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Biomedical subjects

S L Handley

Publications and source records attributed to S L Handley.

At least 37 records · Page 2Linked to original sources
PubMed1993

The effects of alpha 2-adrenoceptor antagonists on the inhibition of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes by 5-HT1A receptor agonists in the mouse.

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), gepirone, buspirone and ipsapirone dose-dependently antagonized the head-shakes induced by 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) (1.0 mg kg-1) in mice, when these agents were given i.p. 10 min beforehand. 2. para-Chlorophenylalanine (pCPA) abolished the effect of 8-OH-DPAT (0.1 mg kg-1) and of buspirone (1.0 mg kg-1). (+/-)-Pindolol (5.0 mg kg-1) also antagonized the effect of 8-OH-DPAT (0.1 mg kg-1). 3. The alpha 2-adrenoceptor antagonists, RX811059 (1.0 mg kg-1), idazoxan (0.5 mg kg-1), yohimbine (1.0 mg kg-1) and 1-(2-pyrimidinyl)-piperazine (1-PP) (2.0 mg kg-1) i.p. prevented the antagonistic effect of 8-OH-DPAT (0.1 mg kg-1) on DOI-head-shakes. 4. Orally-administered buspirone, given 60 min beforehand, only reduced DOI-head-shakes at doses of 60 mg kg-1 and above. However, when buspirone (1.0 mg kg-1) was administered orally twice daily for 21 days, DOI-head-shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. 5. A single oral dose of buspirone (1.0 mg kg-1) strongly antagonized DOI-head-shakes when given 24 h after the last of 4 daily doses of 1-PP (2.0 mg kg-1, p.o.) but had no effect on DOI-head-shakes 24 h after the last of 4 daily doses of water (p.o.). 6. A single oral dose of 1-PP (2.0 mg kg-1) abolished the inhibitory effect of i.p. buspirone(1.0 mg kg-1) on DOI-head-shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1-PP (2.0mg kg-1, p.o.) on these days.7. The ability of 5-HT1A receptor agonists to antagonize DOI-head-shakes may be due to an effect at presynaptic 5-HT receptors. It is suggested that 1-PP, formed from buspirone, may act at a2-adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI-head shakes, but that tolerance occurs to this effect of I-PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Serotonin mechanisms in animal models of anxiety.

1. Responses to serotonergic drugs in animal models of anxiety are reviewed. Pre- and postsynaptic mechanisms and multiple sites of postsynaptic action contribute to conflicting findings. 2. Paradoxical responses to both serotonergic and non-serotonergic agents support the concept of multiple anxiety mechanisms. Non-anxiety factors, such as effects on cognition and behavioral inhibition, must also be taken into account. 3. Immediate 'anxiogenic' and delayed 'anxiolytic' effects most closely mimic the clinical effects of recently introduced anxiolytic drugs such as the selective serotonin reuptake inhibitors and buspirone. Thus the relevance to anxiety of immediate 'anxiolytic' effects of such agents in animal models is in question.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

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.

5,7-Dihydroxytryptamine↗
PubMed1991

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.

Animals↗
PubMed1991

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.

5-Hydroxytryptophan↗
PubMed1987

Behavioural evidence for an interdependence between GABAA receptors and beta 2-adrenoceptors.

The possibility of a functional interdependence between central GABAA receptors and beta 2-adrenoceptors has been investigated using the ability of both types of agonist to potentiate the tic (head-twitch) response to 5-methoxy-N,N-dimethyltryptamine in the mouse. At a dose which selectively antagonised beta 1- but not beta 2-adrenoceptors, ICI 118,551 abolished the effects of single doses of muscimol, diazepam and pentobarbitone. Conversely, bicuculline abolished the potentiation caused by the beta 2-adrenoceptor agonist procaterol. Thus there is preliminary evidence that these two receptor types do show mutual interdependence.

Animals↗
PubMed1987

Effects in the X-maze anxiety model of agents acting at 5-HT1 and 5-HT2 receptors.

Three 5-HT agonists produced a dose-related fall in open/total arm entry ratio in the elevated X-maze model of anxiety at doses which did not affect total entries. The relative potency, 8-hydroxy-2-(di-n-propylamino)tetra lin (8-OH-DPAT) much greater than 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) greater than or equal to 5-methoxy-3(tetrahydropyridin-4-yl)1H-indole (RU 24969), was unrelated to the occurrence of wet dog shakes and suggests that 5-HT1 rather than 5-HT2 receptors may be involved. However, the 5-HT2 receptor antagonists ritanserin, ketanserin and seganserin caused an anxiolytic-like increase in entry ratio, although only ritanserin produced this effect across the dose range tested. +/- Pindolol, an antagonist at 5-HT1 receptors, showed a biphasic dose-response curve with a fall in entry ratio at one high dose. The effect of a submaximal dose of 8-OH-DPAT was prevented by pindolol but not by a similarly anxiolytic dose of ritanserin or diazepam. A higher dose of diazepam caused intense muscle hypotonia in combination with 8-OH-DPAT. Since open/total entry ratio appears to represent choice, rather than suppression or delay, of a response, the effects seen may indicate involvement of 5-HT receptors in anxiety separately from any change in the ability to withhold a response. The precise role of each receptor subtype, however, remains to be determined.

