The putatively antipsychotic agent amperozide produces behavioural stimulation in the rat. A behavioural and biochemical characterization.
Amperozide (FG 5606; N-ethyl-4-[4',4'-bis(p-fluorophenyl)butyl]-1-piperazinecarboximide ) is a new putatively antipsychotic compound with a postulated 5-HT2 antagonistic profile. Somewhat surprisingly amperozide dose dependently induced a behavioural stimulation in reserpinized and in nonpretreated rats. The behaviour consisted of both forward and backward locomotion as well as forepaw circling and a grooming like behaviour. Since the behavioural pattern clearly differ from that produced by classical dopaminergic or serotonergic agonists (e.g. apomorphine or 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT), and has not been previously reported, we decided to investigate the origin of this effect. In the behavioural paradigms it was not possible to antagonize the amperozide stimulation in reserpinized rats with the dopamine receptor blockers haloperidol, raclopride or R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine, SCH 23390. Neither the 5-HT2 receptor blocking agent ritanserin nor the tryptophan and tyrosine hydroxylase inhibitor DL-3,4-dihydroxy-phenyl-alpha-propylacetamide, H22/54, could block the motoric stimulation or the forepaw circling behaviour produced by amperozide. However, the noradrenaline synthesis inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulfide, FLA 63, as well as the alpha-adrenoceptor antagonist phenoxybenzamine, could partly inhibit the locomotor stimulation. Hence, noradrenaline seems to be, at least in part, involved in the behavioural stimulatory effect of amperozide. Biochemically amperozide had no effect on the dopamine synthesis rate (DOPA formation) in normal or reserpinized animals in the striatal or the limbic brain regions. In reserpinized animals amperozide also failed to antagonize the decrease in DOPA formation after apomorphine and 3-hydroxy-benzylhydrazine HCl, NSD 1015, in these regions.(ABSTRACT TRUNCATED AT 250 WORDS)
Waters
N
N
Department of Pharmacology, University of Göteborg, Sweden.
Pettersson
G
G
Carlsson
A
A
Svensson
K
K
D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism / Q000031:analogs & derivatives; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D009647:Normetanephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology
D018377:Neurotransmitter Agents; D010879:Piperazines; D011619:Psychotropic Drugs; D009647:Normetanephrine; C049058:amperozide; D012701:Serotonin; D012110:Reserpine; D006916:5-Hydroxytryptophan; C001746:3-methoxytyramine; D001058:Apomorphine; D003913:Dextroamphetamine; D004298:Dopamine