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Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons
Pm3. Neuro-Psychopharmocol6 Biol Psychiot. Printed inGreat Brttain. All ri&~ts mmwd.
198.3, Vol. 7. PP. 765-768 Copyri&
DIFFBBENTIAL ACTIONS
OF CLA!SSICAL AND ATYPICAL
ON MOUSE NIGROSTIUATAL
0
027%5846183 $0.00 + 50 1983 Per3amcm Press Ltd.
NEUROLEPTICS
NEURONS
PAUL L. WOOD, PAUL S. MCQUADE, PIERRE ETIENNE, SAMARTHJI LAL AND N.P. VASAVAN NAIR Douglas
Hospital
Research
Centre,
Verdun,
Quebec
H4H lR3
(Final form, July 1983)
Abstract Etienne, Samarthji Lal and N.P. Vasavan Wood, Paul L., Paul S. McQuade, Pierre ferential actions of classical and atypical neuroleptics on mouse nigrostriatal Prog. Neuro-Psychopharmacol. 6 Biol. Psychiat. 1983, 1(4-6) :765-768.
Nair: Difneurons.
1. The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum. 2. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release. 3. At high doses, sulpi ride increases both dopamine metabolism and release. 4. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent. Keywords: nigrostriatal thioridazine, sulpiride
dopamine
metabolism,
dopamine
(CPZ); dihydroxyphenylacetic Abbreviations : chlorpromazine horovani 11 i c acid (HVA) ; 3-methoxytyrami ne (3-MT)
release,
acid
mouse,
clozapine,
(DOPAC);
dopamine
(DA);
Introduction The neurochemical differentiation of classical and atypical neuroleptics until recently has focussed on possible differential actions in the extrapyramidal and mesolimbic DA projections. However, these studies have not revealed a consistent preferential action of neuroleptics in Similarly, the potent anticholinergic actions of atypical either DA system (Coyle, 1982). neuroleptics do not explain the unique pharmacological profile of these agents (Coyle, 1982). In the present study, we have therefore evaluated the suggestion that atypical neuroleptics have an inhibitory presynaptic action on DA nerve endings (Rebec et al., 1979).
Methods Receptor binding. Brain membrane preparations from male Sprague Dawley rats were assayC3H3-spiperone, C3Hl-WB4101, C3Hl-aminoclonidine, C3Hl-ketanserin and r3HI-QNB as described previously (Wood et al., 1983).
used to binding
DA metabol i tes. Male Swiss Hauschke mice were treated tip) with neuroleptics 15 to 180 mlnutes prior to sacrifice by microwave irradiation (Wood et al., 1983). DOPAC, HVA, DA and 3-MT were subsequently assayed in striatal extracts by gas chromatography-mass fragmentography (Wood, 1982a) . Statistics.
Data were
analyzed
with
the
multiple
765
comparison
test
of
Dunnett
(Wood,
198%).
766
P.L. Wood et al.
1
Table Receptor
binding
profiles
of
neuroleptics
IC Drug
3
3
H-Spip Na
t
Na
H-WE
5.0
24
Perphenazine
6.8
6.4
14
11.3
15.1
6
Clozapine Thioridazine Sulpi
ride
303
395
14
79
17
8
173
>10,000
83
Mol indone
400
3H-ket
(42)
5.9
vitro
(nM)
3H-AC
(a(l)
Haloperidol
CPZ
50
--in
3H-QNB
(X2)
>lO ,000
960 > 1,000
(M)
132
>5,000
3.9
>5,000 286
18.4
293 >10,000
22
100
20
49
3800
>10,000
>10,000
>5,000
2300
>10,000
> 5,000
>5,000
Results Receptor binding. All the examined neuroleptics were binding (Table 1). Clozapine, thioridazine and CPZ all activity (C3Hl-QNB) . No consistent differences between regard to a(~, O(Z or Sz binding sites, were observed.
