Flerobuterol: a potential antidepressant drug related to beta-adrenergic agonists. Experimental profile in mice.

The potential antidepressant effect of flerobuterol (dl-(fluoro-2 phenyl)-1 t-butylamino-2 ethanol), a new drug related to beta-adrenoceptor agonists, was evaluated and compared with imipramine and salbutamol using classical psychopharmacological tests in mice. Like imipramine and salbutamol, flerobuterol (0.5-32 mg kg-1, ip) fully prevented apomorphine (16 mg kg-1, sc)- and partly reversed reserpine- and oxotremorine-induced hypothermia. At higher doses (16-32 mg kg-1), flerobuterol enhanced the toxic effects of yohimbine. Unlike imipramine, flerobuterol and salbutamol did not reduce immobility duration in the behavioural despair test. Salbutamol and flerobuterol decreased locomotor activity. Flerobuterol did not induce mydriasis, did not prevent oxotremorine-induced tremors or salivary and lacrimal gland secretion and did not reduce reserpine-induced palpebral ptosis. Propranolol (8 mg kg-1, ip) but not alpha-methyl-paratyrosine (75 mg kg-1, ip) prevented the flerobuterol-induced antagonism of apomorphine-induced hypothermia. Our results suggest that flerobuterol demonstrates potential antidepressant activity, which could be related to beta-adrenoceptor activation in mice.

Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals.

Single administration of the new drug modafinil was followed by an increase in locomotor activity in mice and in nocturnal activity in monkeys. Stereotyped behaviour in mice and rats, and potentiation of amphetamine-induced stereotyped behaviour were not observed; however, at the highest dose used, a slight potentiation of apomorphine-induced stereotyped behaviour was observed in rats. The modafinil-induced increase in locomotor activity in mice was prevented by the centrally acting alpha 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, and by reserpine but not by the mixed dopamine D-1/D-2 antagonist, haloperidol, the dopamine D-2 antagonist, sulpiride, the peripherally acting alpha 1-adrenoceptor antagonist, phentolamine, the alpha 2-adrenoceptor antagonist, yohimbine, the beta-adrenoceptor antagonist, propranolol, or by the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine. Likewise, the modafinil-induced increase in nocturnal activity in monkeys was prevented by prazosin. Interestingly, modafinil did not produce obvious peripheral sympathetic effects in mice and rats (no salivation, no contraction of the pilomotor muscles, slight mydriasis only at high doses). Therefore, modafinil appears to produce a strong stimulating effect in rodents and in primates. These effects could be linked to modulation (stimulation) of central alpha 1-adrenoceptors unaccompanied by peripheral sympathetic effects, which is unexpected.

A possibe alpha-adrenergic mechanism for drug (CRL 40028)-induced hyperactivity.

CRL 40028 (benzhydryl sulfinyl acetohydroxamic acid)-induced stimulation in mice, measured as an increase in locomotor activity was studied following an intraperitoneal injection of drugs known to block alpha-adrenergic receptors. Phenoxybenzamine (20 mg/kg), prazosin (0.5-1 mg/kg) and yohimbine (2 mg/kg) prevented the development of CRL 40028-induced hyperactivity. These results suggest that stimulation of an alpha-adrenergic postsynaptic receptor is of importance for the stimulant effect of CRL 40028.