The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats

doi:10.1124/jpet.102.035303

Assistant Professor of Medicine (Clinician-Educator)

QUICK SEARCH:

[advanced]

	Author:		Keyword(s):
Year:		Vol:		Page:

This Article

	Full Text
	Full Text (PDF)
	Submit a response
	Alert me when this article is cited
	Alert me when eLetters are posted
	Alert me if a correction is posted
	Citation Map

Services

	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Kapur, S.
	Articles by Andrews, J. S.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Kapur, S.
	Articles by Andrews, J. S.

Vol. 302, Issue 3, 1129-1134, September 2002

The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats

S. Kapur, X. Langlois, P. Vinken, A. A. H. P. Megens, R. De Coster and J. S. Andrews

Clarke Division, CAMH, Toronto, ON, Canada (S.K.); and Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, Beerse, Belgium (X.L., P.V., A.A.H.P.M., R.D.C., J.S.A.)

All atypical antipsychotics avoid extrapyramidal side-effects yet differ in their propensity to cause other side-effects,like prolactin elevation. We proposed that the atypical antipsychoticswith a propensity for prolactin elevation would show a higherpituitary versus striatal D2 receptor occupancy. To investigatethis hypothesis, we tested four atypical antipsychotics, two thatare commonly associated with prolactin elevation (amisulprideand risperidone) and two that are less frequently associated (quetiapineand olanzapine). In particular, we calculated their ED₅₀ valuesto increase plasma prolactin and block peripheral pituitary D2receptors to their ED₅₀ values to antagonize apomorphine-inducedstereotypy and occupy central striatal D2 receptors. All antipsychoticsdose dependently increased prolactin levels and antagonized apomorphine-inducedstereotypy. However, the central to peripheral potency (ED₅₀ forapomorphine antagonism to ED₅₀ for prolactin elevation) differedremarkably across these drugs: amisulpride (21764), risperidone(14), quetiapine (10), and olanzapine (1.7). Compounds displayinga higher peripheral potency brought about higher prolactin levelsfor a given level of functional central antagonism. This dissociationbetween central and peripheral effects was explained by the differentialoccupancy of D2 receptors in the striatum versus in the pituitary[ratio of striatal/pituitary ED₅₀ values (milligram per kilogram)for D2 occupancy): amisulpride (17/0.026 = 654), risperidone (0.89/0.081= 14), quetiapine (24/4.1 = 6), olanzapine (0.30/0.43 = 0.7).These results indicate that dissociation between central and peripheralD2 receptor occupancy is a major determinant of the degree ofprolactin elevation observed at therapeuticdoses.

0022-3565/02/3023-1129$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

J. Watson, S. Wright, A. Lucas, K. L. Clarke, J. Viggers, S. Cheetham, P. Jeffrey, R. Porter, and K. D. Read
Receptor Occupancy and Brain Free Fraction
Drug Metab. Dispos., April 1, 2009; 37(4): 753 - 760.
[Abstract] [Full Text] [PDF]

M Chandran and M El-Shazly
Catatonia, neuroleptics and brain damage - a case report
J Psychopharmacol, March 1, 2009; 23(2): 223 - 226.
[Abstract] [PDF]

J. de Leon, N. B. Sandson, and K. L. Cozza
A Preliminary Attempt to Personalize Risperidone Dosing Using Drug-Drug Interactions and Genetics: Part II
Psychosomatics, July 1, 2008; 49(4): 347 - 361.
[Full Text] [PDF]

P. Fitzgerald and T. G Dinan
Prolactin and dopamine: What is the connection? A Review Article
J Psychopharmacol, March 1, 2008; 22(2_suppl): 12 - 19.
[Abstract] [PDF]

J. Walters and I. Jones
Clinical questions and uncertainty -- prolactin measurement in patients with schizophrenia and bipolar disorder
J Psychopharmacol, March 1, 2008; 22(2_suppl): 82 - 89.
[Abstract] [PDF]

K. Rasmussen, M.-A. Hsu, S. Noone, B. G. Johnson, L. K. Thompson, and S. K. Hemrick-Luecke
The Orexin-1 Antagonist SB-334867 Blocks Antipsychotic Treatment Emergent Catalepsy: Implications for the Treatment of Extrapyramidal Symptoms
Schizophr Bull, November 1, 2007; 33(6): 1291 - 1297.
[Abstract] [Full Text] [PDF]

