BIOL PSYCHIATRY 1992;31:827-831
827
Effect of Substituted Benzamides on Prolactin Secretion in the Rat Tatsuya Kakigi, Kiyoshi Maeda, Kenji Tanimoto, Hiroyuki Kaneda, and Takeshi Shintani Introduction Dopamine regulates the release of prolactin from the anterior pituitary via its receptor on the lactotroph (Meites and Clemens 1972). The prolactin receptor appears to be of the D2 type, as few DI receptors actually exist in the anterior pituitary and Dt probes fail to modulate prolactin release (Kaneda et al 1989). In addition, !)2 agonists reduce plasma prolactin levels and !)2 antagonists increase them. Sulpiride is a substituted benzamide with predominantly D2 activity, that is a potent stimulator of prolactin release in ~mimals (Debeljuk et al 1975). Moreover, when used in humans, it frequently elicits hyperprolactinemia with galactorrhea amenorrhea (Buvat et al 1978). The latter change is a particulary troublesome side effect of sulpiride use (Salminen and Lehtonen 1980). Sultopride and tiapride are substituted benzamides structurally related to sulpiride that are used clinically as neuroleptics. Sultopride is usually prescribed for mania and schizophrenia, while tiapride is often used in the treatment of emotional disturbances and abnormal behavior in the elderly. Tiapride has also been demonstrated to be effective in the treatment of dyskinesia (Price et al 1978; Lees et al 1979). In the present study, we compared the potency of sultopride and tiapride in promoting prolactin secretion with that of sulpiride. The stereospecificity of the effect of sulpiride on prolactin secretion in unanesthetized freely moving rats was examined.
Methods Male Wistar rats weighing 250-300 g were housed one per case at a temperature of 22 - 2°C with a 12-hr light--dark cycle, food and water were available ad libitum. An indwelling right atrial catheter was implanted according to the method described previously (Tanimoto et al 1981) and was kept patent with heparinized PVP solution. After catheterization, the animals were allowed to regain their preaperative weight (7-10 days) before subsequent experimentation. Drags were administered in a volume of I ml/kg intravenously at three doses (0.01,
From the Departmentof Psychiatry, Kobe University School of Medicine, Kobe CrK, KT, IlK, TS), and Hyogo Institute of Clinical Research (KM), Himeji, Japan. Address reprint requests to Kiyoshi Maeda, MD, Hyogo Instituteof Clinical Research, 520 Saisho-kou,Himeji, 670 Japan. Received January 17, 1991; revised December 10, 1991. Present address (TK): Maryland PsychiatricResearch Center, Universityof Maryland, College Park, MD. © 1992 Society of BiologicalPsychiatry
0006-3223/92/$05.00
828
BIOL PSYCHIATRY 1992;31:827-831
T. Kakigi et al
0.03, and 0.1 mg/kg) through the indwelling catheter without anesthesia and with minimal stress. The drugs used were as follows: (-)-sulphide, racemic sulphide, tiapride (Fujisawa Co., Japan) and sultopride (Mitsui Pharm. Co., Japan). All experiments began between 10:00 ana 11:00 AM. Blood samples were taken at - 15, 0, 15, 30, and 60 min after the IV administration of drugs, and were heparinized and centrifuged at 4°C. The blood sample volume was 0.6 ml. After separation of plasma, the blood cells were suspended in the same volume of saline and returned to ~he s e r e animal after the subsequent blood savn~ple was collected. Plasma