CEREBRAL ACTIVATING PROPERTIES OF INDELOXAZINE HCL AND ITS OPTICAL ISOMERS

The cerebral activating actions of indeloxazine HCl and its optical is omers were evaluated in comparison with those of several selective mon oamine uptake inhibitors. The effects of indeloxazine and its optical isomers on monoamine uptake were also determined. Indeloxazine was equ ipotent to the (-)-isomer in desynchronizing the spontaneous electroen cephalogram (EEG) in both mature and aged rats and in accelerating rec overy of consciousness induced by concussive head trauma in mice, wher eas the (+)-isomer showed about 3 times less potent activity than inde loxazine and the (-)-isomer. The potency of indeloxazine and the (-)-i somer in inhibiting [C-14]norepinephrine (C-14-NE) uptake was approxim ately 25-30 times more potent than that of the (+)-isomer. Maprotiline and viloxazine, selective NE uptake inhibitors, also showed facilitat ory actions in concussed mice. Selective 5-hydroxytryptamine (5-HT) up take inhibitors such as citalopram, alaproclate, and zimeldine showed little effect. Indeloxazine, the (-)-, and the (+)-isomers facilitated passive avoidance learning behavior with a bell-shaped response curve in normal rats. The potency of the (+)-isomer inhibiting [C-14]5-HT u ptake was equipotent to those of both indeloxazine and the (-)-isomer. While citalopram, alaproclate, and zimeldine also facilitated the acq uisition of learning behavior, maprotiline and viloxazine, as well as the dopamine uptake inhibitor amantadine, showed little influence on t he latency of step-through behavior. Amitriptyline, with anticholinerg ic activity, impaired learning behavior. Indeloxazine, its optical iso mers, citalopram, alaproclate, and zimeldine also ameliorated cyclohex imide-induced disturbance of learning behavior in mice, while maprotil ine and viloxazine showed little effect. These results indicate that i ndeloxazine and its optical isomers possess facilitatory effects on th e CNS, and the pharmacological profile of indeloxazine and its optical isomers with NE and 5-HT uptake inhibitory activity were wider than t hose of other selective monoamine uptake inhibitors and the classical tricyclic antidepressant tested in the present study. In addition, it is suggested that central serotonergic and noradrenergic systems might be involved in learning behavior and central arousal action, respecti vely.