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Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment
European Journal of Pharmacology, 65 (1980) 455--456 © Elsevier/North-Holland Biomedical Press
455
Rapid communication HYPOPHYSECTOMY PREVENTS THE STRIATAL DOPAMINE RECEPTOR SUPERSENSITIVITY PRODUCED BY CHRONIC HALOPERIDOL TREATMENT
ROBERT E. HRUSKA, LYNN M. LUDMER and ELLEN K. SILBERGELD Neurotoxicology Section, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Building 36, Room 4A22, Bethesda MD 20205, U.S.A. Received 1 July 1980, accepted 8 July 1980
Haloperidol (HAL) blocks dopamine (DA) receptors in the striatum and pituitary. When rats are chronically treated with HAL, the DA receptors in the striatum are increased in number (Butt et al., 1977). This is thought to be a compensatory response to the chronic block of these receptors. The block of the pituitary DA receptors alters the levels of some hormones, which includes an elevation in the release of prolactin. In order to determine the role of pituitary secretions on the striatal DA receptors, we examined the effect of chronic HAL treatment in rats after hypophysectomy (Hypox). Male rats were obtained from Taconic Farms on the day after Hypox. These rats were maintained on a drinking solution, which contained 5% dextrose and a balanced salt solution (203 mg% NaC1, 8.3 mg% KC1, 3.5 mg% CaC12 and 1.7 mg% MgC12), and housed at 25°C, the warmest part of the animal room. At the same time a group of weightmatched control rats were obtained and housed in the same area. The experiment was initiated on the second day after Hypox. Onehalf of the control rats and one-half of the Hypox rats were injected daily, i.p., with 1.0 mg/kg HAL for 3 weeks. The remaining rats were injected with saline. Then treatment was discontinued for one week before decapitation. The skull was inspected to insure that removal of the pituitary in Hypox rats had been complete. DA receptors were measured in the striata using [3H]spiroperidol in our
routine assay procedure (Hruska and Silbergeld, 1980). As shown in table 1, the tissue from the control rats had the expected increase in the number of striatal DA receptors after chronic HAL treatment, while the DA affinity for the ligand was unchanged. Hypox, by itself, did not alter the number or the affinity of the DA receptors. However, Hypox did prevent the development of striatal DA receptor supersensitivity normally produced by chronic HAL, while the receptor affinity was again unchanged. It should be noted that during the 4 weeks of this experiment, the Hypox rats either did not gain or lost weight, while the control rats gained an average of 130 g. Chronic HAL treatment did not appear to affect weight gain in either treatment group. Failure to gain weight did not affect the striatal DA receptors, since the Hypox rats injected with saline had the same number and aff~mity of DA receptors as did control rats injected with saline.
This experiment suggests that the striatal DA receptor supersensitivity produced by chronic HAL treatment depends on the presence of the pituitary. The possibility is not excluded that HAL acts directly on the striatum, but the results do suggest that HAL requires a pituitary factor. This factor could act alone without HAL, act in conjunction with HAL, or alter still another factor which might modulate the striatal response to HAL.
456 TABLE 1 Effect of chronic treatment wit.h haloperidol on striatal dopamine receptors. Each group o f rats, control (Con) or hypophysectomy (Hypox), was divided equally and treated chronically with either saline (Sal) or haloperidol (Hal) as described in the text. The dissociation constant (KD) and maximum number of binding sites (Braax) were determined by linear regression analyses of Scatchard plots which were obtained from seven concentrations of [ 3H ]spiroperidol. Group
n
K D (pM)
Bmax (fmol]mg protein)
ABmax (%)
Con-Sal Con-Hal
6 6
9.82 + 0.69 12.33 -+ 1.56
374 + 19 480 -+ 19 1
-+28.3
Hypox-Sal Hypox-Hal
5 5
11.86 + 0.77 8.93 + 1.34
381 + 27 392 + 32
+2.9
I Significantly increased compared to the Con-Sal group, P < 0.005 by Student's t-test.
