Effect of benztropine on haloperidol-induced prolactin secretion

Neuropsychobiology 5: 327-331 (1979) Effect of Benztropine on Haloperidol-Induced Prolactin
Secretion1
S. Lal, T. Mendis, P. Cervantes, H. Guyda and J.L. De Rivera Departments of Psychiatry, Montreal General Hospital and McGill University; Douglas Hospital, and Protein and Polypeptide Laboratory, Montreal, PQ Key Words. Prolactin • Cholinergic mechanisms • Benztropine • Haloperidol

Abstract. The effect of benztropine on haloperidol-induced prolactin secretion was investigated in
10 normal male volunteers. Benztropine had no. effect on basal prolactin secretion but significantly enhanced the increase induced by haloperidol. The magnitude of the enhancement, however,. was relatively small. These data suggest that in man cholinergic mechanisms have no effect on basal prolactin, secretion but exert a weak inhibitory effect under conditions of dopamine receptor block-ade. Differences in intrinsic anticholinergic properties may account for some of the variations in po-tency of different neuroleptics in increasing circulating prolactin concentrations. Introduction
only weak stimulatory effects on prolactin secretion (Nair et al., 1978) in man. In order to In previous work we found that in patients investigate the possible role of anticholinergic maintained on chronic neuroleptic therapy mechanisms in neuroleptic-induced prolactin some of the groups had higher basal prolactin secretion, we have looked at the effect of concentrations if they were also receiving con- benztropine, a muscarinic receptor-blocking comitant anticholinergic antiparkinsonian drugs agent, on haloperidol-induced prolactin secre- (De Rivera et al, 1976). Whereas there is evi- tion in normal subjects. Haloperidol was chosen dence that cholinergic mechanisms modulate because of its weak central antimuscarinic prolactin secretion in animals (Chen and Meites 1975; Gala et al., 1976, Subramanian and Gala, 1976; McLean and Nikitovitch-Winer, 1975), less information is available in man. Subjects and Methods
Neuroleptics show considerable variation in 10 physically healthy, nonobese male volunteers, central anticholinergic potency (Snyder et al., aged 21- ST years and on no medication, served as 1974) and also in their capacity to stimulate subjects. After an overnight fast, at 7:30–8:00 a.m., a prolactin secretion (Langer et al., 1977). Re- 19-gauge scalp vein needle was inserted into an arm cently, it has been shown that clozapine, an vein and kept open with heparin saline. 60 and 90 effective antischizophrenic agent with potent min after insertion of the needle (–45 and –15 min), central antimuscarinic properties (Miller and baseline samples of blood were drawn. Immediately Hiley, 1974), has no (Sachar et al, 1976) or after the sample at –15 min, subjects received either .benztropine mesylate (2 mg intramuscularly, Cogentin®) or saline intramuscularly. 15 min later, at 1 This work was supported by grants from the time 0 min, the subjects were injected with haloperi- Medical Research Council (Canada). Additional sup- dol (1 mg intramuscularly, Haldol® or saline intra- port was received from the G.W. Stairs Memorial muscularly. Additional samples of blood were taken Fund, McGill University and Merck Frosst Labora- al 30, 60, 90, 120 and 150 min. Specimens were centri- fuged and the serum stored at –20 °C until assayed for prolactin by radio immunoassay (Hwang et al., the subjects received benztropine prior to 1971). Subjects remained recumbent throughout the haloperidol than when they received saline procedure. Also, in view of the fact that prolactin secretion may increase during a daytime nap (Parker et al, 1973), subjects were asked to remain awake during tropine plus saline were not significantly dif- the test session. Each of the 10 subjects was tested with benztropine plus haloperidol and saline plus halo- ferent from those following saline plus saline peridol. 7 of the volunteers were also tested with benztropine plus saline and saline plus saline. The 7 of the subjects complained of restlessness sequence of treatments was randomized. The interval and irritability (akathisia) after receiving halo- between treatments was at least 72 h. Data were peridol, and 2 other subjects appeared restless analyzed by factorial analysis of va.ricurce with re- during the test though did not complain of this peated measurements and the paired t test. symptom. When pretreated with benztropine, these symptoms were abolished or considerably attenuated. Haloperidol with or without benz- tropine had a sedative effect in 7 of the sub- Haloperidol induced at least a twofold in- jects. No discomforting side effects were re- crease in prolactin above baseline values in 9 of ported after saline or benztropine in the absence the 10 subjects. The mean baseline concentra- tion (samples at –45 and –15 min) was 6.3 ± 1.1 ng/ml (mean ± standard error of the mean), Discussion
