The distribution of histamine H1-receptors in the rat brain: An autoradiographic study

THE DISTRIBUTION IN THE

OF HISTAMINE

RAT BRAIN:

H,-RECEPTORS

AN AUTORADIOGRAPHIC STUDY

J. M. PALACIOS. J. K. WAMSLE~ and M. J. KUHAR Departments of Pharmacology and Experimental Johns Abstract--The

Hopkins

University

localization

of histamine

scopic level by quantitative revealed

high receptor

concentrations

pans. the nucleus of the

tractus

solitarii

distribution

H,-receptors

with

and

in the mam-

brain, and most of the biochemical components of a putative histaminergic synapse have been characterized in the rat brain (SCHWARTZ. 1977;

SCHWARTZ. BARRIN, GARBARG. LLORENS, PALACIOS & POLLARD, 1978; GREEN, JOHNSON& WEINSTEIN, 1978; TAYLOR,

1972;

SCHWARTZ.

BAUDRY, GARBARG, MARTRES & TAYLOR, 1975). In addition,

BARBI&,

VERDIERE, 1979;

histamine receptors

of the

HI and Hz types are also present in brain (SCHWARTZ GREEN et al., 1978; SCHWARTZ, BARBIN,

DUCHEMIN, GARBARG, PALACIOS, QUACH &

ROSE,

1980; SCHWARTZ, 1979). The recent use of C3H]mepyramine has allowed direct binding studies of histamine HI-receptors. The c3H]mepyramine binding sites in the brain (CHANG. TRAN & SNYDER, 1978 ; HILL. EMSON & YOUNG, 1978; TRAN. CHANC &

SNYDER. 1978; CHANG, TRAN &

SNYDER. 1979a) and peripheral

(HILL, YOUNG & MAR-

of a pharmacologically

rele-

vent H, -receptor.

the

appropriate

a procedure

that allows

the ‘in oitro’ labeling and subsequent

autoradiographic receptors in mounted tissue sections (YOUNG & KUHAR. 1979a). The conditions for the autoradiographic localization of HI-receptors using [3H]mepyramine have also been described (PALACIOS. YOI!NG & KUHAR, 1979). In this paper, we present the detailed anatomical distribution of H,-histamine receptors in the rat brain, the species where most of the available neurochemical data on the histaminergic system has been obtained. of neurotransmitter

micron

sections

and thaw from

in the

relationship!,

(b) the

known

of histamine

EXPERIMENTAL

and

for the ‘;)I oifro’

conditions described

labeling

of recep-

for the USC of [3H]mepyr(Yorluc

&

KVHAR.

iY79rr;

Sprague-Da\\ with

men&.

onto

subbed

Ic> rat5

pentobarbital

reported

Human

postmortem

den death

with

more. sodium

potassium

containing

or non-specific

tissues buffer

also 2,uM

binding,

period

rapid dipping under

square

Mass.).

(Burroughs

of cold.

slide.

The

emulsion-coated tissues stained

For

The

descrlbcd

were observed and dark-field

Olympus

JM and

(Olympus a Leitz

microscope Slides

were

with

examined

IO esposc

illumination

and

Wctflar.

Rockville, two

using

Jupm)

Company.

(Leitr.

by

for 6

and photographed

a Hinsch-Goldman

Company.

a

chpb. The

(Yor 1~; 6i I<( IIAK.

Optical

Ortholus

equipped

Instrument

paper

to one \tlth

were developed

1979a). Autoradiograms bright-field

by ;I

(~30 s)

with glut

were allowed

the autoradiograms

as previously

hy ;I IO min

protected

with

under

U.S.A.). servers.

con-

autoradiograph!.

were

and secured

coverslips

weeks. after which

(Bunton

medium Wellcomc).

bath temperature

were attached

assemblies

in New

Salts were eliminated air.

as

obtaming

the tissues were rinsed

dry

coverslips

piece of Teflon

both

For

in buffer and a subsequent

in fresh buffer.

a current of the

labeled

mcubatcd

in water and the tissues dried rapid11

emulsion-coated end

hIstory) in BaItI-

(0.3 M. pH 7.5, 2 4 C),

time was 40 min at ice-water

rapid in and out dipping

drug Olfice

were were

the incubation

triprolidine

sudmale

(28.3 Ci’mmol,

Boston,

At the end of the incubation. washing

no recent

receptors

Mounted

Corp.,

were obtained

Examiner’s

C3H]mepyramine

Nuclear

the

e\perl-

and a 22 qear-old

with

phosphate

5 nM

England

samples

history)

HI-histamine

previously.

in each e+

came from

male (3 h post mortem:

with the Medical

Maryland.

Six to ten Microtomc

slides. Tissues

in this stud)

stab wound

in cooperabon

Cryostat

were pooled

tissue

from a 50 year-old

(4 h postmortem:

microtomc

X rats In 3 Independent

at autopsy

no drug

on

for storage.

microscope

animals

of tissue from

described

mounted

nitrogen

were cut on a Harris

The results

observation

many) procedure

male

were

in liquid

mounted

microscope

PROCEDURES

Briefly,

under anesthesia

at least 3 different

periment.

an

been

systems. effects

regions

chucks and frozen

incubation

We have recently described

have

nuclei

mg;kg) by perfusion with phosphate buffered salmc: containing 0. I”,, formaldehyde. The brains were removed.

blank

tors and the specific

The

Areas with

(60

tained

amine

anatomical

micro-

layer of the hilus

and other

pharmacological

PALACIOS c’r crl.. 1979).

have all the properties

The overall

polymorphic nuclei

(18@250 g) were killed

RIAN, 1977; CHANG. TRAN & SNYDER, 1979/1) tissues

localization

the brain.

of the vagus nerve. Possible

(a) specific

(c) the central

malian

et al., 1978;

throughout

pontine

nucleus

at the light

[3H]mepyramine.

are discussed.

HISTAMINEis possibly a neurotransmitter

SNYDER 8~

was studied

of the stria terminalis.

Sciences.

21205. U.S.A.

were labeled i/l vitro with

of the hypothalamus. motor

and Behavioral

Maryland

of these receptors

and the dorsal

terminals

and Psychiatry

Baltimore.

in the rat braln

Receptors

nuclei

of histamine

of histaminergic

antihistaminics

H,-receptors

are: the bed nucleus

ventromedial

distributions

distribution

a widespread

Therapeutics

of Medicine.

autoradiography.

autoradiograms

of the area dentata.

School

(;erBou

Maryland.

independent

ob-

16

d. M.

PALACIOS.