L. R. Gardell, K. E. Vanover, L. Pounds, R. W. Johnson, R. Barido, G. T. Anderson, I. Veinbergs, A. Dyssegaard, P. Brunmark, A. Tabatabaei, et al.
ACP-103, a 5-Hydroxytryptamine 2A Receptor Inverse Agonist, Improves the Antipsychotic Efficacy and Side-Effect Profile of Haloperidol and Risperidone in Experimental Models
J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 862 - 870.
[Abstract] [Full Text] [PDF]

S. Natesan, K. A. Svensson, G. E. Reckless, J. N. Nobrega, K. B. L. Barlow, A. M. Johansson, and S. Kapur
The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D2 Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat
J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 810 - 818.
[Abstract] [Full Text] [PDF]

K. Rasmussen, M. J. Benvenga, F. P. Bymaster, D. O. Calligaro, I. R. Cohen, J. F. Falcone, S. K. Hemrick-Luecke, F. M. Martin, N. A. Moore, L. K. Nisenbaum, et al.
Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H1 Receptor Affinity Than Olanzapine
J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1265 - 1277.
[Abstract] [Full Text] [PDF]

J. J Hagan and D. N C Jones
Predicting Drug Efficacy for Cognitive Deficits in Schizophrenia
Schizophr Bull, October 1, 2005; 31(4): 830 - 853.
[Abstract] [Full Text] [PDF]

R. WAHL and R. OSTROFF
Reversal of Symptomatic Hyperprolactinemia by Aripiprazole
Am J Psychiatry, August 1, 2005; 162(8): 1542 - 1543.
[Full Text] [PDF]

R. Knegtering, P. Baselmans, S. Castelein, F. Bosker, R. Bruggeman, and R. J. van den Bosch
Predominant Role of the 9-Hydroxy Metabolite of Risperidone in Elevating Blood Prolactin Levels
Am J Psychiatry, May 1, 2005; 162(5): 1010 - 1012.
[Abstract] [Full Text] [PDF]

A. Doran, R. S. Obach, B. J. Smith, N. A. Hosea, S. Becker, E. Callegari, C. Chen, X. Chen, E. Choo, J. Cianfrogna, et al.
THE IMPACT OF P-GLYCOPROTEIN ON THE DISPOSITION OF DRUGS TARGETED FOR INDICATIONS OF THE CENTRAL NERVOUS SYSTEM: EVALUATION USING THE MDR1A/1B KNOCKOUT MOUSE MODEL
Drug Metab. Dispos., January 1, 2005; 33(1): 165 - 174.
[Abstract] [Full Text] [PDF]

J. Tauscher, T. Hussain, O. Agid, N. P. L.G. Verhoeff, A. A. Wilson, S. Houle, G. Remington, R. B. Zipursky, and S. Kapur
Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics
Am J Psychiatry, September 1, 2004; 161(9): 1620 - 1625.
[Abstract] [Full Text] [PDF]

B. Vreeland and E. Kim
Managing the Clinical Consequences of Psychiatric Illness and Antipsychotic Treatment: A Discussion of Obesity, Diabetes, and Hyperprolactinemia
Journal of the American Psychiatric Nurses Association, June 1, 2004; 10(3_suppl): S17 - S24.
[Abstract] [PDF]

D. Mamo, S. Kapur, C. M. Shammi, G. Papatheodorou, S. Mann, F. Therrien, and G. Remington
A PET Study of Dopamine D2 and Serotonin 5-HT2 Receptor Occupancy in Patients With Schizophrenia Treated With Therapeutic Doses of Ziprasidone
Am J Psychiatry, May 1, 2004; 161(5): 818 - 825.
[Abstract] [Full Text] [PDF]

				M Chandran and M El-Shazly Catatonia, neuroleptics and brain damage - a case report J Psychopharmacol, March 1, 2009; 23(2): 223 - 226. [Abstract] [PDF]

				J. de Leon, N. B. Sandson, and K. L. Cozza A Preliminary Attempt to Personalize Risperidone Dosing Using Drug-Drug Interactions and Genetics: Part II Psychosomatics, July 1, 2008; 49(4): 347 - 361. [Full Text] [PDF]

				P. Fitzgerald and T. G Dinan Prolactin and dopamine: What is the connection? A Review Article J Psychopharmacol, March 1, 2008; 22(2_suppl): 12 - 19. [Abstract] [PDF]