and this increased to a mean individual peak of 29.4 ± 6.7 ng/ml (range 11.5–80). When Neuroleptics increase prolactin secretion in benztropine was given prior to injection of animals (Clemens et al., 1974) and man (Langer haloperidol, all 10 subjects showed at least a et al, 1977). The prolactin-elevating potency doubling of baseline concentrations. Values in- correlates well, in general, with clinical neuro- creased front 6.3 ± 0.8 to 37.7. ±. 6.4 ng/ml leptic potency (Langer et al., 1977) which in (range 18- 80). The mean prolactin, concentra- turn correlates with potency of dopamine tions• after haloperidol. were higher following receptor blockade (Seeman et at, 1976). In benztropine pretreatment at each time interval addition to dopaminergic modulation (Martin et (fig. 1), but none of the differences were statis- al., 1974); cholinergic mechanisms may also tically significant. Also, the difference in mean play a role in prolactin secretion though this has individual peak concentration was not statis- tically significant. However, when the data were In the rat, the presence of a tuberoinfun- analyzed by factorial analysis of variance, the dibular cholinergic pathway has been described prolactin concentrations for the 30 to 150 min (Carson et a!., 1977). Pilocarpine or physostig- sampling period were significantly higher when mine inhibit prolactin secretion (Chen and Fig. 1. Effect of benztropine
on haloperidol-induced prolactin secretion. 10 male volunteers were injected with either haloperi-dol, 1 mg intramuscularly at time 0 min (o), or benztropine, 2 mg intramuscularly, 15 min before haloperidol (●). Each point re-presents the mean + standard error of the mean. 7 of the sub-jects also received either benz-tropine alone (▲) or saline alone (∆). The increase induced by haloperidol is significantly greater following benztropine pretreat- Meites, 1975; Grandison and Meites, 1976), receiving haloperidol plus benztropine than and atropine reverses the effect of pilocarpine when they received haloperidol without benz- in both the estrogen-primed male and the pro- tropine. Thus, a nonspecific stress effect is un- estrous rat (Grandison and Meites, 1976). In likely to account for differences observed in the the monkey, atropine leas no effect on basal prolactin secretion but potentiates the elevation induced by perphenazine (Gala et al, 1976): These data are compatible with an inhibitory References
muscarinic-cholinergic mechanism. However, pilocarpine has no effect on neuroleptic- Carson, K.A.; Nemeroff, C.B.; Rone, M.S.; .Young- Blood,.W.W.; Prange, A.J.; Hanker, J.S., and Kizer, (Grandison and Meites, 1976), and in the J.S.: Biochemnical and histochemical evidence pseudopregnant animal there is evidence for a for the existence of a tubero-infundibular cho- stimulatory cholinergic mechanism controlling linergic pathway in the rat. Brain Res. 129: 169- the nocturnal surge of prolactin secretion (McLean and Nikitovitch-Winer, 1975). In man, Clien, H .J. and Meites, 1.: Effects of biogenic amines neither physostigmine (Sachar et at, 1976) nor and TRH on release of prolactin and TSH in the the muscarinic receptor agonist bethanechol rat. Endocrinology 96: 10-14 (1975). Clemens, J.A.; Smalstig, E.B., and Sawyer; B.D.: Anti- (McCallum et at, 1976) affect basal prolactin psychotic drugs stimulate prolactin release. Psycho- secretion. Also, atropine has no effect on meto- pharrnacologia 40: 123-- 127 (1974). clopramide-induced prolactin secretion (Mc- De Rivera, J.L.; Lal, S.; Ettigi, P.; Hontela, S.; Muller H.F., and Friesen, H.G.: Effect of acute and chronic neuroleptic therapy on serun prolactin groups of patients who were receiving anticho- levels in men and women of different age groups linergic antiparkinsonian drugs in addition