Table Actions
Drug
of
neuroleptics
on mouse
(mdkg)
DOPAC
58*
Control
4
active displacers of possessed significant classical and atypical
i3H! spi perone anticholinergic agents, with
2
striatal
DA metabolites
HVA (pmol/mg
53+
60
min
DA proteinIS
post-drug
3-MT
2
565 * 10
4.3 + .25
3" 5" 8?:
108 f
3"
486 * 12
(LoI
136 f 227 f 228 f
124 149
f f
5” 6”
429 452
f 145: + ll*
7.1 t .30" 6.5 f .ZlJ; 7.6 * .16*
Perphenazine
(I .O)
224 f
8”
149
*
6”
486
f
5”
7.6 f .35"
CPZ
(2.5)
202
f
12J:
127 +
8*
531 *
8*
5.9 f .22*
Mol i ndone
(2.5)
162
f
lO*
149 f
6"
509 f 13
8.4 f .46*
‘,%
98t 151 f
3" 5"
72 f 94*
5" 4*
510 + 15 512 f 13
4.9 f .40:: 6.4 f .31*
(IS)
224
(30)
271 f
8* 7"
121 * 111 +
5" 8*
548 f 13 510 * 15
4.6 f .21 4.3 f .30
1::;
582 6 103 f 6* 174 f 17"
60+ 66 * 95+
6 5" 8*
620 * 20 598 f 15 649 f 18
2.6
Haloperidol
Sulpi
[:.:I
ride
Thioridazine
Clozapine (60)
* p co.05;
$ Mean f
f
S.E.M.
(N = 7-10)
3.0 f .ll” +
.lO”
2.5 f .15*
Differential
effect<
of neuroleptics
on nigrostriatal
767
neurons
Haloperidol, perphenazine, CPZ and molindone all produced potent increases DA metabolism. Haloperidol and perphenazine also produced small decreases in DOPAC, HVA and 3-MT (Table 2). The atypical agents clozapine and thioridazine increased DOPAC in DA steady-state levels. and HVA but 3-MT was either not affected or decreased (Table 2). The decreased 3-MT noted (Table 3). Sulpiride also elevated with clozapine was delayed in onset but was long-lived (Table 2). striatal DDPAC and HVA with increased 3-MT being noted at high-doses
Table Time course
of
Min
clozapine
(60 mg/kg)
DOPAC
3
actions
on mouse striatal
HVA (% of
DA metabolites
DA
3-MT
control)
15
139”
127”
109
90
30
208*
140;:
112
92
60
344”
1915:
120
61”
120
335”
226”
126*
59”
180
2 80~~
226”
124n
73”
* p CO.05
(N t 7-10)
Discussion The clinical absence of extrapyramidal side effects for clozapine is now well documented (De Maio 1972; Ackenheil et al., 1974; Gerlach et al., 1974; LaPierre et al., 1980). Similarly thioridazine (Crowley and Hydinger-Macdonald 1981) and sulpiride (Rao et al., 1981) have a lesser potential for extrapyramidal reactions than classical agents. Clozapine also possesses a unique behavioral profile in the monkey (Spealman et al ., 1983). Detailed in vivo studies have also demonstrated that tlotapine does not increase DA release in the ratsxtum (Groppetti et al., 1978; Huff and Adams 1980) and that this agent is a potent antagonist of presynaptic dopaminergic agents (Rebec et al,, 1979). Our studies using 3-MT as an index of DA release (Ponzio et al., 1981; Wood et al., 1982) also suggest that clozapine as well as thioridazine do not permit a coupling of release to the increased presynaptic DA metabolism as reflected by elevations in DOPAC (Wood et al., 1982). These inhibitory actions may well reflect the unique increases in striatal and sobstantia nigra GABA turnover elicited by these drugs but not by classical neuroleptics (Marco et al., 1978). This increase in GABAergic activity could well lead to the observed decreases in DA release (Wood, 1982b) . Sulpiride may well not be an atypical neuroleptic but merely enter the CNS to a lesser degree (Nishibe et al., 1982). Indeed, in our studies, high doses of sulpiride induce a neurochemical profile similar to the classical agents. Similarly, in the monkey, sulplride does not possess an atypical profile (Liebman et al ., 1978). In summary, our data indicate that the atypical neuroleptics clozapine and thioridazine possess a presynaptic inhibitory action on DA neurons which may be dependent upon enhanced GABAergic activity (Mao et al., 1978). In contrast, sulpiride does not appear to be an atypical agent but may cross the blood brain barrier poorly.
Acknowledgements This work was supported by the Douglas Hospital Research Centre. We wish to thank Sandoz, Endo, McNeil, Schering and Ravizza Laboratories for the generous supply of drugs used in this study. We also wish to thank J.W. Richard, M. Thakur and C. Pilapil for their expert technical assistance.
P.L. Wood et al.
