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PubMed1981

A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists.

1 The effect of the putative 5-hydroxytryptamine (5-HT) receptor antagonists, methysergide, methergoline, mianserin, cyproheptadine, cinanserin (all at 10 mg/kg), methiothepin (5 mg/kg) and (-)-propranolol (20 mg/kg) on the behavioural responses to tranylcypromine (10 mg/kg) followed 30 min later by L-tryptophan (100 mg/kg) was examined.2 Methysergide, methergoline, methiothepin and (-)-propranolol inhibited head weaving, forepaw treading and hind-limb abduction. Methysergide and methergoline increased reactivity. In contrast, cypropheptadine, cinanserin and mianserin had no effects on the behaviour.3 Similar findings were obtained when the behaviours were elicited by administration of tranylcypromine (10 mg/kg) followed by the putative 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg).4 When the behaviours were elicited by the putative 5-HT receptor agonist, quipazine (50 mg/kg), all the drugs effectively inhibited head weaving and forepaw treading.5 When the dose of cypropheptadine was doubled to 20 mg/kg an inhibition of the tranylcypromine/L-tryptophan induced behaviours was seen.6 Methiothepin produced a marked inhibition of apomorphine-induced locomotor activity whilst all the others enhanced this response, suggesting that only methiothepin inhibits the 5-HT behaviours by dopamine antagonism and that the increased reactivity seen following tranylcypromine/L-tryptophan after pretreatment with methysergide or methergoline might be due to enhanced dopamine function.7 Pretreatment with p-chlorophenylalanine resulted in enhanced behavioural responses to both 5-MeODMT and quipazine.8 Both methergoline and methiothepin decreased the rate of 5-HT synthesis in whole brain but not spinal cord and methergoline decreased spinal cord 5-HIAA concentration. None of the other drugs had any significant effects on the concentration of 5-HT, 5-HIAA or 5-HT synthesis rate in brain or spinal cord.9 Experiments with compounds structurally related to quipazine and with molecular models suggested that quipazine produces behavioural changes probably by stimulating the 5-HT receptor in a similar way to 5-HT but that it would bind weakly, in agreement with ligand-receptor binding studies.10 It is suggested, therefore, that cyproheptadine, cinanserin and mianserin fail to inhibit 5-HT and 5-MeODMT-induced behaviours because they are weak antagonists whilst they are able to inhibit the same behaviours induced by quipazine because it is a weak agonist.11 These data indicate that extreme care should be taken in accepting or rejecting 5-HT as a mediator of behaviours or of other responses unless several antagonists or agonists have been examined.

Animals↗
PubMed1985

Monoaminergic involvement in the pharmacological actions of buspirone.

Buspirone, MJ-13805 and MJ-13653 did not produce a '5-hydroxytryptamine (5-HT) syndrome' in rats at doses up to 20 mg kg-1. These drugs were very weak 5-HT uptake blockers (IC50 much greater than 10 microM) compared to drugs such as chlorimipramine. These drugs did not inhibit either monoamine oxidase (MAO)-A or MAO-B. The Ki values for these agents as inhibitors of [3H]-5-HT and [3H]-ketanserin binding to rat frontal cortex or hippocampal membranes were in the microM range, well above the brain concentrations achieved after an oral dose of 25 mg kg-1. Parenterally administered buspirone blocked apomorphine-induced stereotypy, inhibited the 5-HT syndrome elicited by 5-methoxy-N,N-dimethyltryptamine, and delayed the onset of p-chloroamphetamine induced behaviours.

Animals↗
PubMed1985

A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors.

