Neurochem[ Int[ Vol[ 29\ No[ 2\ pp[ 166Ð189\ 0886
Copyright Þ 0886 Elsevier Science Ltd
\
Pergamon
Printed in Great Britain[ All rights reserved
9086Ð9075:86 ,06[99¦9[99
PII] S9086Ð9075"85#99982Ð8
EFFECTS OF CHRONIC NEUROLEPTIC TREATMENTS
ON DOPAMINE D
0
AND D
1
RECEPTORS] HOMOGENATE
BINDING AND AUTORADIOGRAPHIC STUDIES
NING HUANG\
0
ARIEL R[ ASE\
0
CAROLINE HE
BERT\
0
NICO M[ VAN GELDER
0
$ and TOMA
S A[ READER
0\1
0
Centre de Recherche en Sciences Neurologiques\ De
partements de Physiologie\ Faculte
de Me
decine\
Universite
de Montre
al\ C[P[ 5017\ Succursale Centre!ville\ Montre
al\ Que
bec\ Canada
1
Centre de Recherche en Sciences Neurologiques\ De
partements de Psychiatrie\ Faculte
de Me
decine\
Universite
de Montre
al\ C[P[ 5017\ Succursale Centre!ville\ Montre
al\ Que
bec\ Canada
"Received 15 March 0885^ accepted 14 July 0885#
Abstract*The antipsychotic e}ects of neuroleptics are believed to be mediated via dopamine D
1
receptor
blockade^ however\ the anatomical and pharmacological targets of these drugs remain somewhat con!
troversial[ The purpose of this study was to examine the e}ects of chronic clozapine "CLZ# and haloperidol
"HAL# treatments on the densities of DA D
0
and D
1
receptors[ Adult male SpragueÐDawley rats "299Ð
249 g# were treated for 10 days with either HAL "0 mg:kg:day\ i[p[#\ CLZ "19 mg:kg:day\ i[p[# or saline[
Three days after ending the treatments\ the brains were removed and used for biochemical assays of tissue
DA and metabolites as well as for receptor studies[ DA D
0
and D
1
receptors were labelled with
ð
2
HŁSCH12289 and ð
2
HŁraclopride\ respectively\ and measured in the neostriatum by binding studies\ and
in autoradiograms of forebrain sections by quantitative densitometry[ The autoradiographic measurements
revealed signi_cant increases in the densities of D
1
receptors in nucleus accumbens\ in the medio!ventral\
latero!dorsal and latero!ventral quadrants of the rostral neostriatum\ in caudal neostriatum and in globus
pallidus of both HAL! "17Ð33)# and CLZ!treated "04Ð74)# animals[ The HAL!induced up!regulation of
D
1
receptors in rostral and caudal neostriatum was homogenous\ but CLZ produced a more uneven
increase\ with the highest absolute densities measured in latero!dorsal neostriatum\ as well as with changes
in the medio!dorsal rostral neostriatum[ For D
0
receptors\ only CLZ and not HAL\ produced signi_cant
increases in _ve regions\ namely nucleus accumbens "32)#\ latero!dorsal rostral neostriatum "05)#\ caudal
neostriatum "29)#\ globus pallidus "56)# and substantia nigra "01)#[ The observation that CLZ\ contrary
to HAL\ also has an e}ect on D
0
receptor densities may explain the greater therapeutic and selective e.cacy
with fewer side!e}ects of this agent\ in comparison to other neuroleptics[ Þ 0886 Elsevier Science Ltd[ All
rights reserved
The dopamine "DA# hypothesis of schizophrenia is class of antipsychotic drugs with a high e.cacy to
based on the correlation between the clinical e.cacy
attenuate both positive and negative symptoms of the
of antipsychotic drugs and the blockade of DA D
1
disorder\ and has been shown e}ective in patients
receptors "Van Rossum\ 0855^ Creese et al[\ 0865^
which had become resistant to other neuroleptics[ This
Seeman\ 0879\ 0876^ Seeman et al[\ 0865\ 0882#[ On the
newer drug causes fewer extrapyramidal side!e}ects\
other hand\ the extrapyramidal side!e}ects associated
and little or no signs of tardive dyskinesia and super!
with most neuroleptics are also seemingly related to
sensitivity psychosis "Chouinard et al[\ 0883# are seen
D
1
receptor occupancy "Klawans\ 0862^ Baldessarini\
in patients[ Many pharmacological di}erences have
0863^ Marsden\ 0864^ Marsden and Jenner\ 0889#
been documented between CLZ and other neu!
although muscarinic "Snyder et al[\ 0863# and sero!
roleptics such as haloperidol "HAL#[ These include
tonin receptors "Meltzer et al[\ 0878b# have also been
selective e}ects on the striatal regions\ as well as
implicated[ Clozapine "CLZ# is a prototype of a new
di}erent a.nities for various DA receptor subtypes[
Although the antipsychotic e}ects of CLZ may be
*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
related to DA D
1
receptor blockade\ like the action of
To whom all correspondence should be addressed[
HAL\ the anatomical target"s# and pharmacological
$Present address] Department of Chemistry\ Queen|s Uni!
versity\ Kingston\ Ontario\ Canada K6L 2N5[
speci_city remain controversial\ and a preferential
166