Single and repeated administration of neuroleptic drugs to rats: Effects on striatal dopamine-sensitive adenylate cyclase and locomotor activity produced by tranylcypromine and L-tryptophan or L-dopa

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_jreading 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,Ndimethyltryptamine (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.

Section: Resultsmentioning

confidence: 95%

A Behavioural and Biochemical Study in Rats of 5‐hydroxytryptamine Receptor Agonists and Antagonists, With Observations on Structure‐activity Requirements for the Agonists

Green¹,

Hall²,

Rees

1981

“…For instance, catecholamines have been suggested to have a role (Deakin & Green, 1978); reserpinised rats fail to exhibit some behavioural effects of 5-HT receptor stimulation (Tricklebank et al, 1984) and dopamine antagonists attenuate the syndrome (Heal et al, 1976). Squires & Lassen (1975) suggested that the syndrome may be dependent on N-substituted derivatives of 5-HT which are partly deaminated by MAO-B.…”

Section: Introductionmentioning

confidence: 99%

Relationship between extracellular 5‐hydroxytryptamine and behaviour following monoamine oxidase inhibition and l‐tryptophan

Sleight

Marsden

Martin

et al. 1988

1 The present study investigates the effects of selective and a non-selective monoamine oxidase (MAO) inhibitors combined with L-tryptophan on MAO-A and -B activity, hypothalamic extracellular 5-hydroxytryptamine (5-HT) in vivo and the occurrence of the 5-HT behavioural syndrome.2 Selective inhibition of intraneuronal MAO-A with MDL 72394 (0.5 mg kg-', i.p.) had no effect on extracellular 5-HT and following administration of L-tryptophan (50mg kg-', i.p.) the 5-HT behavioural syndrome was not induced. 3 Selective inhibition of MAO-A at all sites with clorgyline (5 mg kg-', i.p.) increased extracellular 5-HT but did not induce the 5-HT behavioural syndrome when combined with L-tryptophan administration. 4 Selective inhibition of MAO-B with selegiline (10mg kg-', i.p.) had no effect on extracellular 5-HT and the 5-HT behavioural syndrome was not observed after L-tryptophan administration. 5 Inhibition of MAO-A and -B with a higher and therefore non-selective, dose of MDL 72394 (2mg kg-') markedly increased extracellular 5-HT but failed to induce the 5-HT behavioural syndrome after L-tryptophan administration. 6 Inhibition of MAO-A and -B at all sites in the brain (tranylcypromine 20 mg kg-', i.p. or clorgyline 5mgkg-' plus selegiline 10mgkg-') increased extracellular 5-HT and induced the behavioural syndrome on administration of L-tryptophan. 7 The results demonstrate that inhibition of MAO-A and -B both within amine neurones and elsewhere in the brain is essential for the development of the 5-HT behavioural syndrome. Whilst the syndrome is associated with increased extracellular 5-HT this does not appear necessarily to result in the syndrome and may indicate that increased extracellular 5-HT is not solely involved in the induction of the '5-HT behavioural syndrome'.

“…This does not appear to be due to the dopamine receptor blocking action of this drug as several other neuroleptics examined (haloperidol, spiroperidol and a-flupenthixol) do not have this action (Heal et al, 1976). It seems probable that the enhancement is due to blockade of 5-HT receptors by chlorpromazine.…”

Section: Discussionmentioning

confidence: 89%

“…Since it has been demonstrated previously that the 5-HT hyperactivity syndrome is mediated via a postsynaptic dopaminergic system (Green & GrahameSmith, 1974) the question arises as to why repeated administration of other neuroleptics, which demonstrably increase dopaminergic sensitivity (Heal et a., 1976) does not result in increased 5-HT responses. No definitive answer can yet be given to this but it seems reasonable to suppose that transmitter interactions are modulatory and some alteration in the sensitivity of a dopaminergic system need not result in changes in 5-HT function.…”

Section: Discussionmentioning

confidence: 99%

“…Acute chlorpromazine administration inhibits this behavioural response (Grahame-Smith, 1971b;Heal, Green, Boullin & Grahame-Smith, 1976) as does pretreatment with several other neuroleptic drugs (Heal et al, 1976). Presumably this is because they block the dopaminergic system involved in this behavioural response to 5-HT receptor stimulation (Green & Grahame-Smith, 1974).…”

Section: Introduedonmentioning

confidence: 99%

See 1 more Smart Citation

Repeated Chlorpromazine Administration Increases a Behavioural Response of Rats to 5‐hydroxytryptamine Receptor Stimulation

Green

1977

1The hyperactivity syndrome produced in rats by administration of tranylcypromine (20 mg/kg i.p.) followed 30 min later by L-tryptophan (50 mg/kg i.p.) is generally considered to be due to increased 5-hydroxytryptamine (5-HT) functional activity. It is inhibited by chlorpromazine (30 mg/kg i.p.) injected 60 min before the tranylcypromine. However, chlorpromazine injection for 4 days either at a dose of 30 mg/kg once daily or 5 mg/kg twice daily results in an enhanced hyperactivity response to tranylcypromine and L-tryptophan administration 24 h after the final dose of chlorpromazine. 2 One injection of chlorpromazine (30 mg/kg) did not produce enhancement 24 h later and the inhibition of the tranylcypromine/L-tryptophan hyperactivity observed after acute chlorpromazine injection was seen if the rats were given tranylcypromine and L-tryptophan 1 h after the fourth chlorpromazine (30 mg/kg) dose. 3 Chlorpromazine (30 mg/kg) once daily or 5 mg/kg twice daily for 4 days resulted in rats displaying enhanced behavioural responses to the suggested 5-HT agonist 5-methoxy N,N-dimethyltryptamine (2 mg/kg) on day 5. 4 Chlorpromazine (30 mg/kg) once daily for 4 days produces a slight increase in brain 5-hydroxytryptamine (5-HT) concentration on day 5, but no difference in the rate of brain 5-HT synthesis or the rate of 5-HT accumulation after tranylcypromine and L-tryptophan administration. SThere is some evidence that chlorpromazine blocks 5-HT receptors. It has also been observed that several other neuroleptic drugs do not produce enhanced 5-HT responses after repeated administration. It is suggested therefore that the enhanced behavioural response to 5-HT receptor stimulation following repeated chlorpromazine administration may be because this drug blocks 5-HT receptors.