.I

K. WAWSll

1 and

%I

J. KI IIAK

seen in white matter areas. Thus increase could not be identified

on control

[ ‘H]mcpyraminc

slides

(those

and triprolidine)

incubated

with

and thus should be

regarded as specific binding sites for the H, antagonist. Areas containing concentrations of autoradiographic grains were classified as follow~s HI&

(41 70 grams

per 529

quart

microns

of

11sslle)

Modcratc (30 39 grains~j29 pm’ Low (20 29 grains329 Very low C‘nntrol

)

pm’)

I < 20 grains529

pm’)

or displaced tissue UIUCS

less than

were consistently

IO grains/529 grn’.

C‘ortc,.\c~rldhasa/ qanylitr. cortex vcas consistently brain showing

Lnmma IV of the cerebral

labeled throughout

most prominently

the forc-

as a wide band in

lateral aspect or the cortex (Fig. 21. The grain density in lamina IV varied from moderate in temporal areas (Fig. 7) to IOU in other regions. .4 very low level of 12

,

1

r’

4

8

16

grains

MEPYRAMINE (nM)

‘H-

uust

slightly

above Icv~l\ seen over

matter) were spread evenly throughout putamen (Fig. 3). Moderate

FG. 1. Saturation of [‘H]mepyramine binding to rat brain mounted tissue sections. Ten micron sections (at the levels A 3CCU-A 4000 of the atlas of KONIG & KLIPPEL. 1963) were incubated with increasing [‘Hlligand concentrations as described in the text. Blank values were obtained by adding 2 nM triprolidine to the incubation. The points in the lines are the mean of three separate samples and the experiment was replicated twice with similar results.

levels of grain densities

were seen in rostra1 regions of the forebrain just dorsal to the rhinal

sulcus and 111.I circular

area just

ventral to the forceps minor (not shown). Moderate to low levels of grains pyriform (Figs

cortex

could bc Jsmonstrated

and

3. 12). The

surrounding

the

in the

claustrum

receptor levels In these areas were

moderate in rostra1 regions of the Corebrain, becoming progressively Lirnhrt

Grain denstttes were determmed by counting grams in a grid containing eyepiece using a loOX oil immersion ob~rctivc on a Zeiss (Zeiss. West Germany) dual-viewing bmocular microscope.

white

the caudate-

strta

lower in more caudal areas.

trnd oJfirc.ror!.

terminalis

l‘hc bed nucleus of the

urns.

showed

one 01 the

highest

grain

densities 111portions

above the anterior

while demonstrating

only modcrate levels below the

lcvcl of this

commissurc

(Fig.

commissure.

12). High

levels of

receptors could also be seen in the nucleus of the tractus

RESULTS Characteristics rut bruin

oJ the binding

mounted

of [‘H]mepyrumine

to

tissue sections

diagonalis

Iamina terminalis

Biochemical studies of the binding

the

radiographic grains could hc nucleus (Fig. The

of [-‘H]mepyr-

amine to brain membranes from different species have

and

organum

(not shown)

low

we:11

vasculosum

levels of auto-

m the lateral septal

I?).

hippocampus

oi

had a h1gl1 concentratron

rcccptors in its most rostra1 tip

Proceeding caudally.

revealed considerable species differences not only in

high levels of grains occupied only the polymorphic

the regional distribution

and molecular layer ol’ CA3 extending into the poly-

of the binding

but also in the characteristics

(CHANG

el al.,

1979). As our previous

1979~: PALAC‘IOS VI (I/..

studies were done mostly

in

morphic layer of the hilus of the area dentata (Fig. 6). Large numbers

of grains could also bc seen in the

guinea-pig tissues, the characteristics of the binding of

ventral part of the subiculum

[‘Hlmepyramine

moderate dorsally) of the hippocampal formation

to rat brain mounted tissue sections

were investigated. Figure curve

of

sections

I shows a typical saturation

C3H]mepyramine containing

to

mounted

hypothalamus.

rat

brain

hippocampus,

thakdmus and cortex. As reported for the binding membranes, the affinity H,-receptor

of [3H]mepyramine

was lower in the rat brain (Ku

to

III

the prcsubicular cortex (Fig. :i. The umygdala had a wide \;uiation

dcnsitics.

Virtually

medial

amygdaloid

moderate grain densities rostrally

in receptor

nucleus

showed

and high levels in

caudal areas (Figs 4.7). The pars lateralis of the basal

approx

amygdnloid with

studies

nucleus

showed

this

same distribution

low to moderate grain densities while the pars

medialrs throughout

mamtained

moderate

densities

of

label

ns extent. Receptor icvels in the cortical

in

the brain

amygdaloid nucleus were also low rn rostra1 portions

increase in grain density

over that

of the amygdala. becoming moderate in more caudal

all areas of gray matter

showed a slight

The

and

for the

5 nM) than in the guinea-pig (K,, = 0.5 nM). Autorudiographic

(the grain density was

Autorad~ography of histamine H,-receptors in rat brain

ievels. LOWlevels of HI-receptors were seen throughout the central amygdaloid nucleus and the pars POSterior of the lateral amygdaloid nucleus. The pars anterior of the lateral amygdaloid nucleus contained very few autoradiographic grains. Low levels of antoradiographic grains were localized over the lamina pyramidalis, polymorphi~a and plexiformis OF the tuberculum olfactorium and in the lateral nucleus of the olfactory tract (Fig. 12). Very low levels were seen over the lamina granularis externa and lamina molecularis of the olfactory bulb (not shown). r~za~a~l~s.There was a paucity of autoradiographi~ grains throughout the thalamus. Moderate levels were found only in the nucleus periventricularis of the tbalamus (Fig. 5). Low grain levels coufd be seen in the nucleus reuniens, nucleus rhomboideus, reticular nucleus of the thalamus. nucleus subparafas~icularis and the nucleus posteromedjanus thalami (Fig. 13). The rest of the thalamic nuclei contained a very low amount of uniformly distributed autoradiographic grains. ~.v~~thfl~~i~~sand su~t~aiam~s. The highest autoradiographic grain densities for me~yram~ne binding sites in the hypothalamus occurred in the supraoptic and suprachiasmatic nuclei, in all parts of the ventromedial nucleus, and in the nucleus premammillaris ventralis (Figs 3, 4. 5, 13). Moderate grain densities were identified in the nucleus preopticus medialis, nucleus preo~ticus periventrjcularis aad in the nucleus paraventricularis (filiformis); (Fig. 5). Moderate levels of grains were seen enveloping the lateral and dorsal surfaces of the posterior mammillary nucleus (not shown). The dorsa1 premammiiiary nucleus and the nucleus periventricularis fhypothalami) were also moderately labeled with mepyramine. Low levels of autoradiographic grains could be identified over the nucleus preopticus magnocellularis” nucleus preopticus lateralis, caudal portions of the anterior hypothalamic nucleus, the lateral and posterior hypothaiamic nuclei, both divisions of the nucleus dorsomedia& the arcuate nucleus and infundibulum, the lateral preI~amrni~~ary nucleus, subthalamic nucleus and caudal portions of the zona incerta (Figs 13, 14). Midbrairl ad metuthalurnus. The nucleus tractus optici basalis (Gillian) displayed moderate levels of autoradiographic grains (not shown). Other areas of the midbrain were low or very low in grain levels. Areas of iow grain densities included the nucleus tractus optici-pars medialis, the ventral and dorsal nuclei of the lateral geniculste body, the pars caudalis of the Edinger-Westphal nucleus, the nucleus of the oculomotor nerve, the stratum gr~~urn superficiale of the superior colliculus. caudal portions of the inferior colliculus, the nucleus linearis oralis, the red nucleus, rostra1 portions of the periaquaductal gray matter. the interpeduncular nucleus and the zona compacta of the substantia nigra. Very low levels of autoradiographic grains could be seen in parts of the zona reticulata of the substantia nigra.