Radioligand binding techniques have demonstrated the existence of 5-hydroxytryptamine (5-HT) binding subtypes: 5-HT2, 5-HT1A and 5-HT1B. These techniques have also indicated that certain drugs appear to show sub-type specificity: 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a 5-HT1A agonist; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1-H indole (RU 24969), a 5-HT1B agonist; and ritanserin, a 5-HT2 antagonist. (-)-Propranolol is a 5-HT1 antagonist of uncertain sub-type specificity. An examination has been made in mice and rats of the behavioural and biochemical effects of these drugs to determine whether the binding sites have physiological functions and further characterise the behavioural models. Administration of carbidopa (25 mg kg-1) plus 5-hydroxytryptophan (100 mg kg-1) produced head-twitch behaviour in mice which was antagonized by ritanserin (ED50 = 65 micrograms kg-1) but not (-)-propranolol (20 mg kg-1). 8-OH-DPAT (1-10 mg kg-1 s.c.) and RU 24949 (5 mg kg-1 i.p.) did not produce head-twitch behaviour. 8-OH-DPAT decreased 5-HTP- but not 5-methoxy-N-N-dimethyltryptamine (5 mg kg-1)-induced head-twitch by a (-)-propranolol-insensitive mechanism. Locomotor activity produced in mice by RU 24969 (3 mg kg-1) was antagonized by (-)-propranolol (20 mg kg-1) but not the (+)-isomer. (-)-Propranolol did not antagonize the behaviour induced in rats. In mice, both 8-OH-DPAT and RU 24969 markedly inhibited whole brain 5-HT synthesis and this effect was not antagonized by (-)-propranolol. In rats, 8-OH-DPAT (3 mg kg-1 s.c.) produced all the behavioural changes seen after quipazine (25 mg kg-1). (-)-Propranolol inhibited the behaviour changes produced by both agonists, while ritanserin antagonized the behaviour produced by quipazine but not 8-OH-DPAT. It is concluded, therefore, that the 5-HT1A receptor exists between the 5-HT2 receptor and the behavioural effectors. 8-OH-DPAT (at 20 degrees C ambient temperature) rapidly decreased rat body temperature, an effect antagonized by (-)-propranolol but not ritanserin. Quipazine (at 27 degrees C ambient temperature, but not 20 degrees C) increased body temperature but the effect was not blocked by either antagonist. Ritanserin does not antagonize apomorphine-induced locomotion in either species. 9 We suggest that 5-HT-induced head-twitch behaviour in mice is a useful 5-HT2 receptor model and the temperature change following 8-OH-DPAT injection in rats may be a 5-HT,A model. While (-)- propranolol antagonizes 8-OH-DPAT effects in rat, it does not inhibit 8-OH-DPAT effects in mice, and instead antagonizes RU 24969-induced locomotion. Its status as a 5-HT, antagonist remains illdefined.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in the hot-plate and tail-flick tests, but not in the shock titration test. Intrathecal yohimbine showed a dose-related lowering of pain thresholds in saline and 5-MeODMT-treated animals. Phentolamine and prazosin produced normal dose-related curves in the hot-plate test and biphasic effects in the shock titration and tail-flick tests. These results demonstrate a functional interaction between alpha 2-adrenoceptors and 5-HT agonist-induced analgesia at a spinal level in rats.

Adrenergic alpha-Antagonists↗
PubMed1986

The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions.

Alanine↗
PubMed1986

The effects of monoamine oxidase inhibitors on the ejaculatory response induced by 5-methoxy-N,N-dimethyltryptamine in the rat.

The ejaculatory response and other components of the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1, i.p.) were studied following single and repeated treatment of rats with eight different monoamine oxidase (MAO) inhibitors. Single and repeated treatment with the 5-HT agonist 5-MeODMT, and with low doses of the potent releaser of 5-HT, p-chloroamphetamine (PCA) were also included in the study. Repeated but not single treatment with 5-MeODMT reduced strongly but reversibly the ejaculatory response and the behavioural responses. Repeated but not single treatment with the nonselective and irreversible MAO inhibitors nialamide and pargyline reduced markedly the ejaculatory response but only slightly the 5-HT behavioural responses. Repeated treatment with the irreversible MAO-B inhibitor (-)-deprenyl, with the irreversible MAO-A inhibitor, clorgyline, with the reversible MAO-A inhibitor moclobemide, and with low doses of PCA did not affect either of the responses. Repeated but not single combined treatment with clorgyline plus PCA caused an almost complete blockade of all the four responses. The selective and reversible MAO-A inhibitors (as well as 5-HT releasers) amiflamine, alpha-ethyltryptamine, and alpha-methyltryptamine reduced markedly the ejaculatory response after both single and repeated treatments. The behavioural responses were blocked only after repeated treatment. It is concluded that single and repeated treatments of rats with different MAO inhibitors do not produce a common alteration in 5-HT2 receptor functions. Repeated treatment with 5-MeODMT caused a blockade of 75-95% of the ejaculatory response and 5-HT behavioural responses. A similar strong blockade was only produced by the combined effect of MAO-A inhibition and 5-HT release.

Animals↗
PubMed1989

Involvement of 5-HT2 receptors in the behaviours produced by intrathecal administration of selected 5-HT agonists and the TRH analogue (CG 3509) to rats.

