The ambivalent behaviour "stretched approach posture" in the rat as a paradigm to characterize anxiolytic drugs.
The effect of various psychotropic drugs on the ambivalent behaviour "stretched approach posture" (SAP) in the rat was assessed. SAP was elicited after a mild startle reaction due to physical contact with an electrified prod at one end of a straight runway. Using ethological observation methods, SAP as well as intention movements, prod contact, crossings, rearing, exploration, grooming and immobility were recorded. The benzodiazepine receptor agonists chlordiazepoxide, diazepam and alprazolam, the 5-HT1A receptor agonists flesinoxan and ipsapirone and the 5-HT uptake inhibitor clomipramine selectively (no effect on crossings) reduced SAP. Except for alprazolam, these drugs also reduced intention movements. In addition, chlordiazepoxide and diazepam enhanced prod contact. Reductions of SAP and intentions with concomitant reductions of crossings (nonspecific antiambivalent effects) were established for the alpha 2-adrenoceptor agonist clonidine and the MAO inhibitor clorgyline. The 5-HT uptake inhibitor fluvoxamine suppressed intention movements, but not SAP. The mixed 5-HT/NA uptake inhibitor imipramine did not significantly affect SAP or intentions, but reduced crossings. The 5-HT2C/1B receptor agonist m-CPP, the inverse BZD receptor agonists FG 7142 and DMCM, and the alpha 2-adrenoceptor antagonist yohimbine, to all of which putative anxiogenic effects have been ascribed, had no effect on SAP directed towards the prod. m-CPP, however, produced an increase in the stretched posture directed away from the prod (SAwayP). FG 7142 reduced intentions while strongly enhancing immobility (freezing). SAwayP and/or freezing may possibly reflect anxiogenic properties of drugs. The putative anxiogenic drug pentylenetetrazol false positively reduced SAP while increasing exploration. The dopamine-D2 receptor antagonist haloperidol and the catecholamine releaser dl-amphetamine had no effect on ambivalent behaviour. The muscarine receptor antagonist scopolamine reduced SAP and intentions while stimulating crossings. Finally, the 5-HT2C receptor antagonist ritanserine, the CCKA receptor antagonist devazepide, the CCKB receptor antagonist L-365.260 and the strychnine-insensitive glycine site antagonist 7-Cl-kynurenic acid were without effect on the behaviours in this paradigm using single doses. In conclusion, SAP and intention movements were reduced selectively by anxiolytic agents from different classes, including benzodiazepine receptor agonists, 5-HT1A receptor agonists and a 5-HT uptake inhibitor, whereas an alpha 2-adrenoceptor agonist and a MAO inhibitor reduced SAP non-selectively. SAP in relation to other behaviours may therefore serve as a valuable paradigm to characterize anxiolytic drugs.
Department of CNS Pharmacology, Solvay Duphar B.V., Weesp, The Netherlands.
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Molewijk
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van der Poel
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Olivier
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D003010:Clorgyline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009068:Movement / Q000187:drug effects*; D011187:Posture; D051381:Rats; D017208:Rats, Wistar
D014151:Anti-Anxiety Agents; D003010:Clorgyline; D003000:Clonidine; D000525:Alprazolam