th S-FIT, and DZ receptor blocking capacity, was ~~~~~~~ in the treatment schedule as a ~~e~~~e drug.
Male Wistar rats weighing between 210-230 g (ALAR, Sollentuna, Sweden) at the beginning of the study were used. The rats were housed in groups of four under standard laboratory conditions (temperature 21*C1 humidity 55 f 5%, lights to 19 : 00 h). There was free access on from 7 : to shaded pelleted food (Ewos R3, S&lert%je, Sweden) and water at all times. 2.2. Drug freatments Groups of rats received S.C. injections of ritanserin (OS mg/kg), haloperidol (0.5 mg/kg), clozapine (20 mg/kg) or the combination of baloperidol (0.5 mg/kg) and ritanserin (0.5 mg/kg) once a day for 18 days (9 : 00 a.m.). The control rats received an equal amount of vehicle. The rats were d~apitat~ 24 h after the last injection.
coordinates: A8920-8620), nucleus accumbens (A9410-8920), prefrontal cortex (A9820-8920), nucleus raphe dorsalis (A350-160) and nucleus raphe medialis (Pl~80) were microdissected according to the Palkovits punch technique. The tissue samples were homoge~~ in 100 ~1 of 0.1 M ice-cold per&lo& acid containing 1.34 mM EDTA and 2.6 mM sodium bisulphite as preservatives and 2.5 x 10T8 M of a-methyldopa and Nmethyl-5-HT as internal standards for HPLC. The concentrations of DA, 3,4dihydroxyphenylaeetic acid (DOPAC), homovanillic acid (HVA), S-NT and 5-hydroxyindoleacetic acid (S-HIAA) were determined by HPLC with electrochemical detection (Lappalainen et al., 1990). 2.5. statistical analysis Statistical analysis of the data was carried out by analysis of variance (ANOVA) followed by Tukey’s test for post-hoc analyses. A commercially available statistical software package (Systat@, IL, USA) was used for these purposes. If the variances of the data were unequal, log transformation was performed before the ANOVA. A P value lower than 0.05 was considered to be statistically si~fic~t.
2.3. Drugs
3. R@SuRs
Ritanserin (donated by Janssen Pharmaceutics, Beerse, Belgium) was dissolved in a minimum amount of ethyl alcohol and diluted further with 1 n&f tartaric acid. Haloperidol (Serenase@, Orion, Helsinki, Finland), from the commercially available ampoules, was diluted identic~y to ritanserin. Clozapine was dissolved in a drop of 2 M HCl and the pH was adjusted with 1 M NaOH and diluted further with 1 mM tartar& acid. The drugs were injected in a volume of 1 ml/kg.
3.1. Eflects of chronic treatment with clozapine, ritanserin, haloperidol or the combination of ritanserin and ha!operidol on dopamine metabolism
2.4. Dissection and monoamine analysis After decapitation the brains were removed quickly and frozen on dry ice. Coronal sections were cut in a cryostat at - 10 O2 and slices stored at - 70 0 C. Nucleus caudatus (K&rig and Klippel
The results are summarized in table 1. The levels of HVA in nucleus ~udatus were reduced by chronic halope~dol (P = 0.023) and the ~t~se~n-h~ope~dol combination (P = 0.001) (overall ANOVA; F = 8.204, P c 0.001). The chronic haloperidol and ritanserin-haloperidol combination also reduced the concentration of DOPAC (29 and 35%, respectively) in nucleus caudatus but the changes did not reach statistical significance. In the nucleus accumbens only the iitanserin-haloperidol combination reduced the concentration. of HVA (P = 0.013) si~fic~~y (overall ANOVA; F = 3.759, P = 0,012). Chronic
TABLE 1
TFStmimt NwSws raudahrs V&i& ckxsipine Rituerin R&pwidol ~rnb~ti~~
DA
IX3PAC
582.9134*9 556.6 f 42.9 653.7 f 68.8
117.6rt20.8
654.2f 46.4 601.2f66.5
89.5f 13.7 82.4f 15.2
WA
H-IT
S-WAA
126.6$22‘8
37_7k4.3
101.4&18.4
26.0f 1.4
38.9k4.1
12.3k2.3 13.1k1.6 13.6f1.2
16.9f2.1 16.2f3.4 19.9k3.3