prolactin was measured b~', a specific radioimmunoassay using rat prolactin antibody and standards provided by the NIDDK (Maeda and Frohman 1978). ~2SI-prolactin was purchased from Amersham (USA). The intraassay and interassay variances were 3.6% and 7.1%, respectively. The preinjection plasma prolactin level was obtained as a mean of the - 15 and 0 min plasma samples. The net prolactin increment indicates the difference between the preinjection prolactin level and that at 15 min after IV injection of a drug, because the peak plasma prolactin level was always obtained 15 min alter administration. ED2oowas defined as the dose that increases the plasma prolactin level to twice the preinjection level, and was estimated from the linear portion of the dose-response curve. The data was analyzed statistically by Student's t-test. Results Prolactin levels after ( -)-sulphide administration were significantly elevated at all doses tested when compared to the preinjection level. Similarly, any doses of sultopride significantly elevated the plasma prolactin level from the pleinjection baseline, with a prolonged increase observed following the highest dose. A significant rise in plasma prolactin was obtained with the two higher doses of racemic sulphide (0.03 and 0.1 mg/kg), but not with the dose of 0.01 mg/kg. Tiapride induced a modest but significant increase in plasma prolactin only at the highest dose (Figure 1). Because there was no significant difference in the prolactin increment produced by 0.03 and 0. l mg/kg of ( -)-sulpiride, the net prolactin increment appeared to have almost reached its upper limit with the highest dose of (-)-sulphide. Following sultopfide or racemic sulphide, dose-related and significant changes in the net prolactin increment were found between theses doses. The ED20o was 3.4 gg/kg for ( - )-sulphide, 7.5 pLg/kg for sultopride, 25.1 p~g/kg for racemic sulphide, and 99.4 ~tg/kg for tiapride. Thus, (-)-sulpiride was most potent in producing increases in the plasma prolactin. Sultopride was more potent than racemic sulphide, and tiapride was least potent in prolactin release among the four substituted benzamides examined. Discussion We showed a stimulatory effect of sultopride and tiapride, as well as sulphide, on prolactin secretion in the rat. Their rank order of potency was (-)-sulphide, sultopride, racemic sulphide, and tiapride. (-)-Sulphide was eight times more potent than racemic sulphide in elevating the plasma prolactin level. Sulphide preparation used in this study contained the same amount of the (4-)- and (-)-enantiomers. Although we did not specifically examine the potency
Substituted Benzamides and Prolactin
BIOLPSYCHIATRY 1992;31:827-831
(-)-8ULPXRZDE
PRL, n g l m l
1507
i00
I00
inj. I
50
~ 0
0"1" -15
T'-kk
m 15
**
i
n 30
45
60
0~ ~ , -15 0
150
100"
i00
50
0~ -15
1",
i 15
, 30
, 45
,min 60
, 45
--rain 60
TZAPRZDE
**
ml.
m 0
, 15
PRL, ng/ml
150"
b
•
50
8ULTOPRZDB
PRL, n,glml
8ULPZRIDE
PRL, n g l n l
150'1
829
n 30
50
--
45
60
f
-15
~
1_--
|
-|
|
0
15
30
Figure 1. Effect of four substituted benzamides [(- )-sulpiride, sultopride, sulpiride, and tiapride) on prolactin secretion at three different doses in freely moving rats. --O--, --I-, and --[}- represent doses of 0.01, 0.03, and 0.1 mg/kg, respectively. Vertical bars show the SEM. * and ** represent p < 0.05 and p < 0.01, respectively.
