilatory response is inhibited by microinjection of
PDGF-BB, but not PDGF-AA, into the dorsocaudal

4-2. Codeine

brainstem, which activates the PDGF receptor

Codeine is the most widely used centrally-acting(PDGFR)- 58). A marked reduction of the late decline

drug to suppress excessive cough. Microinjection of

in hypoxic ventilatory response occurs in micecodeine into the caudal NTS suppresses fictive coughheterozygous for a mutation in the PDGFR-. An

responses in animal models 9). Intravenous codeine

antagonist of PDGFR- also reduced the late decline

inhibits the depolarization of cough-related NTS

inwild-typeneurons in parallel with suppression of fictive coughlittermates. Blockade of NMDA receptors attenuates

hypoxic

induced by electrical stimulation of afferent nerves 6,

the reduction of late decline in hypoxic ventilatory

63, 64).

response induced by the PDGR-BB/PDGFR- signal

different affinities

Exogenous

response

PDGF-BBin

Codeine binds to -, - and -receptors with65)

and decreases transmitter

postsynapticallyrelease by activating K+ channels and/or inhibiting

decreases the TS-evoked EPSCs in the second-orderN- and P/Q-type Ca2+ channels. It has been

NTS

58,

59).

ventilatoryneurons,suggesting

PDGF-BB/PDGFR-
glutamatergic

signaltransmission

that

the

demonstrated in the second-order NTS neurons ofinhibitsthethe brainstem slice that codeine (0.3-3.0 mM)

This

might

inhibits TS-evoked EPSCs by activating -receptors-

60).

participate in controlling the ventilatory response

and4-aminopyridine-sensitive

during hypoxia.

presynaptic sites 66). Furthermore, codeine decreases

K+

channelsatthe frequency of spontaneous and miniature EPSCs
4. Modes of action of central antitussives on thethrough activating presynaptic - and -receptors

second-order neurons

which are independent on K+ and Ca2+ channels 52).

4-1. Cough-gating mechanism

These results suggest that the antitussive effects ofCough is produced in the cough reflex arc

codeine are, at least partly, derived from interruption

constituted of airway afferent nerves, the centralof the peripheral afferent inputs to the second-ordercough network (cough center) and respiratoryneurons and from dampening of the basal activity ofefferent nerves 3, 7, 9, 61). Electrical microstimulation of

NTS network. The concentration of codeine istheneighboring

calculated at 0.4-1.2 mM based on the total volume ofventrolateral area induces cough reflex and lesion ofblood (7 ml/100 g), when codeine is administered into

the NTS abolishes cough induced by stimulation ofguinea pigs at 10-30 mg/kg subcutaneously or orally

caudalNTS

afferent nerves

including9, 62).

theIt has been proposed thewhich was reported to inhibit cough reflex in guinea

presence of a cough-gating mechanism in the caudal

pig cough model. This is equivalent to the effective

NTS, which receives afferent inputs and sends a

concentration of codeine (0.3-3.0 mM) to inhibit thetriggering signal for cough generation to the

NTS synaptic transmission.

cough/respiratory network6, 7).

The cough-gating

mechanism is able to account for the fact that

4-3. Dextromethorphan

antitussives do not alter breathing at doses that

Dextromethorphan(DEX),anon-opioid

inhibit cough, suggesting the presence of a neuronal

dextrorotatory morphinan derivative, is thought tocomponent important for cough that does notelevate the cough threshold and suppress coughing

participate

67).

in

breathingpattern

generation.

Therefore, the caudal NTS is a main region for the

DEX inhibits voltage-dependent Na+ and Ca2+

channels. Further, DEX acts as an antagonist of-8-

NMDA receptors 68) or an agonist of  receptors 69).

inhibitory mechanism of central antitussives in the

The drugs having characteristics of blocking the

NTS network. Neuropharmacological investigationand of stimulating the on the NTS synaptic transmission may provide thereceptors possess the antitussive activity. In thebasis of novel therapeutic approaches for coughsecond-order NTS neurons, DEX (0.1-1.0 mM)

reflex.

NMDA receptors

62)

reversibly decreases the TS-evoked EPSC with anincreasedpaired-pulse

ratio

in

a

Conflicts of interest

concentration-dependent manner. Neither a -1

The authors declare no conflicts of interest,

receptor antagonist nor a -1 and -2 receptor ligand,financial or otherwise.

haloperidol, blocks the DEX-induced inhibition ofTS-evoked EPSC. DEX decreases the frequency ofminiature EPSCs without effect on their amplitude.

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