17

Pens. Areas displaying high grain concentrations include the pontine nuclei, the nucleus reticularis tegmenti pontis, nucleus suprageniculatus facialis. nucleus of the facial nerve (VII), the medial vestibular nucleus and the nucleus raphe magnus (Figs 10. 14). Moderate amounts of autoradio~ra~hic grains were jdent~~ed in the nuclei on the Noor of the IV ventricle including the dorsal raphe nucleus. the mesencephalic nucleus of the trigeminal nerve, the locus coeruleus, nucleus tegmenti dorsalis lateralis and the nucleus tegmenti dorsalis (Gudden); (Fig. 9). Other areas with this concentratian of grain density include the superior central nucleus. the dorsal nucleus of the lateral lemniscus, nucleus tegmenti ventralis (Gudden). nucleus originis of the trigeminal nerve (V). external preo~ivary nucleus. rostra1 portions of the nucleus of the trapezoid body, spinal nucleus of the trigeminal nerve-pars dorsomedialis. the superior olivary nucleus and the superior vestibular nucleus (Figs 10. 14). A low grain density was seen in the nucleus of the trochlear nerve (IV). ventral nucleus of the lateral lemr&us, nucle~~s raphe pontis. spread along the corpus trapezoideum, the dorsal and ventral cochlear nuclei, the dorsal and ventral nucleus par~~brachiaI~sand the lateral vestibukr nucleus. The nucleus reticuk~ris pontis oralis contained very low levels of autoraciiographic grains. ~~~u~~~. High autoradjographic grain concentrations were identified over the nucleus tractus solitarii and the dorsal motor nucleus of the vagus nerve (X). Moderate grain densities were seen over the nucleus of the hypogiossal nerve (XII), the nucleus ambiguus, the nucleus reticularis parvocellularis, nucleus raphe pallidus and the lateral reticular nucleus (Figs 10, 14). Low levels were seen over the inferior olivary nucleus and accessory nuclei and the nucleus intercalatus. The dorsal and ventral medullary reticular nuclei and the spinai nucleus of the tripeminal nerve contained very low levels of autoradiographic grains. Crrrh&m. Only control levels of autoradiographic grains could be ~denti~ed in the cerebell~im, but this observation seems to be peculiar to the rat {Fig. I I ). Our investi~~~tions of the guinea-pig cerebellum demonstrated a large concentration of grains over the molecular layer. We have also examined human ccrebellum and found mepyramine binding sites conccntrated in the molecular layer although with a density much lower than that seen in the guinea-pig (Pai.,,rcCIOSVt al., 1979). DISCUSSION

In these studies, we have localized with quantitative, light microscopic auto~dio~raphic methods, HI-histamine receptors in rat brain. More specifical]y, we are Utilizing [‘H]mepyramine binding which has been extensively characterized kinetically and pharmacologically in homogenates of brain and in our mounted tissue sections (CHANGYTai._ 1978; HI~.L cf

J. M.

P~~I.AC‘IOS.

J. K. WAMSL~,Sand M J Kt

ISAH

FIG. 3. A. LOH. powr‘r photomtcrograph 01 111~a~rtorad,ugraplttc pram distrihutton over rostr.tf t,,rcbr;tttt Dark-field illumination causes the @rains to appear u bite on the coverslip against (he dark ),ackpro,,nd Of the liSSw. !‘&to the very 10% concentratton ol’ grains (hut still htghcr than background) tfvcI most <,f the tissue. In this scctton rhc ~l~~~~str~~nl t(‘) t up. tfe&hx! 15, h;cvr!ly .I 1Ou ~~~n~~ntr~iti~fl of H,-reCeptors. Hhife the media) prcoptto nutieus tpoml cont;nned moderate icveh. and (he d,~,~,f pnr(,cn cf the bed nucleus of the stria (crminali~ IS() conratrts high lc\c)s of H,-rcccptors, bar I mm. U. Brtght-field photomicrograph of it t~ssuc section stamcd with pyrontn Y. Note (hc )~!_x(uJ~ (rf (hc supraoptic nucleus (SO).C‘. Dark-field photomicrograph of’ H allowng visualtration of (he d($(r(nu(ion of autoradiographic grains. Note the htgh ILSYCIof gratns QX~ aver the supr;ioptlc nuclcu, ,arrou ). &,I

ICW If

FIG. 1. A. Histamine

(H, ) rcceptctr~ Ivcal~xd ;tutaradlu@rap2ltl~lll! II, Ixtrth of the tft;li;ttnw. h~poth&. mus and amygdala. High levels of grains can he seen (11 the wntromcdtal hypo(n;(lamus ;h\ma) wtth somewhat more moderate Icvrls tn 11~ ,tmygdal;t B;u I mm. B. Higher magntlication dark-field photomicrograph of the amygdaloid complex as seen 111A, C. Bright-field photomicrograph of the same area seen in B indicating the approximate localiration of various amygdaloid nuclei. Bar = 100 11. Fig. 5. ‘Two 10% p~wur dark-field photomicrogntphs J~prctmp the ;rtituradiograph(c gr,(tn ~iIstr(hu(i(?n dyer sections taken through the thalamus. Xote the l~theling of the midline th;tl;tmic nuclet .tnd man\ of the nuclei of the l~~p~)ti~~~l~~~n~~s. Bar I mm.