23.2f 2.4a 17.9f2.9 b
13.9* 1.5 14-o* 1.7
18,4&2.0 19.1f2.9
NscIm llmunbens W&Ck
5os.6rt10.5
161.2f19.1
32.0&2-t%
(ismq?he
19.911.9
24.1f 1.1
636‘6&§6.0
R&rwrin ~~~~~i ~rnb~a~on
4889i30.9 478.9 f 42.1 537.0 f 49.7
16l.t f 145.8 f 120.6 f 147.3 f
27.4 f 29.5 f 23.6 f 209f
24.0f1.3 17.7& 1.4 18.011.8 23.7 f 4.0
28.6jz27 255.3f2.5 27.6i2.6 26.5 $z1.6 38.0f 3.4 41_4&2.4
24.7 19.7 16.1 25.6
1.6 2.4 2.3 25 ’
~~~~~~tju~i~Q
V&i&! c%xaptie Ritans&rJ
Sl.&f 4.x 79.4k24.2 69.0f 10.7
11.3f 3.x 15.2& 3.9 14.1 f 2.5
6.0fO.6 4.1 f 0.7 7.2* 1.5
~~~d~
76.3 f 7.3 75.9i6.8 79.7 f 9.2
62.lf
11.6f 1.6
6.1rt0,7
78.1f 9.2
4mk4.3 36.1+3.1
~rnb~ti~
71.9fll.6
14.2f
6.8k1.2
78.8i55.2
38.2f1.4
9.3
2.7
a P =@ 0.023 vs. uxltrol group; b P = 0.001 vs. control group; c P = 0.013 vs. cantrol group.
h~ope~dol ~eatm~t alone also tended to reduf: the ~~~n~a~o~ of HVA ~26~j* but the decrease was uou-si~i~~t* Chronic treatment with clozapine failed to alter the levels of DA or its rnetabolites in the nuclei studied. There were no significant alterations in the concentrations of DA or its rneta~~t~ in subst~t~a nigra. The concentrations of DA, DOPAC and HVA in nuclei rapbe dorsalis and medialis were not determined. The ~n~~at~o~ of DA (data not shown) in prefrontal cortex was not altered by the drug trea~ents and the. levels of DOPAC and PfVA were below the det~tion limit.
The results are summarized in table 2. Chronic treatment with ritanserin significantly reduced the c~n~n~atio~s of S-HT (P = ~.02gj and S-HMA (Ps= 0.034) in nu&us raphe dorsalis (overall A~OVAs; F = 4.082, P s ~.~~9 and F = 3.493, P
= 0.018 for S-PIT aud S-ZIQfAA,~s~~ve~yj~ Althougb the chronic h~ope~do~ event tended to counter the decrease of 5-HT and S-WTAA concentrations iuduced by chronic ritanserin, the difference between the effect of ritanseriu alone and of the ritanserin-haloperidol combiuation was not st~t~s~~y significant. There were no significant dteratious in 5-HT or 5-IBAA concentrations in the nucleus raphe mediahs, substantia nigrq nucleus caudatus, nucleus acoumbens or prefrontal cortex.
The major finding of the present study cvas that the ~~comitant chronic administration of ritanserin and haloperidol inhibited the nigrostriatal DAergic activity in the same way as did hdoperidol treatment alone. Akbough acute blockade of S-I-IT, receptors with ICI 169369 modulates the h~op~~do~=~du~ activation of DA neurons in s~at~m (SaUer et d., 1990), such
nt with clozapine (20 q/kg per per day). hatoperidol (0.5 q/kg of ritanserin and haloperidol day) on the concentrations of 5-HT eus raphe dorsalis, nucIeus raphe rtex. The values are pmo~/~ proto e&h rats, except for S-EK#AAin p and plenty cortex, where
is
c~b~a~~ tnl #r&x Vehicle Clozapine I timbinatiori
121.1* 5.6 127.4 f 12.8 77.7* 9.8 a
114.9* 4.0 125.1 f 14.9 82.65 9.9 b 108.61t 4.9 109.1 f 8.3
57.3f 7.2 51.9 f 110.8 47.7.1* 9.7 47.99 6.2 42.Q 4.6
66.911: 4.4 73.9f 7.2 67.9& 8.5 7X7* 5.2 &is+ 7.9
6.8& 11.7* 9.8f 8.2a 15.9*
11.5f 12.9& 12.8~ 12.6* ll.Of
0.1 2.1 2.1 0.4 1.1
1.3 1.0 1.4 0.6 1.1
a P = 5.028 vs. endow group; b P = 0.034 vs. control group_
may not be effective to prevent the f nigrostriatal DAergic neurons inin duced by chrouic haloperidol treatment. A deDA activity is usually assoction of Eps. The present ~~e~t~ data suggest that, cocky, HIT,
a
r nucleus caudatus. This is in line of a recent iu vivo brain dialysis
eridol-ritanserin
treatments