of (+)-suipiride, it might be less potent in stimulating prolactin release than the other enantiomer. The reduced effect of racemic sulpiride on prolactin secretion was probably due to dilution. Orally administe~d (-)-sultopride has been reported to be 30 to 100 times as potent as (+)-sultopride in its effect on prolactin secretion in rats (Mizuchi et al 1984). If (+)-sulphide has no ability to release prolactin at all, the potency of (-)-sulpiride should theoretically be twice that of racemic sulpiride, and the reason for this discrepancy remains unclear. However, (-)-sulpiride has been demonstrated to be twice as potent as racemic sulpiride and 50 times more active than (+)-sulpiride in a [3H]spiperone binding study using rat striatal membranes (Mizuchi et al 1982). We demonstrated here that sultopride was 3-4 times more potent than sulpiride in stimulating prolactin. This is consistent with the estimate by Mizuchi et al (1984) that sultopride had a 4 - 6 times lower potency than sulpiride. Mizuchi et all (1982) showed
830
BIOLPSYCHIATRY 1992;31:827-831
T. Kakigi et al
in a binding study with [3H]spiperone that sulphide had only 25% of the affinity of sultopride for the D2 receptor. Tiapride had 25% of the effect of sulphide and 7-8% of that of sultopride on prolactin secretion in this study. In human studies (L'Hermite et al 1978), tiapride has approximately 50% of the potency of sultopride when given intramuscularly. The discrepancy between these studies may be due to either the very high doses of drugs administered (sultopride: 1.5 mg/kg; tiapride: 3.0 mg/kg) or the difference in the way of drug administration. A very high dose of these drugs stimulates prolactin secretion maximally so that a dose-response relationship cannot be observed (Mizuchi et al 1984). Effect of tiapride on prolactin secretion was one-fourth of that of sulphide in the present study. This result is in agreement with a finding reported by Apud et al (1987) that tiapride inhibits [3H]spiperone binding to rat pituitary membranes with an affinity 5-7 times lower than that of sulphide. Thus, chronic treatment with sultopfide would seem to be likely to elicit the galactorrhea-amenorrhea syndrome more frequently than treatment with sulpiride. However, it has been demonstrated that amenorrhea actually occurs in 13.8% and 12.0% of the female patients receiving sultopride and sulpiride, respectively (Kudoh et al 1986). In the present study, the substituted benzamides were administered to rats by acute IV injection. In contrast, these compounds are usually administered orally and chronically to patients. The metabolism of these drugs in humans may also differ from its metabolism in rats. Administration of the highest dose of sultopride caused a prolonged elevation of the plasma prolactin level, which was not seen following administration of the most potent prolactin releaser, (-)-sulphide. This prolonged effect of sultopride on prolactin release might be relevant to the occurrence of galactorrhea-amenorrbea syndrome. A long-lasting effect of sultopride on prolactin secretion was previously reported in rats (Mizuchi et al 1984) and in humans (L'Hermite et al 1978), and was not seen with sulphide or tiapride. The half-lives of sultopride and racemic sulpiride were approximatey 1. i and 1.3 hr, respectively, when doses of 100 mg/kg were administered intraperitoneally to rats (Mizuchi et al 1983). Thus, the present results obtained in rats may not be easily extrapolated to humans. The substituted benzamides are considered to stimulate prolactin secretion by blocking pituitary dopamine receptors. These compounds are reported to be without any effect on prolactin release in the absence of dopamine in vitro and to reverse the inhibition of prolactin secretion by dopamine from the rat anterior pituitary in vitro (L'Hermite et al 1978). Their potency in promoting prolactin secretion is considered to be correlated with their D2 receptor-blocking effect. These results therefore indicate that (-)-sulpiride, sultopride, racemic sulphide, and tiapride in this order, possess the potency to act as receptor blockers on the pituitary D2 receptor. We appreciate NIDDK for the generous gift of the rat prolactin kit. We also express our thanks to Fujisawa Co. and Mitsui Pharm. Co. for providing the drags used in the present study. We also thank Dr. Carol A. Tammin~a for reviewing the manuscript.
References Apud JA, Masotto C, Monopoli A, Ongini E, Rovescalli AC, Racagni (3 (1987): Effects of repeated
tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat. Pharmacol Res Comm 19:119.