1. The behavioural effects of the intrathecal injection of a thyrotrophin-releasing hormone (TRH) analogue L-orotyl-L-histidyl-prolineamide (CG 3509, 0.5 micrograms), the non-selective 5-HT1 and 5-HT2 receptor agonist 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT, 2-100 micrograms) and the selective 5-HT2 receptor agonist 2,5-dimethoxy-alpha,4-dimethyl-benzene ethamine hydrochloride (DOM, 2-25 micrograms) were compared with the response of systemically administered 5-MeODMT (2 mg kg-1, i.p.) in rats, to establish whether the agonist-induced behaviours were mediated by bulbospinal 5-HT1 or 5-HT2 receptors. 2. Intrathecal injection of 5-MeODMT or DOM produced dose-related back muscle contractions (a previously undocumented behaviour) and wet-dog shakes which were both markedly attenuated by ritanserin pretreatment (1 mg kg-1, i.p.) indicating the involvement of 5-HT2 receptors. In contrast, reciprocal forepaw treading, flat body posture and Straub-tail were evoked by 5-MeODMT but not by DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. However, as ritanserin pretreatment reduced the reciprocal forepaw treading induced by intrathecal 5-MeODMT, this behaviour may be facilitated by 5-HT2 receptor activation. 3. Intrathecal 5,7-dihydroxytryptamine (5,7-DHT, 2 x 150 micrograms) treatment decreased thoraco-lumbar spinal cord 5-HT (-95%) and potentiated the back muscle contractions produced by intrathecal DOM injection without altering the wet-dog shake behaviour. None of the components of the 5-HT syndrome produced by 5-MeODMT (2 mg kg-1, i.p.), with the exception of a small increase in wet-dog shakes, was significantly altered by intrathecal 5,7-DHT (which reduced thoraco-lumbar spinal cord 5-HT by 84%). Taken together these data suggest that the only 5-HT agonist-induced behaviour mediated by the activation of 5-HT2 receptors located postsynaptic to bulbospinal 5-hydroxytryptaminergic (5-HTergic) neurones was back muscle contractions. 4. The wet-dog shake and forepaw licking behaviors produced by intrathecal CG 3509 (0.5 micrograms) were attenuated when ritanserin was administered intrathecally 30 min before, but not when it was given at the same time as CG 3509 and neither behaviour was altered by intrathecal 5,7-DHT. This suggests that bulbospinal 5-HTergic neurones are not involved in the production of these TRH analogue-induced behaviours and that the 5-HT2 receptors which mediate these behaviours are not located in the spinal cord.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1989

An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats.

1. Reserpine (2.5 mg kg-1 i.p.) decreased rat brain 5-hydroxytryptamine (5-HT) by 86% 24 h later but most components of the 5-HT-dependent behavioural syndrome induced by p-chloroamphetamine (PCA, 5 mg kg-1 i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg kg-1 i.p.) over 1 h after administration were unaffected. However, Straub tail was increased after giving PCA or 5-MeODMT and head weaving was decreased after giving 5-MeODMT. 2. Frontal cortex extracellular 5-HT concentrations of vehicle pretreated rats before injection of PCA, as calculated from dialysate 5-HT concentrations, were about 1/1000th of corresponding brain values. Extracellular 5-hydroxyindoleacetic acid (5-HIAA) and brain values were comparable with each other. Dialysate 5-HT increased after PCA with peak values at 20-40 min. 3. Reserpine pretreatment reduced dialysate 5-HT concentration before PCA was given but the net increase (AUC) over the 1 h after PCA did not differ significantly from that seen in animals pretreated with vehicle. Dialysate 5-HIAA values slowly decreased after PCA injection in both reserpine and vehicle pretreated groups. 4. The results suggest that PCA causes the 5-HT syndrome by releasing 5-HT from the neuronal cytoplasm but that physiological release of 5-HT occurs from vesicular stores.

Amphetamines↗
PubMed1990

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice.

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM. 6. Verapamil (25mgkg-', i.p.), nicardipine (25mgkg-1, i.p.) and nifedipine (20mgkg-1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5- methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6mgkg-'. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 microM) and nicardipine (IC50:8 microM) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range.7. Hydralazine (5mg kg 1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/L-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8. These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2 + channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Evidence that RU 24969-induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5-HT1B receptor.