FIG.6. Various coronal sections (4 parts 01 (hc Ittppocampal (ormatron under dark-ticld I..\. ( . ii\ i111d bright-field (B. D. F) illuminatton demonstrattng the H ,-rcccptorc as stun from rs in the c‘iudal hrppocampus and adjacent areas. Note the high ct~nccntration of’ rcccptors in the subiculum (S) and prcsubtcular cortex. Also note the high concentration of receptors in Iamina IV of the cortex tit this level (appears in the upper right-l~;tnd corner 01’ the pl~crt~,rnlcropraph). This area corresponds IO arca 41 01 KRIW (KRIFI;. 1946) and is related to (hc ~orttcal projecttons ctf the auditory system. Bat I mm. 1%. Dark-field and bright-held (C) pi~c,tomicrogr;cplls ticm~mstratmg the high concentration ~)f .tutor;tdtographic grams in the medial ;tmygdaloitl nr~clcu\ (urn) :thout mtdw;t> through the .~nrygdal;t IIHI ,, Il;lr Ftc;. 8. Photomtcrographs showing l-l,-recq)turb in rcgwnx near Mood vessels. .A and f.3demonstrate I~O apparent association of grains with an arteriole tarro\c I f‘ sl~owsthe gram dtstrihution i)ver ntrrow) as seen in F Hat Ftc;. 0. Series of photorntcr~~~r~~ph~ taken lwm labeled \tructurc:.\ near the tloor (II’ the IV ventrtcle. r\ represents total binding areas of ),‘fiJmep!rammc while ( slio\bsnon-spacific iire;ir. I312 giunulc cell layer of the nodulus (N) of the cerebellum and the locu:, coerulcus (Icl demonstrate reflected ‘tissue light’ in C. Only this reflected light is seen m the nodulu\ ((I .\ hut the locus coeruleu\ she\\\ .t moderate specific grain tlenslty ;I% well a\ the reflected light. Bar = I(K) (1 10~;ili~rtio11 111 thr: pontmc regron t+( the ~r~~irtstctll. FIG. IO. A. Ph(~tomicro~r~iph of IIIC If, fic’cpt4x Note the high density of grams in Ltrci(\ WLT the pontm~ nuctc~ rpo) and the nuchXts retlcuiaris tegmetlti pontis (rtp). The dorsal raphc nucleus (rd) I\ I;ilreled rr~~&r:itely .tnd the supcrtor ccntml ni:clcus (ncz) is labeled somewhat ;tt a lower )evcl. B. Control d,trk-field photomicrograph of .t SW~IOII X~JacUlt tcl the one seen in ,A. Grains in this picture indicate non-spccttie htndtng 01 the [3H]mcpvramtttc. Bar z- 500 I$ C. section of brain stem tissue at the Ic\~l ~3f the mcdt;tl \cstihular nucleus (vm) r\~rtoradropriipllcc grams can be seen throughout this nuclem as sell as the nucleus cd nerve WI (nvll). Note the intense labeling in the nucleus raphe magnus (rm) and the low labeling m the cochlear nuclet of the auditory system (cod. cov). Bar = 1mm. D. Section through the brainstem at the level of the area postrema (aP). The nucleus of nerve XII (nXlI) and the nucleus tractus solitarti (nts) are heavily labeled with [‘HImepyramine in this photomicrograph. lheir location can be determined by viewing the tissue underneath the emulsion-coated coverslip ustng bright-field illumination as seen in E Bar = 10(111.

~tc;.

11.Dark-field and correspondrng hrrght-tield photomicrographs from rat (A. B). gutnea-ptg (c fl) and human (b, F) cerebcfta. The motccuhtc Ltyer tm) of the puiooa-pip cerehe))Um dcrn~)l~str~itcs man? I-f,_receptors uhile that or the human shrnvs CMI~ ;t sltght collcetltraliot~ and the mo)ecuhtr htyer of the rat shows no f{ ,.rcceptors at ;rll. Agatn. in these pltot~,micrographs the closeness cl 1))~ c&s In the grenule cell layer (g) causes arti(Xtua) ((shut! rcllcctancc vvhtch can be seen cvcnly thrtrrhutcd tn thts layer in all three specimens. p = layer of Purkinte cells. w = white matter. Bar .= 100 jr

FIG. 2. A. Photomicrograph of the autoradiographic grain distribution over a tissue section taken from parietal cortex (corticat area 2 of KRIEG,1946). This tissue section had been incubated in [3H]mepyramine with 2 PM triprolidine and indicates non-specific binding. B. Adjacent tissue section, but incubated in C3H]mepyramine alone indicating total binding. C. Brightfield photomicrograph showing the tissue as it appears below the grain distribution on the coverslip seen in B. The Roman numerals demarcate the approximate levels of the cerebral cortex. Note the apparent specific increase in HI-receptors in lamina IV as seen in B. CC, corpus callosum. Bar = 200 p.

t9

FIG. 4.

Fiti.7.

24

‘?

Abbreviations a

abl abm ac ace ala alp am amb ar ci COd CO\

cP cu dcgi &r hdd hl hp hpv hvmc hvml hvmm io iod iom IC

Ih IIV

mh npd npv nrp ntd ntdl ntm nts ntv, ntVd nVl1 nX nXI1 P pd Pf Pot pom poma POP post Pv Pvr pvs rd re r&i rh rl

Nucleus Nucleus

accumbens amygdaloideus

basalis,

used in Figures

pars lateralis

Nucleus amygdaloideus basalis, pars medialis Nucleus amygdaloideus centralis Nucleus amygdaloideus corticalis Nucleus amygdaloideus lateralis, pars anterior Nucleus amygdaloideus lateralis pars posterior Nucleus amygdaloideus medialis Nucleus ambiguus Nucleus arcuatus Colliculus inferior Nucleus cochlearis dorsalis Nucleus cochlearis ventralis Nucleus caudatus putamen Nucleus cuneatus Nucleus dorsalis corporis geniculati lateralis Nucleus Nucleus salis Nucleus Nucleus Nucleus Nucleus tralis Nucleus alis Nucleus medialis Nucleus Nucleus Nucleus

gracilis dorsomedialis

(hypothalami),

ventromedialis

(hypothalami),

ventromedialis olivaris inferior accessorius olivaris accessorius olivaris

raphe

raphe obscurus reticularis parvocellularis

tlP tml tmm

pars

cen-

tpo tr ts tv tvd tvm tvp VI vm CAA CA1 cc CL co CPF

pars later-

(hypothalami).

