title: The effects of the nonselective benzodiazepine lorazepam and the α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280 on plasma prolactin levels.
abstract: Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.0%, 19.8%, and 32.8%, respectively), suggesting that the α2 and/or α3 receptor subtypes are involved in GABAergic modulation of prolactin secretion, although possible roles of the α1 and α5 receptor subtypes are not excluded. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Erik T
authors.initials: ET
authors.lastname: Te Beek
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.|Clinical Pharmacological Research Center (CPRC), Peking Union Medical College Hospital, Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.|Department of General Hospital Psychiatry, Free University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Gabriël E
authors.initials: GE
authors.lastname: Jacobs
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Nahon
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Cross
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Hay
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D018757:GABA Modulators / Q000008:administration & dosage*; D005858:Germany; D064368:Healthy Volunteers; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage*; D006801:Humans; D008140:Lorazepam / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011388:Prolactin / Q000097:blood*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
chemical_list: C584463:4-amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide; C576237:4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide; D015415:Biomarkers; D018757:GABA Modulators; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; D006574:Heterocyclic Compounds, 2-Ring; D011963:Receptors, GABA-A; D011388:Prolactin; D008140:Lorazepam
keywords: AZD6280; AZD7325; healthy volunteers; lorazepam; prolactin