could be due to the fact that the S-EIT2/D2 receptor affinity ratio may be important in the action of clozapine and other atypical neuroleptics (Meltzer 199Q), and the appropriate ratio may not be et ed by co-administration of haloperidol and ob Altematively, m~h~sms other than 5receptor ~tago~srn may be more import~t in the unique actions of clozapine. This possibiity is suggested by the finding that chronic co-administration of prazosin, an cu,-receptor antagonist, or trihexyphenidyl, an anticholinergic drug, with haloperidol produces electrophysiological effects on DA neurons which resemble those adze by ~lo~p~e (alto and Bunney, 1985). I~teres~~y, &ronic ritanserin treatment sigy reduced the concentrations of S-I-IT and in the nucleus raphe dorsalis, suggesting seriu reduces serotonergic activity in this area. Recently, Stratford and Wirtshaffer (1990) showed that the nucleus raphe dorsalis contains DAergic neurons proj~~g to rne~~bic rather ~~ to striatal areas. Thus, it is tempting to speculate that interactions of DAergic and serotonergic neurons in the nucleus raphe dorsalis could be involved in the antidysthymic and possible antischizophrenic properties of ritanserin as observed in clinical and preclinical experiments @elders et al., 1985; Goldstein and Litwin, 1988). In inclusion, these results suggest that the effects of the classical neuroleptic, haloperidol, on the activity of DA neurons cannot be altered to resemble those of the atypical neuroleptic, clozapine, solely by combining haloperidol with a 5receptor antagonist. A more appropriate S-I-ITa/Da receptor blocking ratio may underlie the fact that clozapine does not induce EPS or, ~tema~vely, the reason could be interactions with other neurotransmitter systems.
ts This work was supported f~~~~y by The Research Foundation of Pharmaca! Ltd., Farmos Group Ltd., the Fmx&h Me&al Foundation, the Medical Research Council of Academy of Finland and tha Foundation for Psychiatric Research in Finland. The excellent technical assistance of Mrs. Wja Simola and Mrs. Maritta Forsblom is gratefully acknowledged.
407
eferemzes Chiodo, L.A. and B.S. Bunney, 1983, Typical and atypical neurolepties: differential effects of chronic administration on the activity of A9 and A10 midbrain dop~er~~ neurous, J. Neurosci. 3,X07. Chiodo, L.A. and B.S. Bumxey, 1985, Possible mechanisms by which repeated clozapine administration differentially affects the activity of two saubpopulations of midbrain dopamine neurons, J. Netuosci. 5.2539. Gelders, Y., D. Ceulemans, MI.-L.J.A. Hoppenbrouwers, A. Reyntjens and F. Mesotten, 1985, Ritanserin, a selective serotonin antagonist in chronic schizophrenia (Abstract, VRh Congress of Biological ~yc~t~) p. 338. Goldstein, J.M. and L.C. Litwin, 1988, ~tip~choti~~e activity of ritanserin following chronic treatment in rats (Abstract), FASEB J. 2, A1404. Ichikawa, J. and H.Y. Meltzer, 1990, The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in viva microdialysis, European J. Pharmacol. 176, 371.
Lappalainen, J., J. Hietala, M. Roulu, T. Seppiil$ B. Sjijhohn and E. Syv&hti, 1990, Chronic treatment with SCH 23390 and haloperidol: Effects on dopaminergic and serotouergic mechanisms in rat brain, 3. Pbarmacol, Exp. Ther. 252,845. Mehzer, H.Y., S. Matsubara and J.-C. Lee, 1990, Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-l. D-2 and serotonin-2 pKi values, J. Pharmacol. Exp. Ther. 251,238. Saller, CF., M.J. Czupryna and A.I. !&&ma, 1990, 5X& receptor blockade by ICI 169369 and other S-HTz antagonists modulates the effects of D-2 dopamine receptor blockade, J. Pharmacel. Exp. Ther. 253,1162. Stratford, T.R. and D. W&&after, 1990, Ascending dopaminergic projections from the dorsal raphe nucleus in the rat, Brain Res. 511,173. White, W.F. and R.Y. Wang, 1983, Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons, Science 221,1054.