Nucleus Nucleus Nucleus

rtp sl sm St sut td 11

dor-

lateralis (hypothalami) posterior (hypothalami) periventricularis (hypothalami) ventromedialis (hypothalami),

rm ro rpc rpo rpoo

pars

pars

dorsalis medialis

Locus coeruleus Nucleus habenulae lateralis Nucleus lemnisci lateralis ventralis Nucleus medialis habenulae Nucleus parabrachialis dorsalis Nucleus parabachialis ventralis Nucleus reticularis paramedianus Nucleus tegmenti dorsalis lateralis Nucleus tegmenti dorsalis Gudden Nucleus tractus mesencephali Nucleus tractus sohtarii Nucleus tegmenti ventralis Gudden Nucleus tractus spinalis nervi trigemini pars dorsomedialis Nucleus originis nervi facialis Nucleus originis dorsalis vagi Nucleus originis nervi hypoglossi Nucleus pretectalis Nucleus premamillaris dorsalis Nucleus parafascicularis Nucleus preopticus lateralis Nucleus preopticus medialis Nucleus preopticus magnocellularis Nucleus preopticus periventricularis Nucleus preopticus. pars suprachiasmatica Nucleus premamillaris ventralis Nucleus perventricularis rotundocelfularis Nucleus periventricularis stellatocellularis Nucleus raphe dorsalis Nucleus reuniens Nucleus reticularis gigantocellularis Nucleus rhomboideus Nucleus reticularis lateralis

FC FLM FMP FR GD GP HI LL LM P PC1 PCM PCS S SM SO ST TO TOL TS TSTH TSV TULC TULl TULP ZI IV V

29

12, 13, 14

magus

Nucleus raphe pontis Nucleus reticularis pontis oralis Nucleus reticularis tegmenti pontis Nucleus septi lateralis Nucleus septi medialis Nucleus interstitialis striae terminalis Nucleus subthalamicus Nucleus tractus diagonalis (Broca) Nucleus lateralis thalami Nucleus lateralis thalami, pars posterior Nucleus medialis thalami, pars lateralis Nucleus mediahs thalami, pars medialis Nucleus posterior thalami Nucleus reticularis thalami Nucleus triangularis septi Nucleus ventralis thalami Nucleus ventralis thalami, pars dorsomedialis Nucleus ventralis medialis thalami, pars magnocellularis Nucleus ventralis medialis thalami, pars parvocellularis Nucleus vestibularis lateralis Nucleus vestibularis medialis Commissura anterior, pars anterior Capsula interna Crus cerebri Claustrum Chiasma opticum Cortex piriformis Columna fornicis Fasciculus cuneatus Fasciculus longitudinalis Fasciculus medialis prosencephali Fasciculus retroflexus Gyrus dentatus Globus pallidus Hippocampus Lemniscus lateralis Lemniscus medialis Tractus corticospinalis Pedunculus cerebellaris inferior Pedunculus cerebellaris medius Pedunculus cerebellaris superior Subiculum Stria medullaris thalami Stratum opticum colliculi superioris Stria terminalis Tractus opticus Tractus olfactorius lateralis Tractus solitarius Tractus striohypothalamicus Tractus spinalis nervi trigemini Tuberculum pyramidalis

olfactorium,

Tuberculum olfactorium, polymorphica Tuberculum olfactorium, plexiformis Zona incerta Nervus trochlearis Nervus trigeminalis

pars pars pars

corticalis,

lamina

interna,

lamina

corticalis,

lamina

__.

CPF

TOL

Autoradiogr~phy of histamine HI-receptors in rat brain

hdd

hp;

or’

hkm hvm’

FtYp

To

am

Ftc. 13. Schematic drawings of the rat brain at the level of the thalamus and hypothalamus, Numerous H,-receptors arc depicted in CA3 and CA4 of the hippoc~lmpus.in the ventromedial hypothalamus. and in the ventral premamm~llary nucleus (pv). Note the high concentr;ttion of receptors in the subiculum (S) and presubicular cortex shown in the lower drawing. ‘The top and bottom figures and levels A 4620 and A 3290 respectively, according to Kowrc &

KLIPPEL

(19631.

31

1. M. 1'a~nrrc.k~. .f. K. WAMSCEY and M. J. KUHAK

ic

ntm nfdi

PCS FiM

FIG. 14. Schematic drawings of three levels of brainstem showing the distnborion of auturadiographx grains fbflowkg fabeiing with @-Qmepyramine. Dense receptor cancentrations are represented in rhe nuckus reticularis tegmenti pantis frtp) the nudei of the pooa, the media3 v&b&r nucleirs fvm). nuchs of the facial nerve fnVII), nucfeua tractus solitarii (nts) and in the dorsal motor nucleus of thr vagus nerve f&X). The top, middle and bottom schematics are lavcls P1.5, P3.9 and P6.5 aLXordiflg to

Autoradiography of histamine HI-receptors in rat brain &.. 197X; TRAN rf al., 1978; CHANG et al., 1979~; PAC,AUOSet a/., 1979). It is important to point out that this site is not the only site at which histamine acts. For example, the I-$,-receptor is not labeled to any significant extent under our conditions (BUCK, DUNCAN, DURANT, GANELLIN & PARX~NS, 1972). However, the mepyramine binding site has all of the characteristics of a physiologically and pharmacologically relevant H,-receptor (CHANG et d., 1978; HILL et d., 1978; TRAN er ul.. 1978; CHANG et ~1..I9790: Ho+t er al., 1977; CHAWS et ui'., 197983. Also, in these studies, we have more or less focused on the areas of the brain showing the highest densities of receptor. However, it seems worth cautioning that even areas with low densities of receptor may be important in some cases for histaminergic transmission or for the action of histaminergic drugs. At present. no correlation has been established between density of rcceptors and physiological response. An important consideration is the possibility that all H,-receptors are not neuronal. There is abundant biochemical, anatomical and electrophysiologica~ data suggesting that histamine is a n~urotransmitter in the brain and this provides substantial support for the notion that H,-receptors are localized to neurons in synaptic areas (SCHWARTZer ~1.. 1979h; SCWWARTZ et d., 1978; GREEN et (II., 1978; SCWWAIUZet ul., 1979~; TAYLOR, 1975). On the other hand, some studies suggest the ~ocaliz~ltion of H,-receptors to non-neuronal sites. For example. preparations of micro-blood vessels from brain have elevated densities of W,-receptors (PER~IXKA. MOSKOWI~Z,REINHARD& SNYDER,1980). Also, studies involving several lesions of the hippocampus and caudate nuclei, i.e. lesions causing a loss of input as well as kainate lesions which destroy cell bodies, did not cause a loss of ~,-receptor binding (CWANG,TRAN & SNYDER, 1980). Our light microscopic studies do not provide sufficient resolution to settle this issue (Fig. 8). Accordingly, our results should be kept in perspective given these possibitities.