Animals↗
PubMed1986

Chronic antidepressant treatment reduces central beta-adrenoceptor sensitivity in a behavioural test.

The ability of beta-adrenoceptor agonists to potentiate the head-twitch response to 5-hydroxytryptophan (5-HTP) in mice was used to assess the in vivo sensitivity of beta-adrenoceptors 48 h after cessation of acute or chronic administration of desmethylimipramine (DMI) or iprindole (IPD). Neither acute nor chronic antidepressant administration significantly altered the head-twitch response to 5-HTP alone. Forty-eight hours after withdrawal from chronic but not acute pretreatment with DMI or IPD the potentiating effects of dobutamine, prenalterol and salbutamol were significantly decreased. This is consistent with a reduction in beta-adrenoceptor density and suggests that the 'spare' beta-adrenoceptor pool is small enough for this to result in functional subsensitivity. Implications of these findings are discussed.

5-Hydroxytryptophan↗
PubMed1986

Involvement of noradrenaline in potentiation of the head-twitch response by GABA-related drugs.

The involvement of noradrenaline in the potentiation of head-twitching by drugs acting at GABA and related receptors has been examined in mice. The direct 5-HT agonist 5-methoxy-N,N-dimethyltryptamine was used to induce the head-twitch. The dopamine beta-oxidase inhibitor FLA-63 depleted whole brain noradrenaline by 90% and potentiated head-twitching when this was measured 4 h after injection. The GABAA-receptor agonists muscimol and 3-aminopropanesulphonic acid (3-APS), a low dose of pentobarbitone, diazepam and picrotoxin (PTX) potentiated control head-twitch rates but had no further effect when head-twitching had been potentiated by FLA-63. The potentiating action of FLA-63 was prevented by the beta-adrenoceptor antagonist metoprolol; the latter having no effect on control head-twitch rates. Muscimol and diazepam potentiation was examined and found to be blocked by metoprolol. The GABAB-receptor agonist baclofen reduced head-twitching. This was also prevented by FLA-63. The role of beta-adrenoceptors in modulating these actions of GABA-related drugs is discussed.

Adrenergic beta-Antagonists↗
PubMed1986

The modulation of head-twitch behaviour by drugs acting on beta-adrenoceptors: evidence for the involvement of both beta 1- and beta 2-adrenoceptors.

Drugs selective for either the beta 1- or beta 2-adrenoceptor have been investigated for their effects on the head-twitch behaviour induced by L-5-hydroxytryptophan (L-5-HTP) in mice. All four agonists, dobutamine and prenalterol (beta 1-), and salbutamol and procaterol (beta 2-), potentiated the effect of L-5-HTP although they were ineffective in inducing the head-twitch when administered alone. The corresponding antagonists, practolol and metoprolol (beta 1-) and butoxamine and ICI 118,551 (beta 2-), were without effect on the L-5-HTP head-twitch. The antagonists each significantly reduced the effect of the corresponding agonists but, while butoxamine and ICI 118,551 were inactive against dobutamine and prenalterol potentiation, both practolol and metoprolol reduced the effect of salbutamol and procaterol. Thus it is argued that dobutamine and prenalterol potentiation is due to an action at beta 1-adrenoceptors, while at least a component of the potentiating effect of salbutamol and procaterol is exerted through beta 2-adrenoceptors. The lack of effect of the antagonists alone is discussed.

5-Hydroxytryptophan↗
PubMed1986

Involvement of the locus coeruleus in the potentiation of the quipazine-induced head-twitch response by diazepam and beta-adrenoceptor agonists.

Head-twitching in rats induced by quipazine was reduced by bilateral lesions of the locus coeruleus (LC) produced by 6-hydroxydopamine. Both beta 1-and beta 2-adrenoceptor agonists potentiated the head-twitch induced by quipazine in sham-operated controls. Lesions of the locus coeruleus increased the responses to the beta 1-adrenoceptor agonists, prenalterol and dobutamine, but reduced the response to the beta 2-adrenoceptor agonists, salbutamol and procaterol. Diazepam (0.25 mg/kg) also potentiated the response to quipazine and this was reversed to inhibition by lesions of the locus coeruleus. These results suggest that the beta 1-adrenoceptors involved are postsynaptic and the beta 2-adrenoceptors are presynaptic to neurones of the locus coeruleus and indicate a dual action of diazepam on the head-twitch induced by quipazine. Possible mechanisms for these effects are discussed.