Buvat J, Thomas K, Racodot A, Blacker C, Ferin F, Inquette M (1978): Changes in pituitary
Substituted Benzamides and Prolactin
PSYCHIATRY 1992;31:827-831
BIOL
831
gonadotropins during the amenorrhoea-galactorrhoeasyndrome due to sulphide. Clin Endocrinol 9:499. Debeljuk L, Rozados R, Daskal H, Velez CV, Mancini AM (1975): Acute and chronic effects of sulphide on serum prolactin and gonadotropin levels in castrated male rats. Proc Soc Exp Biol Med 148:550. Kancda H, Shintani T, Takigi T, Terada T, Tanimoto K (1989): Comparison of prolactin responses to D-I and D-2 antagonists in rats: Ro 22-1319 is a potent D-2 antagonist. Biol Psychiatry 25:517. Kudoh Y, lchimaru S, Kawakita Y, et al (1986): A double-blind evaluation of sultopride (MS5024) vs sulpir~de for the treatment of schizophrenia (in Japanese). Psychiatry ($eishin-igaku) 28:803. Lees Aj, Lander CM, Storn GM (1979): Tiapride in levodopa-induced involuntary movements. J Neurol Neuro~ur& Psychiatry 42:380. L'Hermite M, MacLeod RM, Robyn C (1978): Effects of two substituted benzamides, tiapdde and sultopride, on gonadotropins and prolactin. Acta Endocrinol 89:29. Maeda K, Frohman LA (1978): Dissociation of systemic and central effects of neurotensin on the secretion of growth hormone, prolactin and thyrotmpin. Endocrinology 103:1903. Meites J, Clemens J (1972): Hypothalamic control of prolactin secretion. Vitam Horm 30:165. Mizuchi A, Kitagawa N, Samta S, Miyachi Y (1982): Characteristics of 3H-sultopride binding to rat brain. Fur J Pharmacol 84:51. Mizuchi A, Kitagawa N, Miyachi Y (1983): Regional distribution of sulphide in rat brain measured by radioimmunoassay. Psychopharmacology 81:195. Mizuchi A, Kitagawa N, Saruta S, Tokuda H, Miyachi Y (1984): Effect of sultopride on prolactin secretion in rats. Arch lnt Pharmacodyn Ther 267:232. Price P, Parkes JD, Marsden CD (1978): Tiapride in Parkinson's disease. Lancet 2:1106. Salminen JK, Lehtonen V (1980): Sulphide in depression: Plasma levels and Effects. Curt ?'her Res 27:109. Tanimoto K, Maeda K, Chihara K (1981): Inhibition by lithium of dopamine receptors in rat prolactin release. Brain Res 223:335.
827
Effect of Substituted Benzamides on Prolactin Secretion in the Rat Tatsuya Kakigi, Kiyoshi Maeda, Kenji Tanimoto, Hiroyuki Kaneda, and Takeshi Shintani Introduction Dopamine regulates the release of prolactin from the anterior pituitary via its receptor on the lactotroph (Meites and Clemens 1972). The prolactin receptor appears to be of the D2 type, as few DI receptors actually exist in the anterior pituitary and Dt probes fail to modulate prolactin release (Kaneda et al 1989). In addition, !)2 agonists reduce plasma prolactin levels and !)2 antagonists increase them. Sulpiride is a substituted benzamide with predominantly D2 activity, that is a potent stimulator of prolactin release in ~mimals (Debeljuk et al 1975). Moreover, when used in humans, it frequently elicits hyperprolactinemia with galactorrhea amenorrhea (Buvat et al 1978). The latter change is a particulary troublesome side effect of sulpiride use (Salminen and Lehtonen 1980). Sultopride and tiapride are substituted benzamides structurally related to sulpiride that are used clinically as neuroleptics. Sultopride is usually prescribed for mania and schizophrenia, while tiapride is often used in the treatment of emotional disturbances and abnormal behavior in the elderly. Tiapride has also been demonstrated to be effective in the treatment of dyskinesia (Price et al 1978; Lees et al 1979). In the present study, we compared the potency of sultopride and tiapride in promoting prolactin secretion with that of sulpiride. The stereospecificity of the effect of sulpiride on prolactin secretion in unanesthetized freely moving rats was examined.
