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1 The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway activity) were used as a separate test of non-specific drug effects. 2 Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirone, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl}2 aminopropane (DOI), 1,-3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169 369 and cyproheptadine but not by pindolol or a low (0.25mgkg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg'-. 4 Zimeldine burying inhibition was potentiated by ritanserin, ICI 169 369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5 Zimeldine was administered in drinking water at a dose of lOmgkg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels. 6 Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5-HT receptor subtypes.

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Effects of 5-HT1A agonists and partial agonists on open/total arm entry ratio (OTR) have been examined in the elevated X-maze anxiety model. 8-OH-DPAT (0.05-0.2 mg/kg), RU 24969 (0.5-2.0 mg/kg) and BAY R 1521 (0.1-1.2 mg/kg) produced dose-dependent reductions in OTR, signifying anxiogenic effects. Buspirone reduced OTR only at doses (0.25-5.0 mg/kg) decreasing total entries; gepirone (0.1-5.0 mg/kg) was inactive. Ipsapirone (0.25-5.0 mg/kg) increased OTR and at 1.0 mg/kg antagonised the anxiogenic action of 8-OH-D-PAT, RU 24969 and BAY R 1531. Gepirone (2.5 mg/kg) failed to antagonise 8-OH-DPAT, but the dose was limited by its effect on total entries. The anxiogenic effect of a low dose of 8-OH-DPAT was also prevented by p-chlorophenylalanine (p-CPA) pretreatment and reversed to anxiolytic by 5,7-dihydroxytryptamine lesions of dorsal raphe, which spared median raphe. These lesions also abolished the anxiolytic effect of ipsapirone without affecting the anxiogenic response to yohimbine. This study provides preliminary evidence that 8-OH-DPAT may be capable of acting as an agonist and ipsapirone as an antagonist at a presynaptic site related to dorsal raphe which is separate from the site of action of yohimbine. 5-HT1A agonists and partial agonists may have multiple sites and/or mechanisms of action in the elevated X-maze.