33

and &&ate cortex and b4 nucleus of the stria terminalis. We have observed elevated densities of I-i,-histamine receptors in some of the same areas where we have observed several other types of recep tors. For example. lamina IV of the cerebra1 cortex in the rat has elevated densities of opiate receptors (ATWEH& KUNAR, 1977~; YC)UNC~ & KUHAR, 1979a). benzodiazepine receptors (YOUNC;& KU~AR, 1979h: Youuc & KUtiAR. 19SOa), neurotcnsin receptors (YOUNG & KUWAR,197%). alpha-l adrenergic receptors (Yotr~c; & KUWAR, 19794: YOON~;& KUIIAR, l%Ohf, muscarinic receptors (WAMX.EYet cl!., in press) and 7%.aminobutyrate receptors (PALAUOS.YOUNG& KUHAR, 1980). Also, the nucleus tractus solitarii has high densities of opiate receptors (ATWEH& KUHAR, 197763,as well as other receptors (YoI:N(; & KUNAR. 1979rf: YCRJ~~G & KUHAR, 1980h; WAMSLEY pf ok in press). The per~v~ntricu~ar nucleus of the thalamus also has been found to have elevated densities of including opiate (ATWEW several receptors & KUHAR, 1977c), beta-adrenergic receptors ( PALACIOS& KUHAR, 1480~) as weH as several other receptors. Why certain areas of the brain are receptor ‘hot spots’ is an interesting question. No obvious explanation is apparent and there need not be any special significance to this. But these areas are likely to show a lot of drug interactions.

Detailed information on the hist~~miI~ergic innervation in some areas of the rat brain has been obtained by microchemical analysis of small tissue samples and lesion studies (SCHWAREY, 1977: SCHWARTZ ef ui., 197X). The presence of a widespread inn~r~ti~~ in the forebrain was deduced from the decrease in histidine decarboxylase activity (a marker for histaminergic terminals) after medial forebrain bundle lesions (GARBARC;, BARBIN, FECZR & SCHWARTZ,

1974;

BARBIN, HIRSCH, GARBARC; &

SCHWARTZ, 1975; GARBARG, BARBIN, BISCMOFF.POL-

We observed wide variations in the densities of H,-receptor in the different regions of the rat brain, Some of these areas containing high densities could be linked together on the basis of function. For example, many components of the auditory system had sj~ificant densities of receptors. These areas include the ventral and dorsal cochlear nuclei, the nuclei of the trapezoid body, the superior olive, the ventral and dorsal nuclei of the lateral lemniscus. the inferior colliculus and elevated grain levels in lamina IV of the cortex in the temporal areas. Another system having high densities of receptors in various parts is the limbic system. Areas with high densities of receptors include parts of the amygdala and hippocampus. Areas associated with the limbic system having high densities include parts of the hypothalamus

LARD & S~~WAR~2. 19761. The ce!! bodies of this ascending pathway are thought to be localized in the upper midbrain (SCHWARTZ er ul.. 197X). While most of the areas where we observed signif& cant concentrations of histamine H,-receptors possibly receive hist~~minergic innerv~lt~on, there is striking difference in the relative conce~ltration of both preand postsyn~~ptic ‘markers”, These disparities were &O observed in our initial study in the guinea-pig brain (PALACIOS cf al. 1979). The bed nucleus of the stria term&a& is one of the areas with very high receptor concentration. One of the highest histjdine decarboxylase c(~ncentr~~tions in the brain is afso found in this nuclt~s. However. while the terminals Seem to be concentrated in the ventral part of the nucleus. the receptors are much more dense in the dorsal part (BEN Am, Lr: GALL LA SALLI:. &,RBIN, SCQwART2 & GARRARG. 1977).

J. M. PALACIOS. J. K. WAMSLFW and M. J. KUHAR

-_.________

_~._

__ _.________.._~___ Wwdinc decarbosylase ‘Specific’ [3H~Mep~ramjn~

activity grain density \dpm;h!mg tissue, IO’)’ (per 529 pz of tissue) -..--.-. __.__--_-.. _- ._..I___-.._-._____-__-.__ _. Hyporhalamws

Nucleus Supraopticus

4.3

41.5 + 2.0

Nucleus Suprachiasmaticus

6.3

42.8 + 0.5

Nucleus Arcuatus Nucleus Paraventricularis Nucleus Dorsomedialis Posterior Hypothalamus Nucleus Premammillaris ventralis

6.3 5.3 8.1 77 8.j

IX.3 + 25.9 + 17.7 + 21.5 * 42.5 i

2.6

JO.1 * 1.7

0.x 0.9 2.h 2.3 1.9

,4l~y~da~fl

Medial Nucleus Central Nucleus Basomedial Nucleus Basolateral Nucleus Cortical Nucleus Posterior Lateral Nucleus Anterior Lateral Nucleus

2.3

14.9 * 0.6

1.9

28.8 * 0.8

1.1 I.0 1.1

16.7 _t 0.7 29.4 * I.i 14.0 * 0.8

X.6 f 0.4 .values are from POLLARD tlr(I/. (1976) for the hypothala.

’ Histidine decarhoxylase mus and from BE~VARI et al. (1977) for

I.0

the amygdala.

The hippocampal formation has a relatively low concentration of histidine decarboxylase but is rich in receptors. Mepyramine binding sites within this area are mostly concentrated in the CA, and CA4 regions where the histaminergic innervation appears to be low (BARBIN,GARBARG, SCHWARTZ& STORM-MATHISEN, 19%). Again, in the cases of the amygdala and hypothalamus, there is a lack of correspondence between terminal and receptor densities (Table 1). Both the medial and central nuclei of the amygdala are rich in histidine decarboxylase activity (BEN ARI et ul., 1977), but only the medial nucleus has a high density of H,-receptors. The hypothalamus. the brain region with the highest levels of histamine and histidine d~arboxy~ase, is also very rich in HI-receptors. although there is not a good correlation between histaminergic innervation and receptor concentration in the different hypothalamic nuclei (BROWNSTEIN, SAAVEDRA, PALKOVITS& AXELROD, 1974; POLLARD, BISCHOFF,LLORENS& SCHWARTZ, 1976). Several hypotheses

could be postulated to explain these discrepancies. In the case of the histamine&z system. a second class of receptors, Hz, that is not revealed by our method, and is also present in the brain (SCHWARTZ, 1979; GREENet at.. 1978) has to be considered. On the other hand, one would not expect a total correlation between levels of neurotr~smitter and receptor, but rather a correlation between nerve terminals and receptors. At present, however, the detailed anatomical distribution of histaminergic terminals is unknown. Possible