768
References ACKENHEIL, M., BECKMANN, H., GREIL, W., HOFFMAN, G., MARKIANOS, E. and RAESE, J. (1974) Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. In: The Phenothiazines and Structurally Related Drugs, I.S. Forrest, C.J. Carr and E. Usdin (eds), pp 647-657. Raven Press, New York. COYLE, J.T. (1982) The clinical use of antipsychotic medications. Med. Clin. N. Am. 66: 993-1010. CROWLEY, T.J. and HYOINGER-MACDONALD, M. (1981) Motility, parkinsonism, and prolactin with thiothixene and thioridazine. Arch. Gen. Psychiat. 38: 668-675. DEMAIO, D. (1972) Clozapine, a novel major tranqui Ilizr. Clinical experiences and pharmacotherapeutic hypotheses. At-z. Forsch 22: 919-923. GERLACH, J., KOPPELHUS, P., HELWEG, E. and MONRAD, A. (1974) Clozapine and haloperidol in a Therapeutic and biochemical aspects in the treatment of single-blind cross-over trial: schizophrenia. Acta Psychiat. Stand. 50: 410-424. GROPPETTI, A., PARENTI, M., GALLI, C.L.,%GATTI, A., CATTABENI, F., DIGIULIO, A.M. and Dissociation from HVA RACAGNI, G. (1978) 3-Methoxytyramine and different neuroleptics: and DOPAC. Life Sci. 23: 1763-1768. HUFF, R.M. and ADAMS, R.K (1980) Dopamine release in N.accumbens and sttiatum by clozapine: Simultaneous monitoring by _in vivo electrochemistry. Neuropharmac. 19: 587-590. LAPIERRE, Y.D., GHADIRIAN, A., ST. LAURENT, J. and CHAUDHRY, R.P. (198v Clozapine in acute schizophrenia-efficacy and toxicity. Curr. Ther. Res. 27: 391-400. LIEBMAN, J., NEALE, R. and MAER, N.J. (1978) Differentialbehavioral effects of sulpiride in the rat and squirrel monkey. Eur. J. Pharmacol. 50: 377-383. E. (1978) Turnover rates of MARCO, E., MAO, C.C., REVUELTA, A., PERALTA, E. andTOSTA, y-aminobutyric acid in substantia nigra, N. caudatus, globus pall idus and N.accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics. Neuropharmac. 11:
589-596. DifNISHIBE, Y., MATSUO, Y., YOSHIZAKI, T., EIGYO, M., SHIOMI, T. and HIROSE, K. (1982) ferential effects of sulpiride and metoclopropamide on brain homovani llic acid levels and Naunyn-Schmied. shuttle box avoidance after systemic and intracerebral administration. Arch. Pharmac. 321: 190-194. PONZIO, F., ACHILE G., PEREGO, C. and ALGERI, S. (1981) Differential effects of certain dopaminergic drugs on the striatal concentration of dopamine metabolites with special Neuroscience Letters 27: 61-67. reference to 3-methoxytyramine. RAO, V.A.R., BAILEY, J., BISHOP, M. and COPPEN, A. (198lrA clinical and pharmacodynamic evaluation of sulpiride. Psychopharmacology 2: 77-80. REBEC, G.V., ZIMMERMAN, K.S. and ALLOWAY, K.D. (1979) Classical and atypical BASHORE, T.R., antipsychotic drugs: Differential antagonism of amphetamineand apomorphine-induced alterations of spontaneous neuronal activity in the neostriatum and nucleus accumbens. Pharmacol. Biochem. Behav. 11: 529-538. SPEALMAN, R.D., KELLEHER, R.Tz GOLDBERG, S.R., DEWEESE, J. and GOLDBERG, D.M. (1983) Behavioral effects of clozapine: Comparison with thioridazine, chlorpromazine, haloperidol and chlordiazepoxide in squirrel monkeys. J. Pharmacol. Exp. Ther. 224: 127-134. WOOD, P.L. (1982a) A selected ion monitoring assay for dopamine and itsnetabolites using negative chemical ionization. Biomed Mass Spec. 9: 302-306. WOOD, P.L. (1982b) Actions of GABAergic agents on Topamine metabolism in the nigrostriatal pathway of the rat. J. Pharmac. Exp. Ther. 222: 674-679. WOOD, P.L., NAIR, N.P.V. and BOZARTH, M. (1982rStriatal 3-methoxytyramine as an index of Effects of electrical stimulation. Neuroscience Letters 32: 291-294. dopamine release: WOOD, P.L., NAIR, N.P.V., LAL, 5. and ETIENNE, P. (1983) Buspirone: A potent=1 atypical neuroleptic. Life Sci . (in press).