Male Wistar rats weighing between 210-230 g (ALAR, Sollentuna, Sweden) at the beginning of the study were used. The rats were housed in groups of four under standard laboratory conditions (temperature 21*C1 humidity 55 f 5%, lights to 19 : 00 h). There was free access on from 7 : to shaded pelleted food (Ewos R3, S&lert%je, Sweden) and water at all times. 2.2. Drug freatments Groups of rats received S.C. injections of ritanserin (OS mg/kg), haloperidol (0.5 mg/kg), clozapine (20 mg/kg) or the combination of baloperidol (0.5 mg/kg) and ritanserin (0.5 mg/kg) once a day for 18 days (9 : 00 a.m.). The control rats received an equal amount of vehicle. The rats were d~apitat~ 24 h after the last injection.
coordinates: A8920-8620), nucleus accumbens (A9410-8920), prefrontal cortex (A9820-8920), nucleus raphe dorsalis (A350-160) and nucleus raphe medialis (Pl~80) were microdissected according to the Palkovits punch technique. The tissue samples were homoge~~ in 100 ~1 of 0.1 M ice-cold per&lo& acid containing 1.34 mM EDTA and 2.6 mM sodium bisulphite as preservatives and 2.5 x 10T8 M of a-methyldopa and Nmethyl-5-HT as internal standards for HPLC. The concentrations of DA, 3,4dihydroxyphenylaeetic acid (DOPAC), homovanillic acid (HVA), S-NT and 5-hydroxyindoleacetic acid (S-HIAA) were determined by HPLC with electrochemical detection (Lappalainen et al., 1990). 2.5. statistical analysis Statistical analysis of the data was carried out by analysis of variance (ANOVA) followed by Tukey’s test for post-hoc analyses. A commercially available statistical software package (Systat@, IL, USA) was used for these purposes. If the variances of the data were unequal, log transformation was performed before the ANOVA. A P value lower than 0.05 was considered to be statistically si~fic~t.
2.3. Drugs
3. R@SuRs
Ritanserin (donated by Janssen Pharmaceutics, Beerse, Belgium) was dissolved in a minimum amount of ethyl alcohol and diluted further with 1 n&f tartaric acid. Haloperidol (Serenase@, Orion, Helsinki, Finland), from the commercially available ampoules, was diluted identic~y to ritanserin. Clozapine was dissolved in a drop of 2 M HCl and the pH was adjusted with 1 M NaOH and diluted further with 1 mM tartar& acid. The drugs were injected in a volume of 1 ml/kg.
3.1. Eflects of chronic treatment with clozapine, ritanserin, haloperidol or the combination of ritanserin and ha!operidol on dopamine metabolism
2.4. Dissection and monoamine analysis After decapitation the brains were removed quickly and frozen on dry ice. Coronal sections were cut in a cryostat at - 10 O2 and slices stored at - 70 0 C. Nucleus caudatus (K&rig and Klippel
The results are summarized in table 1. The levels of HVA in nucleus ~udatus were reduced by chronic halope~dol (P = 0.023) and the ~t~se~n-h~ope~dol combination (P = 0.001) (overall ANOVA; F = 8.204, P c 0.001). The chronic haloperidol and ritanserin-haloperidol combination also reduced the concentration of DOPAC (29 and 35%, respectively) in nucleus caudatus but the changes did not reach statistical significance. In the nucleus accumbens only the iitanserin-haloperidol combination reduced the concentration. of HVA (P = 0.013) si~fic~~y (overall ANOVA; F = 3.759, P = 0,012). Chronic
TABLE 1
TFStmimt NwSws raudahrs V&i& ckxsipine Rituerin R&pwidol ~rnb~ti~~
DA
IX3PAC
582.9134*9 556.6 f 42.9 653.7 f 68.8
117.6rt20.8
654.2f 46.4 601.2f66.5
89.5f 13.7 82.4f 15.2
WA
H-IT
S-WAA
126.6$22‘8
37_7k4.3
101.4&18.4
26.0f 1.4
38.9k4.1
12.3k2.3 13.1k1.6 13.6f1.2
16.9f2.1 16.2f3.4 19.9k3.3
23.2f 2.4a 17.9f2.9 b
13.9* 1.5 14-o* 1.7
18,4&2.0 19.1f2.9
