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Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.

Authors
  • Dwyer, Jason M
  • Platt, Brian J
  • Rizzo, Stacey J Sukoff
  • Pulicicchio, Claudine M
  • Wantuch, Caitlin
  • Zhang, Mei-Yi
  • Cummons, Terri
  • Leventhal, Liza
  • Bender, Corey N
  • Zhang, Jean
  • Kowal, Dianne
  • Lu, Shendi
  • Rajarao, S Johannes R
  • Smith, Deborah L
  • Shilling, Adam D
  • Wang, Jianyao
  • Butera, John
  • Resnick, Lynn
  • Rosenzweig-Lipson, Sharon
  • Schechter, Lee E
  • And 1 more
Type
Published Article
Journal
The International Journal of Neuropsychopharmacology
Publisher
Oxford University Press
Publication Date
Oct 01, 2010
Volume
13
Issue
9
Pages
1193–1205
Identifiers
DOI: 10.1017/S1461145709991088
PMID: 20047711
Source
Medline
License
Unknown

Abstract

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

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