Inquiries
and reprint
Dr. Paul L. Wood Douglas Hospital Verdun, Quebec H4H lR3
requests
Research
should
Centre
be addressed
to:
198.3, Vol. 7. PP. 765-768 Copyri&
DIFFBBENTIAL ACTIONS
OF CLA!SSICAL AND ATYPICAL
ON MOUSE NIGROSTIUATAL
0
027%5846183 $0.00 + 50 1983 Per3amcm Press Ltd.
NEUROLEPTICS
NEURONS
PAUL L. WOOD, PAUL S. MCQUADE, PIERRE ETIENNE, SAMARTHJI LAL AND N.P. VASAVAN NAIR Douglas
Hospital
Research
Centre,
Verdun,
Quebec
H4H lR3
(Final form, July 1983)
Abstract Etienne, Samarthji Lal and N.P. Vasavan Wood, Paul L., Paul S. McQuade, Pierre ferential actions of classical and atypical neuroleptics on mouse nigrostriatal Prog. Neuro-Psychopharmacol. 6 Biol. Psychiat. 1983, 1(4-6) :765-768.
Nair: Difneurons.
1. The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum. 2. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release. 3. At high doses, sulpi ride increases both dopamine metabolism and release. 4. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent. Keywords: nigrostriatal thioridazine, sulpiride
dopamine
metabolism,
dopamine
(CPZ); dihydroxyphenylacetic Abbreviations : chlorpromazine horovani 11 i c acid (HVA) ; 3-methoxytyrami ne (3-MT)
release,
acid
mouse,
clozapine,
(DOPAC);
dopamine
(DA);
Introduction The neurochemical differentiation of classical and atypical neuroleptics until recently has focussed on possible differential actions in the extrapyramidal and mesolimbic DA projections. However, these studies have not revealed a consistent preferential action of neuroleptics in Similarly, the potent anticholinergic actions of atypical either DA system (Coyle, 1982). neuroleptics do not explain the unique pharmacological profile of these agents (Coyle, 1982). In the present study, we have therefore evaluated the suggestion that atypical neuroleptics have an inhibitory presynaptic action on DA nerve endings (Rebec et al., 1979).
Methods Receptor binding. Brain membrane preparations from male Sprague Dawley rats were assayC3H3-spiperone, C3Hl-WB4101, C3Hl-aminoclonidine, C3Hl-ketanserin and r3HI-QNB as described previously (Wood et al., 1983).
used to binding
DA metabol i tes. Male Swiss Hauschke mice were treated tip) with neuroleptics 15 to 180 mlnutes prior to sacrifice by microwave irradiation (Wood et al., 1983). DOPAC, HVA, DA and 3-MT were subsequently assayed in striatal extracts by gas chromatography-mass fragmentography (Wood, 1982a) . Statistics.
Data were
analyzed
with
the
multiple
765
comparison
test
of
Dunnett
(Wood,
198%).
766
P.L. Wood et al.
1
Table Receptor
binding
profiles
of
neuroleptics
IC Drug
3
3
H-Spip Na
t
Na
H-WE
5.0
24
Perphenazine
6.8
6.4
14
11.3
15.1
6
Clozapine Thioridazine Sulpi
ride
303
395
14
79
17
8
173
>10,000
83
Mol indone
400
3H-ket
(42)
5.9
vitro
(nM)
3H-AC
(a(l)
Haloperidol
CPZ
50
--in
3H-QNB
(X2)
>lO ,000
960 > 1,000
(M)
132
>5,000
3.9
>5,000 286
18.4
293 >10,000
22
100
20
49
3800
>10,000
>10,000
>5,000
2300
>10,000
> 5,000
>5,000
Results Receptor binding. All the examined neuroleptics were binding (Table 1). Clozapine, thioridazine and CPZ all activity (C3Hl-QNB) . No consistent differences between regard to a(~, O(Z or Sz binding sites, were observed.