Methods Male Wistar rats weighing 250-300 g were housed one per case at a temperature of 22 - 2°C with a 12-hr light--dark cycle, food and water were available ad libitum. An indwelling right atrial catheter was implanted according to the method described previously (Tanimoto et al 1981) and was kept patent with heparinized PVP solution. After catheterization, the animals were allowed to regain their preaperative weight (7-10 days) before subsequent experimentation. Drags were administered in a volume of I ml/kg intravenously at three doses (0.01,
From the Departmentof Psychiatry, Kobe University School of Medicine, Kobe CrK, KT, IlK, TS), and Hyogo Institute of Clinical Research (KM), Himeji, Japan. Address reprint requests to Kiyoshi Maeda, MD, Hyogo Instituteof Clinical Research, 520 Saisho-kou,Himeji, 670 Japan. Received January 17, 1991; revised December 10, 1991. Present address (TK): Maryland PsychiatricResearch Center, Universityof Maryland, College Park, MD. © 1992 Society of BiologicalPsychiatry
0006-3223/92/$05.00
828
BIOL PSYCHIATRY 1992;31:827-831
T. Kakigi et al
0.03, and 0.1 mg/kg) through the indwelling catheter without anesthesia and with minimal stress. The drugs used were as follows: (-)-sulphide, racemic sulphide, tiapride (Fujisawa Co., Japan) and sultopride (Mitsui Pharm. Co., Japan). All experiments began between 10:00 ana 11:00 AM. Blood samples were taken at - 15, 0, 15, 30, and 60 min after the IV administration of drugs, and were heparinized and centrifuged at 4°C. The blood sample volume was 0.6 ml. After separation of plasma, the blood cells were suspended in the same volume of saline and returned to ~he s e r e animal after the subsequent blood savn~ple was collected. Plasma prolactin was measured b~', a specific radioimmunoassay using rat prolactin antibody and standards provided by the NIDDK (Maeda and Frohman 1978). ~2SI-prolactin was purchased from Amersham (USA). The intraassay and interassay variances were 3.6% and 7.1%, respectively. The preinjection plasma prolactin level was obtained as a mean of the - 15 and 0 min plasma samples. The net prolactin increment indicates the difference between the preinjection prolactin level and that at 15 min after IV injection of a drug, because the peak plasma prolactin level was always obtained 15 min alter administration. ED2oowas defined as the dose that increases the plasma prolactin level to twice the preinjection level, and was estimated from the linear portion of the dose-response curve. The data was analyzed statistically by Student's t-test. Results Prolactin levels after ( -)-sulphide administration were significantly elevated at all doses tested when compared to the preinjection level. Similarly, any doses of sultopride significantly elevated the plasma prolactin level from the pleinjection baseline, with a prolonged increase observed following the highest dose. A significant rise in plasma prolactin was obtained with the two higher doses of racemic sulphide (0.03 and 0.1 mg/kg), but not with the dose of 0.01 mg/kg. Tiapride induced a modest but significant increase in plasma prolactin only at the highest dose (Figure 1). Because there was no significant difference in the prolactin increment produced by 0.03 and 0. l mg/kg of ( -)-sulpiride, the net prolactin increment appeared to have almost reached its upper limit with the highest dose of (-)-sulphide. Following sultopfide or racemic sulphide, dose-related and significant changes in the net prolactin increment were found between theses doses. The ED20o was 3.4 gg/kg for ( - )-sulphide, 7.5 pLg/kg for sultopride, 25.1 p~g/kg for racemic sulphide, and 99.4 ~tg/kg for tiapride. Thus, (-)-sulpiride was most potent in producing increases in the plasma prolactin. Sultopride was more potent than racemic sulphide, and tiapride was least potent in prolactin release among the four substituted benzamides examined. Discussion We showed a stimulatory effect of sultopride and tiapride, as well as sulphide, on prolactin secretion in the rat. Their rank order of potency was (-)-sulphide, sultopride, racemic sulphide, and tiapride. (-)-Sulphide was eight times more potent than racemic sulphide in elevating the plasma prolactin level. Sulphide preparation used in this study contained the same amount of the (4-)- and (-)-enantiomers. Although we did not specifically examine the potency
Substituted Benzamides and Prolactin
BIOLPSYCHIATRY 1992;31:827-831
(-)-8ULPXRZDE
PRL, n g l m l
1507
i00
I00
inj. I
50
~ 0
0"1" -15
T'-kk
m 15
**
i
n 30
45
60
0~ ~ , -15 0
150
100"
i00
50
0~ -15
1",
i 15
, 30
, 45
,min 60
, 45
--rain 60
TZAPRZDE
**
ml.
