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.