Adrenergic beta-Agonists↗
PubMed1986

A multivariate investigation of postpartum mood disturbance.

The interrelationships of 'blues' and later postpartum depression with a number of biochemical, medical, and psychosocial variables have been examined in 52 subjects. The two syndromes shared only an impressive association with a prior history of gynaecological problems. Puerperal 'blues' was characterised in addition by associations with primiparity, tearfulness during pregnancy, and reduced plasma total tryptophan in the early puerperium. Depressive symptomatology up to nine months postpartum was related to an excess of male births and to an altered pattern of decline of non-esterified fatty acids immediately postpartum. In each case, the 'risk' variables were statistically independent and combined linearly. Stepwise discriminant analysis successfully discriminated 'blues' and depression from their respective non-cases. 'Blues and postpartum depression were only weakly related and, apart from gynaecological history, each was associated with separate and independent causative factors.

Adolescent↗
PubMed1985

Modulation of 5-hydroxytryptamine-induced head-twitch response by drugs acting at GABA and related receptors.

The effects of drugs acting at the gamma-aminobutyric acid (GABA) receptors and other chloride ionophore-related sites have been studied for their ability to modulate the head-twitch induced by 1-5-hydroxytryptophan (5-HTP) in the mouse. The GABAa receptor agonists, muscimol, imidazoleacetic acid and 3-aminopropanesulphonic acid, produced a dose-related potentiation, while bicuculline inhibited the head-twitch. The GABAb receptor agonist, baclofen, produced dose-related inhibition. Diazepam potentiated the head-twitch while the 'inverse' benzodiazepine receptor agonist ethyl-beta-carboline-3-carboxylate inhibited the head-twitch. The antagonist Ro15-1788 also produced inhibition. Ro05-4864, a ligand for the benzodiazepine 'acceptor' site, potentiated the head-twitch. Pentobarbitone and pentylenetetrazol potentiated the 5-HTP-induced head-twitch at low doses, changing to inhibition as the dose was increased. Picrotoxin in subconvulsant doses, produced only potentiation. More than one site may be involved in the action of these substances. GABA, amino-oxyacetic acid and 1-2-4-diaminobutyric acid inhibited the head-twitch, while the GABA-depletor, 3-mercaptopropionic acid potentiated it. Of all the agents tested, only muscimol produced head-twitching when given alone. It was concluded that both GABAa and GABAb receptors modulate the head-twitch response to 5-HTP.

5-Hydroxytryptophan↗
PubMed1984

Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of 'fear'-motivated behaviour.

An elevated X-maze with alternating open and enclosed arms was investigated as a model for the study of fear-induced behaviour. As predicted, the anxiolytics diazepam and amylobarbitone increased, and the putative anxiogenics ACTH and picrotoxin decreased the proportion of open arm entries. The alpha 1-adrenoceptor agonists phenylephrine and ST587, and the alpha 2-adrenoceptor antagonists idazoxan, piperoxane, RS-21361 and yohimbine decreased relative open-arm entries, thus resembling the putative anxiogenics. On the other hand, azepexole, clonidine and guanabenz, agonists at alpha 2-adrenoceptors, and the alpha 1-adrenoceptor antagonists prazosin and thymoxamine, enhanced the proportion of open arm entries at low doses, suggesting anxiolytic-like properties. A paradoxical fall in open arm entries occurred with these agents at higher doses. These results provide further evidence for the involvement of noradrenergic systems in 'fear'-motivated behaviour.

Adrenergic alpha-Agonists↗
PubMed1984

The pinna reflex and its inhibition by clonidine: relationship to sedation and quantitation of central alpha 2-antagonist potency.

The relationship between sedation and pinna reflex inhibition has been measured for a range of centrally acting drugs. Ability to abolish the pinna reflex was not related to sedative activity as assessed by a behavioural method. Thus, at equisedative doses, diazepam, haloperidol, mianserin, prazosin and indoramin failed to abolish the pinna reflex while phenobarbitone and chlorpromazine caused partial- and clonidine complete-inhibition. At the ED50 for pinna reflex inhibition, guanabenz and guanfacine were significantly less sedative than clonidine. Mepyramine, yohimbine, RS-21361, idazoxan and phenylephrine produced little or no sedation and did not inhibit the reflex. When these agents (except for guanabenz and guanfacine) were tested for their ability to prevent clonidine-induced pinna reflex inhibition, all except the drugs with alpha 2-adrenoceptor antagonist activity were inactive. The potency order of the active agents was idazoxan greater than yohimbine greater than RS-21361 = mianserin. Antagonism of clonidine-induced pinna reflex inhibition may therefore prove to be a useful quantitative model for assessing the central potency of alpha 2-adrenoceptor antagonists.

Adrenergic alpha-Antagonists↗