m 0
, 15
PRL, ng/ml
150"
b
•
50
8ULTOPRZDB
PRL, n,glml
8ULPZRIDE
PRL, n g l n l
150'1
829
n 30
50
--
45
60
f
-15
~
1_--
|
-|
|
0
15
30
Figure 1. Effect of four substituted benzamides [(- )-sulpiride, sultopride, sulpiride, and tiapride) on prolactin secretion at three different doses in freely moving rats. --O--, --I-, and --[}- represent doses of 0.01, 0.03, and 0.1 mg/kg, respectively. Vertical bars show the SEM. * and ** represent p < 0.05 and p < 0.01, respectively.
of (+)-suipiride, it might be less potent in stimulating prolactin release than the other enantiomer. The reduced effect of racemic sulpiride on prolactin secretion was probably due to dilution. Orally administe~d (-)-sultopride has been reported to be 30 to 100 times as potent as (+)-sultopride in its effect on prolactin secretion in rats (Mizuchi et al 1984). If (+)-sulphide has no ability to release prolactin at all, the potency of (-)-sulpiride should theoretically be twice that of racemic sulpiride, and the reason for this discrepancy remains unclear. However, (-)-sulpiride has been demonstrated to be twice as potent as racemic sulpiride and 50 times more active than (+)-sulpiride in a [3H]spiperone binding study using rat striatal membranes (Mizuchi et al 1982). We demonstrated here that sultopride was 3-4 times more potent than sulpiride in stimulating prolactin. This is consistent with the estimate by Mizuchi et al (1984) that sultopride had a 4 - 6 times lower potency than sulpiride. Mizuchi et all (1982) showed
830
BIOLPSYCHIATRY 1992;31:827-831
T. Kakigi et al
in a binding study with [3H]spiperone that sulphide had only 25% of the affinity of sultopride for the D2 receptor. Tiapride had 25% of the effect of sulphide and 7-8% of that of sultopride on prolactin secretion in this study. In human studies (L'Hermite et al 1978), tiapride has approximately 50% of the potency of sultopride when given intramuscularly. The discrepancy between these studies may be due to either the very high doses of drugs administered (sultopride: 1.5 mg/kg; tiapride: 3.0 mg/kg) or the difference in the way of drug administration. A very high dose of these drugs stimulates prolactin secretion maximally so that a dose-response relationship cannot be observed (Mizuchi et al 1984). Effect of tiapride on prolactin secretion was one-fourth of that of sulphide in the present study. This result is in agreement with a finding reported by Apud et al (1987) that tiapride inhibits [3H]spiperone binding to rat pituitary membranes with an affinity 5-7 times lower than that of sulphide. Thus, chronic treatment with sultopfide would seem to be likely to elicit the galactorrhea-amenorrhea syndrome more frequently than treatment with sulpiride. However, it has been demonstrated that amenorrhea actually occurs in 13.8% and 12.0% of the female patients receiving sultopride and sulpiride, respectively (Kudoh et al 1986). In the present study, the substituted benzamides were administered to rats by acute IV injection. In contrast, these compounds are usually administered orally and chronically to patients. The metabolism of these drugs in humans may also differ from its metabolism in rats. Administration of the highest dose of sultopride caused a prolonged elevation of the plasma prolactin level, which was not seen following administration of the most potent prolactin releaser, (-)-sulphide. This prolonged effect of sultopride on prolactin release might be relevant to the occurrence of galactorrhea-amenorrbea syndrome. A long-lasting effect of sultopride on prolactin secretion was previously reported in rats (Mizuchi et al 1984) and in humans (L'Hermite et al 1978), and was not seen with sulphide or tiapride. The half-lives of sultopride and racemic sulpiride were approximatey 1. i and 1.3 hr, respectively, when doses of 100 mg/kg were administered intraperitoneally to rats (Mizuchi et al 1983). Thus, the present results obtained in rats may not be easily extrapolated to humans. The substituted benzamides are considered to stimulate prolactin secretion by blocking pituitary dopamine receptors. These compounds are reported to be without any effect on prolactin release in the absence of dopamine in vitro and to reverse the inhibition of prolactin secretion by dopamine from the rat anterior pituitary in vitro (L'Hermite et al 1978). Their potency in promoting prolactin secretion is considered to be correlated with their D2 receptor-blocking effect. These results therefore indicate that (-)-sulpiride, sultopride, racemic sulphide, and tiapride in this order, possess the potency to act as receptor blockers on the pituitary D2 receptor. We appreciate NIDDK for the generous gift of the rat prolactin kit. We also express our thanks to Fujisawa Co. and Mitsui Pharm. Co. for providing the drags used in the present study. We also thank Dr. Carol A. Tammin~a for reviewing the manuscript.