1. The behavioural effects of the 5-HT1B receptor agonists, RU 24969 and CGS 12066B, have been investigated in C57/B1/6 mice. 2. RU 24969 (1-30 mg kg-1) produced intense and prolonged hyperlocomotion and other behavioural changes. 3. CGS 12066B caused similar effects, but they were much less pronounced, inconsistent and transient irrespective of whether this drug was given i.p. (1-15 mg kg-1) or i.c.v. (0.2-40 micrograms). However, CGS 12066B (7.5 and 15 mg kg-1) caused a dose-related inhibition of RU 24969 (7.5 mg kg-1)-induced hyperlocomotion indicating that the former is a 5-HT1B partial agonist. 4. RU 24969 (7.5 mg kg-1 i.p.)-induced hyperlocomotion was inhibited by the (-)-, but not (+)-isomers of pindolol (4 mg kg-1) and propranolol (20 mg kg-1) but not by metoprolol (10 mg kg-1) or ICI 118,551 (5 mg kg-1), consistent with an involvement of 5-HT1A or 5-HT1B receptors. 5. The response was not altered by the selective 5-HT1A receptor antagonist, WAY 100135 (5 mg kg-1, s.c.), the 5-HT2A/5-HT2C receptor antagonist, ritanserin (0.1 mg kg-1), the selective 5-HT3 receptor antagonist, ondansetron (1 mg kg-1) or the non-selective 5-HT receptor antagonists methysergide (3 mg kg-1) and metergoline (3 mg kg-1). 6. Although spiroxatrine (0.1 mg kg-1) and ketanserin (1 mg kg-1) inhibited RU 24969-induced hyperlocomotion, these effects were probably due to antagonism of dopamine D2 receptors and alpha 1-adrenoceptors respectively. 7. Taken together, these results indicate that RU 24969-induced hyperlocomotion results specifically from activation of central 5-HTIB receptors.8. Lesioning of 5-HT neurones with 5,7-dihydroxytryptamine (75 microg, i.c.v.) or depletion with pchlorophenylalanine(200 mg kg-1, i.p. for 14 days) had no effect on RU 24969-induced hyperlocomotiondemonstrating that the 5-HTIB receptors involved are postsynaptic and that they do not show super sensitivity.9. The involvement of other monoamine neurotransmitter systems in RU 24969-induced hyperlocomotionwas also examined. The response was inhibited by the al-adrenoceptor antagonist, prazosin(1 mg kg-1), the dopamine DI receptor antagonist, SCH 23390 (0.05 mg kg-1) and the dopamine D2 receptor antagonist, BRL 34778 (0.03 mg kg-1), but not by the M2-adrenoceptor antagonist, idazoxan(1 mg kg-1). Lesioning noradrenergic neurones with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine(100 mg kg-1) markedly attenuated this behaviour. These results show that the hyperlocomotion is expressed via noradrenergic and dopaminergic neurones acting on alpha 1-adrenoceptors, DI and D2 receptors.10. RU 24969 decreased brain concentrations of 5-hydroxyindoleacetic acid whilst simultaneously increasing 5-HT, consistent with the reduction of 5-HT neuronal activity by activation of 5-HTlA and 5-HTIB autoreceptors. RU 24969 increased brain 3-methoxy-4-hydroxyphenylglycol, but not noradrenaline, concentrations which supports the involvement of noradrenergic neurones in the expression of hyperlocomotion. RU 24969 did not alter dopamine, dihydroxyphenylacetic acid or homovanillic acid concentrations in the nucleus accumbens suggesting that the dopaminergic neurones terminating there are not directly involved.

Animals↗
PubMed1981

Effect of antidepressants, lithium and electroconvulsive treatment on rat serum prolactin levels.