				J. Walters and I. Jones Clinical questions and uncertainty -- prolactin measurement in patients with schizophrenia and bipolar disorder J Psychopharmacol, March 1, 2008; 22(2_suppl): 82 - 89. [Abstract] [PDF]

				K. Rasmussen, M.-A. Hsu, S. Noone, B. G. Johnson, L. K. Thompson, and S. K. Hemrick-Luecke The Orexin-1 Antagonist SB-334867 Blocks Antipsychotic Treatment Emergent Catalepsy: Implications for the Treatment of Extrapyramidal Symptoms Schizophr Bull, November 1, 2007; 33(6): 1291 - 1297. [Abstract] [Full Text] [PDF]

				L. R. Gardell, K. E. Vanover, L. Pounds, R. W. Johnson, R. Barido, G. T. Anderson, I. Veinbergs, A. Dyssegaard, P. Brunmark, A. Tabatabaei, et al. ACP-103, a 5-Hydroxytryptamine 2A Receptor Inverse Agonist, Improves the Antipsychotic Efficacy and Side-Effect Profile of Haloperidol and Risperidone in Experimental Models J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 862 - 870. [Abstract] [Full Text] [PDF]

				S. Natesan, K. A. Svensson, G. E. Reckless, J. N. Nobrega, K. B. L. Barlow, A. M. Johansson, and S. Kapur The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D2 Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 810 - 818. [Abstract] [Full Text] [PDF]

				K. Rasmussen, M. J. Benvenga, F. P. Bymaster, D. O. Calligaro, I. R. Cohen, J. F. Falcone, S. K. Hemrick-Luecke, F. M. Martin, N. A. Moore, L. K. Nisenbaum, et al. Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H1 Receptor Affinity Than Olanzapine J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1265 - 1277. [Abstract] [Full Text] [PDF]

				J. J Hagan and D. N C Jones Predicting Drug Efficacy for Cognitive Deficits in Schizophrenia Schizophr Bull, October 1, 2005; 31(4): 830 - 853. [Abstract] [Full Text] [PDF]

				R. WAHL and R. OSTROFF Reversal of Symptomatic Hyperprolactinemia by Aripiprazole Am J Psychiatry, August 1, 2005; 162(8): 1542 - 1543. [Full Text] [PDF]

				R. Knegtering, P. Baselmans, S. Castelein, F. Bosker, R. Bruggeman, and R. J. van den Bosch Predominant Role of the 9-Hydroxy Metabolite of Risperidone in Elevating Blood Prolactin Levels Am J Psychiatry, May 1, 2005; 162(5): 1010 - 1012. [Abstract] [Full Text] [PDF]

				A. Doran, R. S. Obach, B. J. Smith, N. A. Hosea, S. Becker, E. Callegari, C. Chen, X. Chen, E. Choo, J. Cianfrogna, et al. THE IMPACT OF P-GLYCOPROTEIN ON THE DISPOSITION OF DRUGS TARGETED FOR INDICATIONS OF THE CENTRAL NERVOUS SYSTEM: EVALUATION USING THE MDR1A/1B KNOCKOUT MOUSE MODEL Drug Metab. Dispos., January 1, 2005; 33(1): 165 - 174. [Abstract] [Full Text] [PDF]

				J. Tauscher, T. Hussain, O. Agid, N. P. L.G. Verhoeff, A. A. Wilson, S. Houle, G. Remington, R. B. Zipursky, and S. Kapur Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics Am J Psychiatry, September 1, 2004; 161(9): 1620 - 1625. [Abstract] [Full Text] [PDF]

				B. Vreeland and E. Kim Managing the Clinical Consequences of Psychiatric Illness and Antipsychotic Treatment: A Discussion of Obesity, Diabetes, and Hyperprolactinemia Journal of the American Psychiatric Nurses Association, June 1, 2004; 10(3_suppl): S17 - S24. [Abstract] [PDF]

				D. Mamo, S. Kapur, C. M. Shammi, G. Papatheodorou, S. Mann, F. Therrien, and G. Remington A PET Study of Dopamine D2 and Serotonin 5-HT2 Receptor Occupancy in Patients With Schizophrenia Treated With Therapeutic Doses of Ziprasidone Am J Psychiatry, May 1, 2004; 161(5): 818 - 825. [Abstract] [Full Text] [PDF]