If indeed a pituitary factor were required, it could be prolactin, since HAL increases prolactin levels in control rats (Clemens et al., 1974), while in Hypox rats there is no question of prolactin release. Hormones of pituitary or target cell origin can have a wide variety of effects on many functions. While sex hormones are well known to affect hypothalamic function (Miillet et al., 1977), the interaction of these hormones with striatal receptors is only a recent finding (Hruska and Silbergeld, 1980). Estrogen treatment of male rats increases the number of striatal DA receptors and increases prolactin levels. Likewise, HAL treatment of male rats increases the number of striatal DA receptors and increases prolactin levels. The increases produced by estrogen or HAL can be blocked by Hypox. These results suggest, therefore, that prolactin may be involved in the development of striatal DA receptor supersensitivity. Clinically, neuroleptics, such as HAL, are chronically administered in the treatment of schizophrenia. Prolonged neuroleptic treatm e n t is associated with the occurrence of tardive dyskinesia, possibly resulting from the development of supersensitive DA receptors in the striatum (Klawans, 1973). Since neuroleptic treatment elevates prolactin levels, it is
tempting to propose that prolactin is a necessaw] factor for the expression of this type of striatal supersensitivity and may be involved in the development of tardive dyskinesia. Further examination of this hypothesis could be of value.
Acknowledgement We thank Terese O'Brien for the preparation of this manuscript.
References Butt, D.R., I. Creese and S.H. Snyder, 1977, Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain, Science 196, 326. Clemens, J.A., E.B. Smalstig and B.D. Sawyer, 1974, Antipsychotic drugs stimulate prolactin release, Psychopharmacologia 4 0 , 1 2 3 . Hruska, R.E. and E.K. Silbergeld, 1980, Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum, European J. Pharmacol. 61, 397. Klawans, H.L., 1973, The Pharmacology of Extrapyramidal Movement Disorders (Karger, Basel). Miiller, E.E., G. Nistico and U. Scapagnini, 1977, Neurotransmitters and Anterior Pituitary Function (Academic Press, New York).
455
Rapid communication HYPOPHYSECTOMY PREVENTS THE STRIATAL DOPAMINE RECEPTOR SUPERSENSITIVITY PRODUCED BY CHRONIC HALOPERIDOL TREATMENT
ROBERT E. HRUSKA, LYNN M. LUDMER and ELLEN K. SILBERGELD Neurotoxicology Section, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Building 36, Room 4A22, Bethesda MD 20205, U.S.A. Received 1 July 1980, accepted 8 July 1980
Haloperidol (HAL) blocks dopamine (DA) receptors in the striatum and pituitary. When rats are chronically treated with HAL, the DA receptors in the striatum are increased in number (Butt et al., 1977). This is thought to be a compensatory response to the chronic block of these receptors. The block of the pituitary DA receptors alters the levels of some hormones, which includes an elevation in the release of prolactin. In order to determine the role of pituitary secretions on the striatal DA receptors, we examined the effect of chronic HAL treatment in rats after hypophysectomy (Hypox). Male rats were obtained from Taconic Farms on the day after Hypox. These rats were maintained on a drinking solution, which contained 5% dextrose and a balanced salt solution (203 mg% NaC1, 8.3 mg% KC1, 3.5 mg% CaC12 and 1.7 mg% MgC12), and housed at 25°C, the warmest part of the animal room. At the same time a group of weightmatched control rats were obtained and housed in the same area. The experiment was initiated on the second day after Hypox. Onehalf of the control rats and one-half of the Hypox rats were injected daily, i.p., with 1.0 mg/kg HAL for 3 weeks. The remaining rats were injected with saline. Then treatment was discontinued for one week before decapitation. The skull was inspected to insure that removal of the pituitary in Hypox rats had been complete. DA receptors were measured in the striata using [3H]spiroperidol in our
routine assay procedure (Hruska and Silbergeld, 1980). As shown in table 1, the tissue from the control rats had the expected increase in the number of striatal DA receptors after chronic HAL treatment, while the DA affinity for the ligand was unchanged. Hypox, by itself, did not alter the number or the affinity of the DA receptors. However, Hypox did prevent the development of striatal DA receptor supersensitivity normally produced by chronic HAL, while the receptor affinity was again unchanged. It should be noted that during the 4 weeks of this experiment, the Hypox rats either did not gain or lost weight, while the control rats gained an average of 130 g. Chronic HAL treatment did not appear to affect weight gain in either treatment group. Failure to gain weight did not affect the striatal DA receptors, since the Hypox rats injected with saline had the same number and aff~mity of DA receptors as did control rats injected with saline.