Table Actions
Drug
of
neuroleptics
on mouse
(mdkg)
DOPAC
58*
Control
4
active displacers of possessed significant classical and atypical
i3H! spi perone anticholinergic agents, with
2
striatal
DA metabolites
HVA (pmol/mg
53+
60
min
DA proteinIS
post-drug
3-MT
2
565 * 10
4.3 + .25
3" 5" 8?:
108 f
3"
486 * 12
(LoI
136 f 227 f 228 f
124 149
f f
5” 6”
429 452
f 145: + ll*
7.1 t .30" 6.5 f .ZlJ; 7.6 * .16*
Perphenazine
(I .O)
224 f
8”
149
*
6”
486
f
5”
7.6 f .35"
CPZ
(2.5)
202
f
12J:
127 +
8*
531 *
8*
5.9 f .22*
Mol i ndone
(2.5)
162
f
lO*
149 f
6"
509 f 13
8.4 f .46*
‘,%
98t 151 f
3" 5"
72 f 94*
5" 4*
510 + 15 512 f 13
4.9 f .40:: 6.4 f .31*
(IS)
224
(30)
271 f
8* 7"
121 * 111 +
5" 8*
548 f 13 510 * 15
4.6 f .21 4.3 f .30
1::;
582 6 103 f 6* 174 f 17"
60+ 66 * 95+
6 5" 8*
620 * 20 598 f 15 649 f 18
2.6
Haloperidol
Sulpi
[:.:I
ride
Thioridazine
Clozapine (60)
* p co.05;
$ Mean f
f
S.E.M.
(N = 7-10)
3.0 f .ll” +
.lO”
2.5 f .15*
Differential
effect<
of neuroleptics
on nigrostriatal
767
neurons
Haloperidol, perphenazine, CPZ and molindone all produced potent increases DA metabolism. Haloperidol and perphenazine also produced small decreases in DOPAC, HVA and 3-MT (Table 2). The atypical agents clozapine and thioridazine increased DOPAC in DA steady-state levels. and HVA but 3-MT was either not affected or decreased (Table 2). The decreased 3-MT noted (Table 3). Sulpiride also elevated with clozapine was delayed in onset but was long-lived (Table 2). striatal DDPAC and HVA with increased 3-MT being noted at high-doses
Table Time course
of
Min
clozapine
(60 mg/kg)
DOPAC
3
actions
on mouse striatal
HVA (% of
DA metabolites
DA
3-MT
control)
15
139”
127”
109
90
30
208*
140;:
112
92
60
344”
1915:
120
61”
120
335”
226”
126*
59”
180
2 80~~
226”
124n
73”
* p CO.05
(N t 7-10)
Discussion The clinical absence of extrapyramidal side effects for clozapine is now well documented (De Maio 1972; Ackenheil et al., 1974; Gerlach et al., 1974; LaPierre et al., 1980). Similarly thioridazine (Crowley and Hydinger-Macdonald 1981) and sulpiride (Rao et al., 1981) have a lesser potential for extrapyramidal reactions than classical agents. Clozapine also possesses a unique behavioral profile in the monkey (Spealman et al ., 1983). Detailed in vivo studies have also demonstrated that tlotapine does not increase DA release in the ratsxtum (Groppetti et al., 1978; Huff and Adams 1980) and that this agent is a potent antagonist of presynaptic dopaminergic agents (Rebec et al,, 1979). Our studies using 3-MT as an index of DA release (Ponzio et al., 1981; Wood et al., 1982) also suggest that clozapine as well as thioridazine do not permit a coupling of release to the increased presynaptic DA metabolism as reflected by elevations in DOPAC (Wood et al., 1982). These inhibitory actions may well reflect the unique increases in striatal and sobstantia nigra GABA turnover elicited by these drugs but not by classical neuroleptics (Marco et al., 1978). This increase in GABAergic activity could well lead to the observed decreases in DA release (Wood, 1982b) . Sulpiride may well not be an atypical neuroleptic but merely enter the CNS to a lesser degree (Nishibe et al., 1982). Indeed, in our studies, high doses of sulpiride induce a neurochemical profile similar to the classical agents. Similarly, in the monkey, sulplride does not possess an atypical profile (Liebman et al ., 1978). In summary, our data indicate that the atypical neuroleptics clozapine and thioridazine possess a presynaptic inhibitory action on DA neurons which may be dependent upon enhanced GABAergic activity (Mao et al., 1978). In contrast, sulpiride does not appear to be an atypical agent but may cross the blood brain barrier poorly.
Acknowledgements This work was supported by the Douglas Hospital Research Centre. We wish to thank Sandoz, Endo, McNeil, Schering and Ravizza Laboratories for the generous supply of drugs used in this study. We also wish to thank J.W. Richard, M. Thakur and C. Pilapil for their expert technical assistance.
P.L. Wood et al.