to chronic neuroleptic treatment had higher circu- Gala, R.R.; Subramanian, M.G.; Peters, J.A., and lating prolactin concentrations than subjects on Jacques, S.: Influence of cholinergic receptor blockade on drug-induced prolactin release in the neuroleptics alone (De Rivera et al., 1976). monkey. Hormone Res. 7: 118- 128 (1976). However, following short-term administration Gauthier, J.; Jus, A.; Villeneuve, A.; Jus, K.; Pires, P. of clozapine, a neuroleptic with potent anti- and Villeneuve. R.: Influence of the antiparkin- muscarinic properties (Miller and Hliley, 1974), sonian drugs on the plasma level of neuroleptics only a small increment in prolactin secretion Biol. Psychiat. 12: 389-399 (1977). was noted (Nair et al., 1978). In the present Grandison, L. and Meites, J.: Evidence for adrenergic study, the antimuscarinic agent, benztropine, mediation of cholinergic inhibition of prolactin had no effect on basal prolactin secretion but release. Endocrinology 99: 775-779 (1976). significantly enhanced the elevation promoted Hwang, P.; Guyda, H., and Friesen, H: A radioimmu- noassay for human prolactin. Proc. natn. Acad. by haloperidol. The magnitude of the increase in mean individual peak, however, was only Langer, G.; Sachar, E.J.; Gruen, P.H., and Halpern, 28%. These data suggest that in man cholinergic F.S.: Human prolactin responses to neuroleptic systems have no effect on basal prolactin secre- drugs correlate with antischizophrenic potency. tion but may exert a weak inhibitory, effect Nature, Lond. 266: 639-640 (1977). under conditions of dopamine receptor block- Martin, J.B.; Lal, S.; Tolis, G., and Friesen, H.G.: In- ade. The results also suggest that. differences in hibition by apomorphine of prolactin secretion in intrinsic anticholinergic properties may account patients with elevated serum prolactin. J. clin. for some of the variations in potency of differ- Endocr. Metab. 39: I80-- 182 (1974). McCallum, R.W.; Sowers, J.R.; Hershman, J.M., and ent neuroleptics in inducing prolactin-secretion. Sturdevant, R.A.L.: Metoclopramide stimulates In addition, thee weak ability of clozapine to prolactin secretion in man. J. clin. Endocr. Metab. induce prolactin secretion (Nair et al., 1978) cannot be explained on the basis of an inhibi- McLean, B.K. and Nikitovitch-Winer, M.B.: Cholin- ergic control of the nocturnal prolactin surge in It is unlikely that benztropine enhances the pseudopregnant rat. Endocrinology 97: 763- prolactin secretion by inhibiting haloperidol metabolism, as Gauthier et al. (1977), have Miller, R.J. and Hiley, R.J.: Antimuscarinic proper- shown that benztropine decreases plasma levels ties of neuroleptic and drug induced Parkinson-ism. Nature, l.ond. 248: 596-597 (1974). Nair, N.P.V.; Lal, S.; Cervantes, P.; Yassa, R., and Stress is known to increase prolactin secre- Guyda, H.: Effect of clozapine on apomorphine tion (Noel et al., 1972). In the present study, induced growth hormone secretion and serum however, the subjects were less distressed after prolactin concentrations in schizophrenia. Neuro- mine receptors. Nature, Lond. 261: 717-719 (1976). Noel, G.L.; Suh, H.K.; Stone, J.G., and Frantz. A.G.: Snyder, S.H.; Greenberq, D., and Yamamura, H.I.: Human prolactin and growth hormone release Antischizophrenic drugs and brain cholinergic re- during surgery and other conditions of stress. J. ceptors. Archs gen: Psychiat. 31: 58--61 (1974). clin. Endocr. Metab, 35: 840- 851 (1972). Subramanian, M.G. and Gala, R.R.: Further studies Parker, D.C.; Rossman, L.G., and Vanderlaan, E.F.: on the effects of adrenergic, serotonergic and Sleep-related, nyctohemeral and briefly episodic cholinergic drugs on the afternoon surge of plas- variation in human plasma prolactin concentra- ma prolactin in ovariectomized, estrogen-treated tions. J. clin Endocr. Metab. 36: 1119-1124 rats. Neuroendocrinology 22: 246-249 (1976). Sachar, E.J.; Gruen, P.H.; Altman, N.; Halpern, F.S., and Frantz, A.G.; Use of neuroendocrine tech-niques in psychopharmacologic research; in Sachar, Hormones, behaviour and psychopatho-logy, pp. 161-176 (Raven Press, New York 1976). Dr. S. Lal, Department of Psychiatry. Montreal Seeman, P.; Lee, T.; Chau-Wong, M., and Wong, K.: General Hospital, Montreal, PQ H3G 1A4 (Canada) Antipsychotic drug doses and neuroleptic dopa-

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