NscIm llmunbens W&Ck
5os.6rt10.5
161.2f19.1
32.0&2-t%
(ismq?he
19.911.9
24.1f 1.1
636‘6&§6.0
R&rwrin ~~~~~i ~rnb~a~on
4889i30.9 478.9 f 42.1 537.0 f 49.7
16l.t f 145.8 f 120.6 f 147.3 f
27.4 f 29.5 f 23.6 f 209f
24.0f1.3 17.7& 1.4 18.011.8 23.7 f 4.0
28.6jz27 255.3f2.5 27.6i2.6 26.5 $z1.6 38.0f 3.4 41_4&2.4
24.7 19.7 16.1 25.6
1.6 2.4 2.3 25 ’
~~~~~~tju~i~Q
V&i&! c%xaptie Ritans&rJ
Sl.&f 4.x 79.4k24.2 69.0f 10.7
11.3f 3.x 15.2& 3.9 14.1 f 2.5
6.0fO.6 4.1 f 0.7 7.2* 1.5
~~~d~
76.3 f 7.3 75.9i6.8 79.7 f 9.2
62.lf
11.6f 1.6
6.1rt0,7
78.1f 9.2
4mk4.3 36.1+3.1
~rnb~ti~
71.9fll.6
14.2f
6.8k1.2
78.8i55.2
38.2f1.4
9.3
2.7
a P =@ 0.023 vs. uxltrol group; b P = 0.001 vs. control group; c P = 0.013 vs. cantrol group.
h~ope~dol ~eatm~t alone also tended to reduf: the ~~~n~a~o~ of HVA ~26~j* but the decrease was uou-si~i~~t* Chronic treatment with clozapine failed to alter the levels of DA or its rnetabolites in the nuclei studied. There were no significant alterations in the concentrations of DA or its rneta~~t~ in subst~t~a nigra. The concentrations of DA, DOPAC and HVA in nuclei rapbe dorsalis and medialis were not determined. The ~n~~at~o~ of DA (data not shown) in prefrontal cortex was not altered by the drug trea~ents and the. levels of DOPAC and PfVA were below the det~tion limit.
The results are summarized in table 2. Chronic treatment with ritanserin significantly reduced the c~n~n~atio~s of S-HT (P = ~.02gj and S-HMA (Ps= 0.034) in nu&us raphe dorsalis (overall A~OVAs; F = 4.082, P s ~.~~9 and F = 3.493, P
= 0.018 for S-PIT aud S-ZIQfAA,~s~~ve~yj~ Althougb the chronic h~ope~do~ event tended to counter the decrease of 5-HT and S-WTAA concentrations iuduced by chronic ritanserin, the difference between the effect of ritanseriu alone and of the ritanserin-haloperidol combiuation was not st~t~s~~y significant. There were no significant dteratious in 5-HT or 5-IBAA concentrations in the nucleus raphe mediahs, substantia nigrq nucleus caudatus, nucleus acoumbens or prefrontal cortex.
The major finding of the present study cvas that the ~~comitant chronic administration of ritanserin and haloperidol inhibited the nigrostriatal DAergic activity in the same way as did hdoperidol treatment alone. Akbough acute blockade of S-I-IT, receptors with ICI 169369 modulates the h~op~~do~=~du~ activation of DA neurons in s~at~m (SaUer et d., 1990), such
nt with clozapine (20 q/kg per per day). hatoperidol (0.5 q/kg of ritanserin and haloperidol day) on the concentrations of 5-HT eus raphe dorsalis, nucIeus raphe rtex. The values are pmo~/~ proto e&h rats, except for S-EK#AAin p and plenty cortex, where
is
c~b~a~~ tnl #r&x Vehicle Clozapine I timbinatiori
121.1* 5.6 127.4 f 12.8 77.7* 9.8 a
114.9* 4.0 125.1 f 14.9 82.65 9.9 b 108.61t 4.9 109.1 f 8.3
57.3f 7.2 51.9 f 110.8 47.7.1* 9.7 47.99 6.2 42.Q 4.6
66.911: 4.4 73.9f 7.2 67.9& 8.5 7X7* 5.2 &is+ 7.9
6.8& 11.7* 9.8f 8.2a 15.9*
11.5f 12.9& 12.8~ 12.6* ll.Of
0.1 2.1 2.1 0.4 1.1
1.3 1.0 1.4 0.6 1.1
a P = 5.028 vs. endow group; b P = 0.034 vs. control group_
may not be effective to prevent the f nigrostriatal DAergic neurons inin duced by chrouic haloperidol treatment. A deDA activity is usually assoction of Eps. The present ~~e~t~ data suggest that, cocky, HIT,
a
r nucleus caudatus. This is in line of a recent iu vivo brain dialysis
eridol-ritanserin
treatments