pharmncoloyical

rrlevance

Classic antihistamine drugs are widely used therapeutic agents (DOUGLAS, 1975). We have observed some interesting relationships between the pharmaco-

logic responses to antihistamines and the distribution of HI-receptors in this study. We propose. at least as a first hypothesis. that many of the areas showing high densities of receptors are those where antihistamine drugs exert their therapeutic effects (Table 2). For example, antihistamines are used in the treatment of motion sickness. Motion sickness is due to overstimulation of the vestibular system (DOUGLAS, 1975: JAJU & WANG, 1971: MOSEY. 1970). The vestibular nuclei in the floor of the fourth ventricle in the medulla have high densities of receptors and may very well be the site where antihistamines alleviate and counteract motion sickness. It is interesting that the anticholinergic properties of antihistaminic drugs were postulated to be responsible for the antimotion sickness effects since the vestibular nuclei are affected by anticholinergic drugs. which are also useful in treating motion sickness (DOUC;LAS. 1975; MONEY. 1970). Recently, WChave found high densities of muscarinic receptors in the vestibular nuclei as well (WAMSLEY et cl/.. in press). This suggests that antihistaminics and anticholinergics are both antimotion sickness drugs because of action at separate receptors which are located in the same anatomical area Antihistamine drugs are also well known for their sedative properties (FAIF~~Y)LD, 1978). Related to this. we have observed high levels of receptors in the raphc nucleus of the midbr~n. an area associated with sleep (JOUET, 1969). We have also noted e!evaccd densities of receptors in lamina IV of the cortex. Severai other drugs with sedative properties such as opiates. muscarinic drugs and alpha 1-adrenergic drugs also have elevated levels ofreceptorsin lamina IV of the cerebral cortex (WAMSLEY, ZARRIN, RIKDSALL& KUHAR. 1980: YOUNG & KWHAR, 1979d: YOUNG& KUHAR, 1980h). It is possible that these receptors could interfere with cortical arousal from thalamic input. When antihis-

Autoradiography

of histamine Hi-receptors in rat brain

35

TAAE 2. TENTATIVECORRELATION BETWEENAREASWITH RECEPTORS AND PHYSIO-

LOGICALEFFECTS OF HISTAMINE AND Drug Action

ANTIHISTAMINE

DRUGS

Anatomical Area

,~f~~ihistai~j~es

Antimotion Sickness Sedation and sleep

Vestibular Nuclei Dorsal Midbrain Raphe nucleus and cerebral cortex

Histumirw

Suppression of Food Intake Release of ADH Production of Thirst Prolactin Secretion Hypothermia Increase Blood Pressure and Heart Rate Retching

tamines are given in high doses, convulsions can occur (WYNGAARDEN& SEEVERS, 1951). Areas often associated with epileptiform activity that have high levels of receptor include the hipp~ampus, amygdala and cerebral cortex. Additional effects have been observed in experimental animals after injection of histamine and antihistaminics by various routes (CALCUTT, 1976; SCHWARTZ et ul., 1979~; GREEN et of., 1978; SCHWARTZ, 1979). Histamine, when injected intracerebroventricularfy causes a depression of food intake (CLINESCHMIDT& LOTTI, 1973). Related to this we observed very high densities of histamine receptors in the ventromedial hypothalamus which is thought to be the satiety center controlling food intake. These effects could also be caused by histamine receptors in the lateral hypothalamus which has been shown to be involved in the control of feeding behavior (STEVENSON, 1969). Injection of histamine also causes a release of antidiuretic hormone probably via an H,-receptor (BHARGAVA, 1974; BHARGAVA, KULS~ES~A, SANTHAKUMARI & SRIVASTAVA, 1973; BENNETT & PERT, 1974; HOFFMAN & SCHMID, 1978; TUOMISTO & ERIKSSON, 1979; DOGTEROM,VAN WIMERSMA GREIDANUS & DE WIED, 1976). Related to this, we observed high densities of receptors in the supraoptic nuclei, an area with ceil bodies containing antid~uretic hormone. Associated with this may be the observation that injection of histamine causes thirst in animals (GERALD & STERN, 1969: GERALD & MAICKEL, 1972; LEIBOWITZ, 1973). One must also consider the posterior hypothalamus. an area with elevated receptor levels, to be involved in the observations that histamine causes thirst since stimulation of this area causes animals to seek water (STEVENSON,1969) The hypothermia observed after histamine injection could be due to the H,-receptors located in the preoptic-anterior hypothalamus area (BREZENOFF & LOMAX. 1970; BRIMBLECOMBE & CALCLJTT. 1974: cos-

Ventromedial Hypothalamus Lateral Hypothalamus Supraopti~ Nucleus Supraoptic Nucleus Posterior Hypothalamic Areas Basal Hypothalamus Anterior Hypothalamus Nucleus Tractus Solitarii Hypothalamus Nucleus Amhiguus

TENTIN, BOULU & SCHWARTZ, 1973; GREEN, Cox &

LOMAX, 1976). The increase in blood pressure and tachycardia observed after histamine injection (for a review, see OWEN, 1977, see abo FINCH & HICKS, 1976) may very well be mediated by the high densities of receptors in the nucleus tractus solitarii and the posterior hypothalamus. It is also possible that the retching and swallowing induced by intra-cerebroventricular injection of histamine (FELI)BERC & SHERwooa, 1954) are mediated by the high densities of receptors in the nucleus ambiguus, an area mediating these functions. While we are not aware of any reports that histamine or antihistaminics affect audition, we would expect there to be some effect on this sensory system given the extensive localization of receptors to auditory areas as described above. Many electrophysiologic studies have found specific histamine responses in many of the areas mentioned above (for a review, see HAAS & WOLF. 1977; SCHWARTZ, PALACIOS, BARBIN, QUACH, GARBARG, HAAS & WOLF, 1979). These observations support, not only the notion that these receptors are functional, but that they are localized to neurons (rather than nonneuronal sites) in many of these areas. While the effects of HI-antihistamine applied by iontophoresis are difficult to interpret because of prominent local anesthetic effects, recent studies with cultured hypothalamic neurons strongIy support the presence of functional H,-receptors in these hypothalamic neurons (GELLER, 1976).

Ackrlowtm~~c~,nrt,ts--The authors acknowledge the technical assistance of Mrs. NAOMI TAYLOR, the clerical assistance of Ms. DARLENEWEIMERand MRS. MARY FLUTKA, and the support of USPHS Grant MH 25951. M. J. KUHAR is the recipient of an RCDA Type II Award MH 00053. J. K. WAMSLEYis the recipient of postdoctoral fellowship HD 05739 and J. M. PALACI~Sis the recipient of a Fogarty International Fellowship TW 02583.