768
References ACKENHEIL, M., BECKMANN, H., GREIL, W., HOFFMAN, G., MARKIANOS, E. and RAESE, J. (1974) Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. In: The Phenothiazines and Structurally Related Drugs, I.S. Forrest, C.J. Carr and E. Usdin (eds), pp 647-657. Raven Press, New York. COYLE, J.T. (1982) The clinical use of antipsychotic medications. Med. Clin. N. Am. 66: 993-1010. CROWLEY, T.J. and HYOINGER-MACDONALD, M. (1981) Motility, parkinsonism, and prolactin with thiothixene and thioridazine. Arch. Gen. Psychiat. 38: 668-675. DEMAIO, D. (1972) Clozapine, a novel major tranqui Ilizr. Clinical experiences and pharmacotherapeutic hypotheses. At-z. Forsch 22: 919-923. GERLACH, J., KOPPELHUS, P., HELWEG, E. and MONRAD, A. (1974) Clozapine and haloperidol in a Therapeutic and biochemical aspects in the treatment of single-blind cross-over trial: schizophrenia. Acta Psychiat. Stand. 50: 410-424. GROPPETTI, A., PARENTI, M., GALLI, C.L.,%GATTI, A., CATTABENI, F., DIGIULIO, A.M. and Dissociation from HVA RACAGNI, G. (1978) 3-Methoxytyramine and different neuroleptics: and DOPAC. Life Sci. 23: 1763-1768. HUFF, R.M. and ADAMS, R.K (1980) Dopamine release in N.accumbens and sttiatum by clozapine: Simultaneous monitoring by _in vivo electrochemistry. Neuropharmac. 19: 587-590. LAPIERRE, Y.D., GHADIRIAN, A., ST. LAURENT, J. and CHAUDHRY, R.P. (198v Clozapine in acute schizophrenia-efficacy and toxicity. Curr. Ther. Res. 27: 391-400. LIEBMAN, J., NEALE, R. and MAER, N.J. (1978) Differentialbehavioral effects of sulpiride in the rat and squirrel monkey. Eur. J. Pharmacol. 50: 377-383. E. (1978) Turnover rates of MARCO, E., MAO, C.C., REVUELTA, A., PERALTA, E. andTOSTA, y-aminobutyric acid in substantia nigra, N. caudatus, globus pall idus and N.accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics. Neuropharmac. 11:
589-596. DifNISHIBE, Y., MATSUO, Y., YOSHIZAKI, T., EIGYO, M., SHIOMI, T. and HIROSE, K. (1982) ferential effects of sulpiride and metoclopropamide on brain homovani llic acid levels and Naunyn-Schmied. shuttle box avoidance after systemic and intracerebral administration. Arch. Pharmac. 321: 190-194. PONZIO, F., ACHILE G., PEREGO, C. and ALGERI, S. (1981) Differential effects of certain dopaminergic drugs on the striatal concentration of dopamine metabolites with special Neuroscience Letters 27: 61-67. reference to 3-methoxytyramine. RAO, V.A.R., BAILEY, J., BISHOP, M. and COPPEN, A. (198lrA clinical and pharmacodynamic evaluation of sulpiride. Psychopharmacology 2: 77-80. REBEC, G.V., ZIMMERMAN, K.S. and ALLOWAY, K.D. (1979) Classical and atypical BASHORE, T.R., antipsychotic drugs: Differential antagonism of amphetamineand apomorphine-induced alterations of spontaneous neuronal activity in the neostriatum and nucleus accumbens. Pharmacol. Biochem. Behav. 11: 529-538. SPEALMAN, R.D., KELLEHER, R.Tz GOLDBERG, S.R., DEWEESE, J. and GOLDBERG, D.M. (1983) Behavioral effects of clozapine: Comparison with thioridazine, chlorpromazine, haloperidol and chlordiazepoxide in squirrel monkeys. J. Pharmacol. Exp. Ther. 224: 127-134. WOOD, P.L. (1982a) A selected ion monitoring assay for dopamine and itsnetabolites using negative chemical ionization. Biomed Mass Spec. 9: 302-306. WOOD, P.L. (1982b) Actions of GABAergic agents on Topamine metabolism in the nigrostriatal pathway of the rat. J. Pharmac. Exp. Ther. 222: 674-679. WOOD, P.L., NAIR, N.P.V. and BOZARTH, M. (1982rStriatal 3-methoxytyramine as an index of Effects of electrical stimulation. Neuroscience Letters 32: 291-294. dopamine release: WOOD, P.L., NAIR, N.P.V., LAL, 5. and ETIENNE, P. (1983) Buspirone: A potent=1 atypical neuroleptic. Life Sci . (in press).
Inquiries
and reprint
Dr. Paul L. Wood Douglas Hospital Verdun, Quebec H4H lR3
requests
Research
should
Centre
be addressed
to: