Analgesic and antipyretic effects of Myrica salicifolia (Myricaceae).

Myrica salicifolia Hoechst (Myricaceae) root extract was found to have analgesic activity in mice. In rats there was antipyretic but no antiinflammatory activity.

Multiple serotonin mechanisms in animal models of anxiety: environmental, emotional and cognitive factors.

Responses to serotonergic drugs in animal models of 'anxiety' are reviewed with emphasis on the elevated X-maze. Evidence for the 'classic' hypothesis, that decreasing serotonergic function is anxiolytic and increasing it anxiogenic, is most consistent in models of behavioural inhibition where the stimulus inhibits an approach response (conflict models). However, paradoxical drug effects are also frequent, especially where the aversive stimulus evokes an active response. Both types of drug effect are equally frequent in the elevated X-maze. 'Anxiety' models may detect multiple sites and mechanisms of action of the same drug; this may indicate multiple anxiety-related neurological mechanisms in the brain. However, not all drug effects in 'anxiety' models are necessarily related to anxiety itself. It is possible that cognitive factors may affect stimulus evaluation, and response inhibition by an aversive stimulus may be a special case of a wider role for serotonin in behavioural control. Clinical implications of these observations are considered.

Effects of beta-adrenoceptor ligands in the elevated X-maze 'anxiety' model and antagonism of the 'anxiogenic' response to 8-OH-DPAT.

Effects of ß-adrenoceptor agonists and antagonists have been examined on open/total arm entry ratio (OTR) over a wide range of doses in the rat elevated X-maze 'anxiety' model. For clenbuterol, terbutaline and adrenaline, OTR was reduced only at doses at or above those reducing total entries; dobutamine was inactive. Neither the ß(1)-adrenoceptor antagonist metoprolol nor the ß( 2)-adrenoceptor antagonist ICI 118,551 affected OTR or total entries. The peripherally acting ß(1)-antagonist practolol was also inactive. The elevated X-maze therefore does not appear to detect ß-adrenoceptor-mediated changes in 'anxiety'. Among the ß-adrenoceptor antagonists which also bind to 5-HT(1) receptors, sotalol and timolol were inactive but restricted doses of alprenolol (0.1 mg/kg) and pindolol (0.1-0.25 mg/kg) caused an anxiolytic-like increase in OTR while propranolol (5-10 mg/kg) and pindolol (1.0 mg/kg) reduced OTR without affecting total entries. These effects may be attributable to the activity of these agents at 5-HT( 1) receptors. Since metoprolol (3.0 mg/kg) and ICI 118,551 (1.0 mg/kg) did not alter the fall in OTR caused by the selective 5-HT(1A) agonist 8-OH-DPAT, the antagonism of this fall by alprenolol (0.5 mg/kg), pindolol (0.5 mg/kg), propranolol (3.0 mg/kg) and timolol (3.0 mg/kg) is most likely to represent a 5-HT(1) receptor antagonist effect of these agents.

Actions and some interactions of 5-HT1A ligands in the elevated X-maze and effects of dorsal raphe lesions.

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.

Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents.

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 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), buspirione, 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 (0.25 mg kg-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-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, 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 10 mg kg-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.

Evaluation of marble-burying behavior as a model of anxiety.

On individual placement in a cage with 20 evenly spaced glass marbles, female MF1 mice buried 7.8 +/- 0.2 marbles. Olfactory stimuli from experimenters hands and sex of mice had no influence on number buried, but most marbles were buried when they were evenly spaced. There was no habituation to these novel objects on serial testing or prehousing with marbles and, in a two-compartment box, mice did not avoid marbles, spending half their time on the marble side. In the pharmacological experiments, locomotor activity was measured separately to indicate the possibility of nonspecific effects. The anxiogenic agents yohimbine and ethyl-beta-carboline-3-carboxylate (beta-CCE) did not enhance burying, yohimbine decreased burying at doses also reducing locomotor activity. Diazepam effects depended on dose: 0.1 mg/kg increased burying, 0.25 mg/kg had no effect and 1.0-5.0 mg/kg reduced it. Diazepam increased locomotor activity from 0.1-2.5 mg/kg and had no effect at 5.0 mg/kg. Zimeldine, 10.0 mg/kg, reduced burying but not locomotor activity. Inhibition of marble burying may be a correlational model for detection of anxiolytics rather than an isomorphic model of anxiety.

Molluscicidal activity of Solanum aculeatum (family: Solanaceae) berries against Biomphalaria pfeifferi, Bulinus globosus and Lymnaea natalensis.

Aqueous suspensions of powder of sun- or freeze-dried berries of the plant Solanum aculeatum (Family Solanaceae), indigenous in Kenya, were tested for molluscicidal activity against Biomphalaria pfeifferi, Bulinus globosus and Lymnaea natalensis under laboratory conditions. One hundred or 50 mg powder L-1 of sun- or freeze-dried berries killed over 60% of the test B. pfeifferi, Bul. globosus and L. natalensis. Whereas 25 mg L-1 of the sun dried material killed less than 60% of the test snails, similar concentrations of the freeze dried molluscicide produced 60-80% mortality in the snails, under similar conditions. Using L. natalensis as the target snail, it was shown that the freeze dried material was more potent than the freeze-dried berries of S. incanum, S. nigrum or leaves of Polygonum senegalensis (Family Polygonaceae), all present in Kenya, and known to possess molluscicidal properties. The powdered material retained molluscicidal activity even after several months storage at room temperature. These findings suggest that S. aculeatum is a potent plant molluscicide, and has the potential for the control of vectors of schistosomiasis and fascioliasis in Kenya.