Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine Ͼ serotonin Ͼ dopamine (Ϸ1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freund's adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D 2 receptor antagonist (Ϫ)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.Multiple neurotransmitters have been implicated in the modulation of nociceptive signaling at both the spinal and supraspinal levels of central nervous system processing (Millan, 2002). Among these, norepinephrine (NE) and serotonin (5-HT) play important roles in modulating nociceptive information via pathways descending from the brainstem to the level of the dorsal horn. Noradrenergic fibers from the locus coeruleus and subcoeruleus descend Article, publication date, and citation information can be found at

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB-1020 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane HCl). EB-1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB-1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB-1020 dose-dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB-1020 dose-dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6-hydroxydopamine (100 μg intracisternally) as neonates; a well-established animal model for attention-deficit hyperactivity disorder (ADHD). These data suggest that EB-1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD.

A(2A) adenosine receptor antagonists have been proposed as a new therapy for Parkinson's disease (PD). Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on L: -3,4-dihydroxyphenylalanine (L: -DOPA)-induced hydroxyl radical generation using in vivo microdialysis in the striatum of freely moving rats. L: -DOPA (100 mg/kg; in the presence of benserazide, 50 mg/kg) given acutely or repeatedly for 14 days generated a high level of hydroxyl radicals, measured by HPLC with electrochemical detection, as the product of their reaction with p-hydroxybenzoic acid (PBA). CSC (1 mg/kg) and ZM 241385 (3 mg/kg) decreased haloperidol (0.5 mg/kg)-induced catalepsy, while at low doses of 0.1 and 0.3 mg/kg, respectively, they did not display an effect. CSC (1 and 5 mg/kg) and ZM 241385 (3 and 9 mg/kg) given acutely, or CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly, increased the production of hydroxyl radicals in dialysates from rat striatum. Both acute and repeated administration of CSC (0.1 and 1 mg/kg) and ZM 241385 (3 mg/kg) decreased L: -DOPA-induced generation of hydroxyl radicals. However, a high single dose of either CSC (5 mg/kg) and ZM 241385 (9 mg/kg) markedly potentiated the effect of L: -DOPA on hydroxyl radical production. The increase in hydroxyl radical production by acute and chronic injection of CSC and ZM 241385 may be related to the increased release of dopamine (DA) and its metabolism in striatal dialysates. Similarly, increased DA release following a single high dose of CSC or ZM 241385 appears to be responsible for augmentation of L: -DOPA-induced hydroxyl radical formation. Conversely, the inhibition of L: -DOPA-induced production of hydroxyl radical by single and repeated low doses of CSC or repeated low doses of ZM 241385 may be related to reduced DA metabolism. Summing up, A(2A) antagonists, used as a supplement of L: -DOPA therapy, depending on the dose used, may have a beneficial or adverse effect on ongoing neurodegenerative processes and accompanying oxidative stress.