Classical neuroleptics and deconditioning activity after single or repeated treatment. Role of different cerebral neurotransmitters.

A dose-dependent inhibition of conditioned avoidance response (CAR) was documented in trained rats after acute treatment with several neuroleptics: haloperidol, chlorpromazine (CPZ), fluanisone and 4-p-fluorophenyl-5-N(N'-o-methoxyphenyl)piperazinoethyl-4-oxazolin-2-one (zoloperone, LR 511). The compounds differently affected the unconditioned escape response (UER), haloperidol and LR 511 being almost inactive. Daily treatment with LR 511 or haloperidol for 7-16 days did not cause the appearance of tolerance in young and adult rats, on the contrary, made in evidence a stronger effect on CAR and on UER. This supersensitive state towards the neuroleptics did not disappear even after 30 days' treatment interruption. The acute administration of some neuroleptics in combination with other centrally active drugs, endowed with different mechanism of action, yielded the following results on CAR: amphetamine (a dopaminergic stimulant) readily antagonized the effect of LR 511 and haloperidol; chlorpheniramine and diphenhydramine (antihistaminics) minimized the effect of small doses of LR 511 and haloperidol while they did not alter that of larger doses; atropine (an anti-cholinergic), metergoline (an anti-5-hydroxytryptaminic (5-HT) and cyproheptadine (an anti-5-HT possessing antihistaminic and anticholinergic properties) protentiated the effect of LR 511 while in part reduced that of haloperidol. CPZ, which was associated only with atropine, behaved like LR 511. The role of various brain neurotransmitters is discussed.