Behavioural pharmacology of the serenic, eltoprazine.
In this paper the effects of serenics (eltoprazine and fluprazine) are described in several animal models for offensive agonistic, defensive agonistic and predatory behaviour. They are compared with the effects of a number of other putative anti-aggressive compounds or drugs used clinically in order to ameliorate aggressive behaviour of psychiatric patients. In isolation-induced offensive aggression in mice, eltoprazine has a marked and potent anti-aggressive activity, although numerous other psychoactive drugs also exert anti-aggressive effects. The behavioural specificity of this anti-aggressive profile was investigated using an ethologically derived animal model, social interaction in male mice. In this model, eltoprazine has a very specific anti-aggressive (serenic) profile, inhibiting aggression while social interaction and exploration are not decreased but even enhanced; inactivity, a measure for sedation, is not affected. Such a profile contrasts sharply with that of neuroleptics (chlorpromazine, haloperidol), psychostimulants (d-amphetamine) or benzodiazepines (chlordiazepoxide), which exert severe sedation (neuroleptics) or even aggression-enhancing effects (BDZ). After subchronic treatment no tolerance for the anti-aggressive effects of eltoprazine occurred. The specific anti-aggressive effects of eltoprazine were also found in rat models of offensive agonistic behaviour. In one such model - resident-intruder aggression - eltoprazine reduced offensive behaviour specifically, leaving social interactions and exploration intact, and did not induce sedation or other unwanted side-effects. The neuroleptic haloperidol was very sedative in this model, as was the 5-HT1A-agonist buspirone. Benzodiazepines (chlordiazepoxide) have a biphasic effect in this paradigm, enhancing offence at low doses and decreasing it at higher doses, due to muscle relaxation. In another offensive model, colony-aggression, in which a dominant and subordinate male in a colony are confronted with a male intruder, eltoprazine reduced offensive behaviour of both the dominant and the subordinate against the intruder. In contrast, chlordiazepoxide enhanced aggression, at least at lower doses, whereas alcohol had, up to very high doses, no effect on the offensive behaviour. In a brain-stimulation induced offensive model--hypothalamically-induced aggression in rats--eltoprazine specifically reduces offence. Locomotion, a measure for sedation, was either unaffected or even somewhat enhanced, indicating the absence of any sedatory activity of this serenic compound. In contrast, haloperidol heavily sedated animals, making them incapable of aggression.(ABSTRACT TRUNCATED AT 400 WORDS)
Olivier
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Department of Pharmacology, Duphar B.V., Weesp, The Netherlands.
Mos
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Rasmussen
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*
D010879:Piperazines; D011619:Psychotropic Drugs; C063828:eltoprazine