EFFECT OF VA-045 ON CENTRAL NORADRENERGIC NEURONAL SYSTEM IN RATS

1. Administration of VA-045 [2-(nitrooxy)ethyl apovincaminate] and thy rotropin-releasing hormone (TRH) led to improvement in the closed head injury (CHI) induced neuronal dysfunction such as the loss of rightin g reflex and disruption of spontaneous movement in rats. 2. The improv ement seen with effect of VA-045, but not TRH, was abolished in rats p retreated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a se lective noradrenaline (NA) neurotoxin. DSP4 reduced endogenous NA leve ls in all central nervous system (CNS) regions analyzed. 3. The extrac ellular concentrations of NA in the frontal cortex (FC) and in the loc us coeruleus (LC) of urethane anesthetized rats were measured using in vivo microdialysis coupled with high-performance liquid chromatograph y (HPLC) with electrochemical detection. VA-045 had no effect on extra -cellular concentrations of NA, in both FC and LC. Perfusion with clon idine, an alpha(2) adrenoceptor agonist, led to inhibition in NA outpu t 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.