Effect of VA-045 on central noradrenergic neuronal system in rats

1. Administration of VA-045 [2-(nitrooxy)ethyl apovincaminate] and thyrotropin-releasing hormone (TRH) led to improvement in the closed head injury (CHI)-induced neuronal dysfunction such as the loss of righting reflex and disruption of spontaneous movement in rats. 2. The improvement seen with effect of VA-045, but not TRH, was abolished in rats pretreated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a selective noradrenaline (NA) neurotoxin. DSP4 reduced endogenous NA levels in all central nervous system (CNS) regions analyzed. 3. The extracellular concentrations of NA in the frontal cortex (FC) and in the locus coeruleus (LC) of urethane-anesthetized rats were measured using in vivo microdialysis coupled with high-performance liquid chromatography (HPLC) with electrochemical detection. VA-045 had no effect on extracellular concentrations of NA, in both FC and LC. Perfusion with clonidine, and alpha 2 adrenoceptor agonist, led to inhibition in NA output in both FC and LC, and VA-045 antagonized the effect of clonidine. 4. These findings indicate that the mode of action of VA-045 may be, at least in part, related to central NA neuronal systems.