References Apud JA, Masotto C, Monopoli A, Ongini E, Rovescalli AC, Racagni (3 (1987): Effects of repeated
tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat. Pharmacol Res Comm 19:119.
Buvat J, Thomas K, Racodot A, Blacker C, Ferin F, Inquette M (1978): Changes in pituitary
Substituted Benzamides and Prolactin
PSYCHIATRY 1992;31:827-831
BIOL
831
gonadotropins during the amenorrhoea-galactorrhoeasyndrome due to sulphide. Clin Endocrinol 9:499. Debeljuk L, Rozados R, Daskal H, Velez CV, Mancini AM (1975): Acute and chronic effects of sulphide on serum prolactin and gonadotropin levels in castrated male rats. Proc Soc Exp Biol Med 148:550. Kancda H, Shintani T, Takigi T, Terada T, Tanimoto K (1989): Comparison of prolactin responses to D-I and D-2 antagonists in rats: Ro 22-1319 is a potent D-2 antagonist. Biol Psychiatry 25:517. Kudoh Y, lchimaru S, Kawakita Y, et al (1986): A double-blind evaluation of sultopride (MS5024) vs sulpir~de for the treatment of schizophrenia (in Japanese). Psychiatry ($eishin-igaku) 28:803. Lees Aj, Lander CM, Storn GM (1979): Tiapride in levodopa-induced involuntary movements. J Neurol Neuro~ur& Psychiatry 42:380. L'Hermite M, MacLeod RM, Robyn C (1978): Effects of two substituted benzamides, tiapdde and sultopride, on gonadotropins and prolactin. Acta Endocrinol 89:29. Maeda K, Frohman LA (1978): Dissociation of systemic and central effects of neurotensin on the secretion of growth hormone, prolactin and thyrotmpin. Endocrinology 103:1903. Meites J, Clemens J (1972): Hypothalamic control of prolactin secretion. Vitam Horm 30:165. Mizuchi A, Kitagawa N, Samta S, Miyachi Y (1982): Characteristics of 3H-sultopride binding to rat brain. Fur J Pharmacol 84:51. Mizuchi A, Kitagawa N, Miyachi Y (1983): Regional distribution of sulphide in rat brain measured by radioimmunoassay. Psychopharmacology 81:195. Mizuchi A, Kitagawa N, Saruta S, Tokuda H, Miyachi Y (1984): Effect of sultopride on prolactin secretion in rats. Arch lnt Pharmacodyn Ther 267:232. Price P, Parkes JD, Marsden CD (1978): Tiapride in Parkinson's disease. Lancet 2:1106. Salminen JK, Lehtonen V (1980): Sulphide in depression: Plasma levels and Effects. Curt ?'her Res 27:109. Tanimoto K, Maeda K, Chihara K (1981): Inhibition by lithium of dopamine receptors in rat prolactin release. Brain Res 223:335.