could be due to the fact that the S-EIT2/D2 receptor affinity ratio may be important in the action of clozapine and other atypical neuroleptics (Meltzer 199Q), and the appropriate ratio may not be et ed by co-administration of haloperidol and ob Altematively, m~h~sms other than 5receptor ~tago~srn may be more import~t in the unique actions of clozapine. This possibiity is suggested by the finding that chronic co-administration of prazosin, an cu,-receptor antagonist, or trihexyphenidyl, an anticholinergic drug, with haloperidol produces electrophysiological effects on DA neurons which resemble those adze by ~lo~p~e (alto and Bunney, 1985). I~teres~~y, &ronic ritanserin treatment sigy reduced the concentrations of S-I-IT and in the nucleus raphe dorsalis, suggesting seriu reduces serotonergic activity in this area. Recently, Stratford and Wirtshaffer (1990) showed that the nucleus raphe dorsalis contains DAergic neurons proj~~g to rne~~bic rather ~~ to striatal areas. Thus, it is tempting to speculate that interactions of DAergic and serotonergic neurons in the nucleus raphe dorsalis could be involved in the antidysthymic and possible antischizophrenic properties of ritanserin as observed in clinical and preclinical experiments @elders et al., 1985; Goldstein and Litwin, 1988). In inclusion, these results suggest that the effects of the classical neuroleptic, haloperidol, on the activity of DA neurons cannot be altered to resemble those of the atypical neuroleptic, clozapine, solely by combining haloperidol with a 5receptor antagonist. A more appropriate S-I-ITa/Da receptor blocking ratio may underlie the fact that clozapine does not induce EPS or, ~tema~vely, the reason could be interactions with other neurotransmitter systems.
ts This work was supported f~~~~y by The Research Foundation of Pharmaca! Ltd., Farmos Group Ltd., the Fmx&h Me&al Foundation, the Medical Research Council of Academy of Finland and tha Foundation for Psychiatric Research in Finland. The excellent technical assistance of Mrs. Wja Simola and Mrs. Maritta Forsblom is gratefully acknowledged.
407
eferemzes Chiodo, L.A. and B.S. Bunney, 1983, Typical and atypical neurolepties: differential effects of chronic administration on the activity of A9 and A10 midbrain dop~er~~ neurous, J. Neurosci. 3,X07. Chiodo, L.A. and B.S. Bumxey, 1985, Possible mechanisms by which repeated clozapine administration differentially affects the activity of two saubpopulations of midbrain dopamine neurons, J. Netuosci. 5.2539. Gelders, Y., D. Ceulemans, MI.-L.J.A. Hoppenbrouwers, A. Reyntjens and F. Mesotten, 1985, Ritanserin, a selective serotonin antagonist in chronic schizophrenia (Abstract, VRh Congress of Biological ~yc~t~) p. 338. Goldstein, J.M. and L.C. Litwin, 1988, ~tip~choti~~e activity of ritanserin following chronic treatment in rats (Abstract), FASEB J. 2, A1404. Ichikawa, J. and H.Y. Meltzer, 1990, The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in viva microdialysis, European J. Pharmacol. 176, 371.
Lappalainen, J., J. Hietala, M. Roulu, T. Seppiil$ B. Sjijhohn and E. Syv&hti, 1990, Chronic treatment with SCH 23390 and haloperidol: Effects on dopaminergic and serotouergic mechanisms in rat brain, 3. Pbarmacol, Exp. Ther. 252,845. Mehzer, H.Y., S. Matsubara and J.-C. Lee, 1990, Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-l. D-2 and serotonin-2 pKi values, J. Pharmacol. Exp. Ther. 251,238. Saller, CF., M.J. Czupryna and A.I. !&&ma, 1990, 5X& receptor blockade by ICI 169369 and other S-HTz antagonists modulates the effects of D-2 dopamine receptor blockade, J. Pharmacel. Exp. Ther. 253,1162. Stratford, T.R. and D. W&&after, 1990, Ascending dopaminergic projections from the dorsal raphe nucleus in the rat, Brain Res. 511,173. White, W.F. and R.Y. Wang, 1983, Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons, Science 221,1054.