The ability of antidepressant drugs, electroconvulsive treatment (ECT), or lithium chloride (LiCl), to modify prolactin secretion in the rat was studied. Chlorimipramine, citalopram, fluoxetine, imipramine and zimelidine potentiated the low dose 5-hydroxytryptophan (5-HTP)-induced increase in prolactin secretion, suggesting inhibition of serotonin (5-HT) uptake by these drugs. Amitriptyline, doxepin, iprindole, mianserin and trazadone inhibited the prolactin stimulating effects of high doses of 5-HTP and quipazine, suggesting that these drugs have 5-HT receptor blocking properties. Tandamine inhibited only 5-HTP-induced increase in prolactin secretion. Chronic administration of imipramine, potentiated the effect of low dose 5-HTP significantly more than an acute dose. Amitriptyline, produced similar inhibition of the 5-HTP-induced increase in prolactin secretion after both acute and chronic administration. The ability of bupropion and mazindol to inhibit alpha-methylparatyrosine-induced prolactin secretion, and of nomifensine to inhibit reserpine-induced prolactin secretion, is consistent with other evidence that these agents are indirect dopamine (DA) agonists. Desipramine, acutely, had no effect on any of the above paradigms but after chronic administration, potentiated the effect of low dose 5-HTP on prolactin secretion. Nortriptyline had no effect on prolactin secretion after acute or chronic treatment. ECT for 10 days did not affect the ability of a 5-HT agonist or d-amphetamine to modify prolactin secretion. However, chronic, but not acute, treatment with LiCl markedly enhanced the prolactin response to 5-HT agonists and reserpine while shifting the dose response curve for d-amphetamine and apomorphine to the right. These results are discussed in light of current theories of the role of 5-HT and DA in depression.

5-Hydroxytryptophan↗
PubMed1984

Effects of acute administration of 5-methoxy-N,N-dimethyltryptamine upon the latency and duration of post-decapitation convulsions.

The effect of acute administration of rats with the 5-hydroxytryptamine (5-HT) agonist drug 5-methoxy-N,N-dimethyltryptamine on the convulsions released by decapitation was examined. The postsynaptic agonist, 5-methoxy-N,N-dimethyltryptamine, prolonged the latency and duration from the 0.5 mg/kg dose upwards. Methergoline, 2.0 mg/kg intraperitoneally injected immediately prior to 5-methoxy-N,N-dimethyltryptamine, caused some considerable blockade of the effects of the 5-HT agonist on post-decapitation convulsions (PDG's). Long-term p-chloroamphetamine (2x10 mg/kg) and p-chlorophenylalanine (1 x 300 mg/kg) did not antagonise the 5-methoxy-N-N-dimethyltryptamine induced changes of PDC's but, by themselves, prolonged PDC duration. The utility of the 5-methoxy-N,N-dimethyltryptamine-PDC method for studying 5-HT receptor mechanisms may be worth considering.

Animals↗
PubMed1986

Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine.

The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function.

Analgesics↗
PubMed1986

Long lasting supersensitivity to 5-HT mediated behaviour following monoamine depletion in the rat brain.

The effects of the depletion of 5-hydroxytryptamine (5-HT) in the rat brain upon the 5-HT behavioural syndrome (ejaculatory response, abduction of hind-limbs, forepaw treading, and Straub tail) induced by 5-methoxy-N,N-dimethyltryptamine (1 mg/kg intraperitoneally) were investigated. The 5-HT depletion was produced by p-chlorophenylalanine (PCPA 2 X 200 mg/kg intraperitoneally) or by reserpine (5 mg/kg subcutaneously). It resulted in rapidly developing and long-lasting supersensitivity of the behavioural responses which were enhanced between 2 and 14 days after the PCPA injections and between 1 and 42 days after a single dose of reserpine. The depletion of catecholamines by alpha-methyltyrosine (250 + 125 mg/kg intraperitoneally) had no effect. These results underline the usefulness of the 5-HT mediated behavioural models for studies of changes in 5-HT receptor activity.

Animals↗
PubMed1987

5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested.

Animals↗
PubMed1987

Blockade of central beta-adrenoceptors attenuates tremor induced by 5-hydroxytryptamine (5-HT)-receptor activation in rats.

The effect of beta-adrenoceptor antagonists, varying in lipophilicity and receptor selectivity, were studied on tremor elicited by L-5-hydroxytryptophan (L-5-HTP) in rats pretreated with a peripherally acting decarboxylase inhibitor and a monoamine oxidase inhibitor, or by the directly acting 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). Plasma levels of the beta-adrenoceptor antagonists were determined simultaneously. The non-selective lipophilic adrenoceptor antagonist propranolol was found to dose-dependently reduce tremor intensity, whereas the non-selective hydrophilic adrenoceptor antagonist sotalol had no effect, indicating a central site of action. Furthermore, beta 1-selective blockade with the adrenoceptor antagonist metoprolol had no effect on tremor intensity, whereas the beta 2-selective antagonist ICI 118,551 dose-dependently suppressed tremor intensity, suggesting that the beta-adrenoceptor subtype involved is of the beta 2-type. These results suggest that blockade of centrally located beta 2-adrenoceptors are able to attenuate the tremor response following 5-hydroxytryptamine receptor activation.

5-Hydroxytryptophan↗