This experiment suggests that the striatal DA receptor supersensitivity produced by chronic HAL treatment depends on the presence of the pituitary. The possibility is not excluded that HAL acts directly on the striatum, but the results do suggest that HAL requires a pituitary factor. This factor could act alone without HAL, act in conjunction with HAL, or alter still another factor which might modulate the striatal response to HAL.
456 TABLE 1 Effect of chronic treatment wit.h haloperidol on striatal dopamine receptors. Each group o f rats, control (Con) or hypophysectomy (Hypox), was divided equally and treated chronically with either saline (Sal) or haloperidol (Hal) as described in the text. The dissociation constant (KD) and maximum number of binding sites (Braax) were determined by linear regression analyses of Scatchard plots which were obtained from seven concentrations of [ 3H ]spiroperidol. Group
n
K D (pM)
Bmax (fmol]mg protein)
ABmax (%)
Con-Sal Con-Hal
6 6
9.82 + 0.69 12.33 -+ 1.56
374 + 19 480 -+ 19 1
-+28.3
Hypox-Sal Hypox-Hal
5 5
11.86 + 0.77 8.93 + 1.34
381 + 27 392 + 32
+2.9
I Significantly increased compared to the Con-Sal group, P < 0.005 by Student's t-test.
If indeed a pituitary factor were required, it could be prolactin, since HAL increases prolactin levels in control rats (Clemens et al., 1974), while in Hypox rats there is no question of prolactin release. Hormones of pituitary or target cell origin can have a wide variety of effects on many functions. While sex hormones are well known to affect hypothalamic function (Miillet et al., 1977), the interaction of these hormones with striatal receptors is only a recent finding (Hruska and Silbergeld, 1980). Estrogen treatment of male rats increases the number of striatal DA receptors and increases prolactin levels. Likewise, HAL treatment of male rats increases the number of striatal DA receptors and increases prolactin levels. The increases produced by estrogen or HAL can be blocked by Hypox. These results suggest, therefore, that prolactin may be involved in the development of striatal DA receptor supersensitivity. Clinically, neuroleptics, such as HAL, are chronically administered in the treatment of schizophrenia. Prolonged neuroleptic treatm e n t is associated with the occurrence of tardive dyskinesia, possibly resulting from the development of supersensitive DA receptors in the striatum (Klawans, 1973). Since neuroleptic treatment elevates prolactin levels, it is
tempting to propose that prolactin is a necessaw] factor for the expression of this type of striatal supersensitivity and may be involved in the development of tardive dyskinesia. Further examination of this hypothesis could be of value.
Acknowledgement We thank Terese O'Brien for the preparation of this manuscript.
References Butt, D.R., I. Creese and S.H. Snyder, 1977, Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain, Science 196, 326. Clemens, J.A., E.B. Smalstig and B.D. Sawyer, 1974, Antipsychotic drugs stimulate prolactin release, Psychopharmacologia 4 0 , 1 2 3 . Hruska, R.E. and E.K. Silbergeld, 1980, Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum, European J. Pharmacol. 61, 397. Klawans, H.L., 1973, The Pharmacology of Extrapyramidal Movement Disorders (Karger, Basel). Miiller, E.E., G. Nistico and U. Scapagnini, 1977, Neurotransmitters and Anterior Pituitary Function (Academic Press, New York).