36

J. M. PALACWS. .I.K. W.AMSLEY and M. J. KCHAR

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of opiate receptors in rat brain. II. The brainstem.

BARBIN G., GARBARG M., SCHWARTZ J. C. & STORM-MATHSEN J. (1976) Histamine synthesizing aflcrrnt~ to the hippocampal region. J. Neurochem. 26, 259-263. BARBIN G., HIRSCH J. C.. GARBARC M. & S(.HWARTZ.J. C. (1975) Decrease in histamine content ;rnd decarboxylase activities in an isolated area of the cerebral cortex of the cat. Brain Res. 92, 170_174. BE”: ARI Y.. Lk GALL. LA SALLE G.. BARRIN G.. ScfiwAK.rz J. C. Cy:GARRARG M. (1977) Histamine s~n~h~si~ing afferents within the am~daloid comples and bed nucleus of the stria termina~is in the rat. Br&n Re,s.138, 185 2%+. FW-WTT C. T. & PEKI‘ A. (1974) Antidiur~sis produced by injections of histamine into the cat supraoptic ntrcicus. Braitt Res. 78, ISI-156. BHARC~AVAK, P. (1974) Some neuropharmacological studies with histamine. J. P~~urt~l~c~~. 5, (SuppI. ! +?;, BHAKGAVA K. P., KUi..SHRESU%A V. K., SANTI~AIUMARI G. & SRIVASTAVA Y. P. (1973) Mechanism of }listamine~indu~eci antidiuretic response. 81: J. Plzurnluc: 47. 700 706. &.AC.R J. W., Dt:N(‘Ar W. A. M.. DL’KAS’I’ C’. J., GANELI.I\: t’. R. & PARSO&SE. M. (1972) Definition histamine Hz-receptors. Nature, Lorrd. 236, 3X5 340. BKEZENOYFH. E. & LOMAX P. (1970) Temperature changes following ory ccntres of the rat. Ezp&~tltrrr 26, 51 .51.

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of histamine in&o the thermoregufat.

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148-167‘ FINCH L. & Hrclts P. E. (19761 fnvofvement

of h~pot~~~~~drnic histamine receptors in the central cardiovascuhtr

actions of

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pathway in rat brain evidenced by lesions of

the medial forebrain bundte. Scioicr N. E If%, X.33,X75. GI:LLEK f-I. M. (1676)Effects of someputative netirotr~~nsmitt~rs on unit activity of tuberaf h~pothaiam~~ neurons irt &ru. Hririir Res. 108. 413 430. &,RALI) M. C. & MA~CKI:L R. P. (1972) Studies on the role of brain histamine in behaviour. Br. J. Pharnrw. 44.46247l. C;~:KALJ>M. (:.& STI:RN W. C. (1969) Interactions of histamine and antihistamines with behaviourai systems. Fe& f’roc. Fedri Am. SCW rs,t. Hial. 27. 272. GREEN M. D.. Cox 3. & LOMAX P. (1976) Histamine H, and I+,-receptors in the central thermor~guiator~ pathway’s of the rat. J. Neurosci. Res. I, 353 39. GKEI:N J. P., Jolr~so~ C. L. & WEINSTEIN H. (197X) Histamine as a neurotransmitter. In PsycBuphffrf~~urclnt/oy~~ A &‘f~.*ration of Progress (eds LWTON M. A., DIMA~C~OA. & KILLAM K. F.), pp. 319.“332. Raven Press, New York. HAAS H. L. & WOLF P. (1977) Central actions of histamine: microelectrophoretic studies. Brain Res. 122, 269-279.

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to histamine H,-receptors

in guinea”pig

Autoradiography f-fl~~ S. J.,

YQI:NC;

of histamine

Hi-receptors

J. M. & MARRIAU D. H. (1977) Specific binding

jntcstinal smooth muscle. Nururr. Lotril 270, X-363. H(>r-_rllt~h W. E. & S~MII) P. Cr. (1978) Cardiovascular

37

in tat brain

of C3H]mepyramine

and antidiuret~c

to histamine H,-receptors

cfTects of central

histamine.

in

Lifi* Sci. 22,

1709-171‘3. JAJ~ B. P. & Wn,uc; S. C. (1971) EfTects o~d~pl~enhyd~mi~~e and dimenhydrin~ite

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IUCLZS

KKIIX; W. J. S. (1946) Connections of the Cerebral Cortex. J. C’onrp. .Yeuro/. 84. 277 323. I.,t~tnow~~z S. F. (1973) Histamme: a stimulating effect on drinking behaviour in the rat. BrcCrl RPS. 63, 440- 444. MoNt,Y K. E. (1970) Motion Sickness. Physiol. Rer. 50. I 30. Owriu D. A. A. fl977) Histamine receptors in the cardiovascular system. Gnr. PAI.ACXE

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Phc~rrmc.

receptor localization

8, 141- 156.

by light microscopic

autoradiography.

208, 137X.-1380. PA~.ACIOSJ. M., Youwc III W. S. & KUHAK M. J. (1979) Autoradiographi~ localization of HI-histamine receptors in brain using [~Hlmepyramine: Preliminary studies. Eur. J. P~~~~~~~i~. 58, 295-304. PALACIOS J. M., YOUN(; III W. S. & K~JHAR M. J. (1980) Autoradiographi~ localization of gamma-alninobutyrjc acid receptors in rat cerebellum, Proc. naln. A&. Sri. U.S.A. 77, 670674. ScG37tf~~

N.

I!

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atlas of ~~techoiamines and acetylcholiflesterasc-fnntaining neurons in the rat brain. II. Hindhr~~in. J. Conrp. Ncwo~. 157. 29.43. PI-KOL:T~AS. .I.. MosKowtTz M. A.. REIKHAR~J. F. & SNurJt K S. H. (19801 ~eurotransmitter Receptor Binding in Bovine Cerebral Microvessels. S&,jrcc,, N. X 208, 6 I O-6I?. POLLAKI) H.. Btsctcocr: S.. LI.ORENSC. & SCRWARTZJ. C. (1976) Histamine and histidine decarboxylase in discrete nuclei ol’ rat hypothalamus and the evidence f’or mast-cells in the median eminence. Erairl Rex 118, 509-513. Smw.w~%

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M. J. ($981) Autoradiographi~

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~o~dren~rgic

localization

of benzodiazepine

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Y()~‘HG IfI W. S. & KUHAK M. J. fi980u) Radiohist~hemical

and alpha-l localization

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receptors in the brain of

localization

in rat CNS. our. 1.

Atitor~ldi~~gr~~h~c V~suaii~~ti~~~.

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