The effect of mepiprazole on central monoamine neurons. Evidence for increased 5-hydroxytryptamine and dopamine receptor activity

In combined biochemical, histochemical and functional studies on central monoamine neurons it has been shown that a pyrozolyl derivative with a phenyl piperazine side-chain (PAP) exerts marked effects on central dopamine (DA) and particularly 5-hydroxytryptamine (5-HT) neurons. The brain 5-HT turnover was reduced with doses down to 0.25 mg/kg, and spontaneous overflow of radioactivity from ³H-5-HT-labelled cortical slices was markedly increased by PAP in a concentration of 10^?6 M. PAP may therefore cause extragranular release of 5-HT stores, since the 5-HT levels were not affected. In agreement with this view, sexual behaviour in the female rat, which is controlled by an inhibitory 5-HT pathway, was inhibited by low doses (0.1–0.5 mg/kg) of PAP. The extensor hindlimb reflex, which is dependent of 5-HT receptor activity, was only increased with higher doses (2.5–10 mg/kg), suggesting that the spinal 5-HT nerve terminals are less sensitive to the releasing action of PAP. A certain direct activation of spinal 5-HT receptors may also be involved, since the actions of PAP in the spinal cord were independent of presynaptic 5-HT stores. The actions of PAP on the DA neurons mainly involve a presynaptic action in the DA nerve terminals leading to increased DA receptor activity. This action may primarily involve a blockade of DA uptake (50% inhibition at 10^?6 M) and/or an extragranular release of DA (two-fold increase in spontaneous overflow at 10^?6 M). The DA turnover was not clearly affected, although a trend to a reduction was observed especially in the nuc. accumbens, probably as a result of a compensatory nervous feedback reducing nervous impulse flow. In agreement with the view mentioned above, PAP mimics amphetamine and not apomorphine in the rotometer model which reveals changes in DA receptor activity. PAP in doses of 0.5–1 mg/kg causes a turning towards the denervated side. The brain noradrenaline (NA) turnover is only significantly increased with somewhat higher doses (5–10 mg/kg) and may be related ot NA receptor blockade, since the L-DOPA-induced increase in flexor activity is blocked by PAP in doses down to 0.5 mg/kg.It is suggested that the extragranular release of 5-HT caused by PAP is partly responsible for the inhibition of conditioned avoidance behaviour and the reduction of threatening behaviour found after PAP in low doses (0.05–0.5 mg/kg). In the clinic, PAP may prove to be a new therapeutic tool in the treatment of depressions due to 5-HT deficiency. Its actions on DA terminals may also prove helpful in this respect. When combined with L-DOPA, PAP may also help to alleviate the motor deficits in parkinsonian patients with a moderate degree of degeneration of the DA system in view of its action on DA uptake and/or release.     

Effect of diazepam on cerebral 5-hydroxytryptamine synthesis.

In the brains of normal and reserpinized rats both diazepam and amino-oxyacetic acid (AOAA) decreased the 5-hydroxytryptophan (5HTP) accumulation induced by the decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD 1015). In reserpinized animals, the action of diazepam was antagonized by picrotoxin and bicuculline in doses which did not themselves influence the NSD 1015-induced rise in 5HTP. In conclusion, diazepam probably depresses 5HT synthesis via GABAergic mechanisms and this effect is not dependent on a functionally intact monoaminergic synaptic transmission.     

Interactions between alinidine and responses to acetylcholine, dopamine and 5-hydroxytryptamine of specific Helix central neurones.

Intracellular recordings were made from identified neurones in the brain of the snail, Helix aspersa. The effect of alinidine on the excitatory and inhibitory responses to acetylcholine and dopamine and on the excitatory response to 5-hydroxytryptamine (5-HT) was investigated. Alinidine was found to reduce the responses to acetylcholine and 5-HT and the excitatory response to dopamine but had no effect on the dopamine inhibitory response. pA2 values were determined for alinidine antagonism to indicate relative potency. The pA2 values against the excitatory responses of acetylcholine, dopamine and 5-HT were 5.8, 5.6 and 5.5 respectively. The pA2 value against acetylcholine inhibition was 3.5. From these studies it is suggested that alinidine interacts preferentially with the sodium inonophore, to a lesser degree with the chloride ionophore and not at all with the potassium ionophore on Helix central neurones.     

Neurophysiological effects of buspirone and isapirone in the hippocampus: comparison with 5-hydroxytryptamine

The neurophysiological effects of two novel anxiolytic compounds, buspirone and isapirone (TVX Q 7821), were compared with those of 5-hydroxytryptamine (5-HT) on the population spike in the CA1 region of the rat hippocampal slice. Micromolar concentrations of the two drugs mimicked the inhibitory effect of 5-HT but unlike 5-HT they did not produce any significant excitation. In slices in which 5-HT was purely excitatory, there was a marked reduction in the inhibitory response to these agents. The effect of isapirone was antagonised by spiperone. These results suggest that buspirone and isapirone are agonists for 5-HT1A receptors in the hippocampus.     

Potentiation of haloperidol-induced catalepsy by dopamine agonists: possible involvement of central 5-hydroxytryptamine

Apomorphine (0.12--2 mg/kg, SC) and d-amphetamine (1--8 mg/kg, IP) were each able, at certain doses, to potentiate the cataleptic state produced by the neuroleptic agent, haloperidol (1 mg/kg, IP). In subsequent biochemical experiments, in which the effects of combinations of apomorphine or d-amphetamine and haloperidol on brain monoamine levels were studied, this behavioural observation was seen to be related to an enhanced utilisation of 5-hydroxytryptamine (5-HT) in certain brain regions. The results suggest not only the possible involvement of 5-HT in the production of catalepsy, but also that the effects of these 'classical' dopamine agonists on other central transmitter systems should be considered when interpreting their various behavioural responses.     

Effect of ergot drugs on central 5-hydroxytryptamine neurons: Evidence for 5-hydroxytryptamine release or 5-hydroxytryptamine receptor stimulation

In combined biochemical and functional studies it has been possible to show that ergocornine (0.5-5 mg/kg) and the ergolene derivative (5R,8R)-8-(4-p-methoxyphenyl-1-piperazinylmethyl)-6-methylergolene (PTR 17402; MPME) (0.25-5 mg/kg) reduce in a dose-dependent way brain 5-hydroxytryptamine (5-HT) turnover in rat as evaluated with the tryptophan hydroxylase inhibitor, alpha-propyl-dopacetamide (H 22/54), whereas 2-Br-alpha-ergocryptine (CB 154; Br-EC) had no effect on brain 5-HT turnover. Effects on 5-HT receptor activity were evaluated using the extensor hindlimb reflex of acutely spinalized rats. It was found that ergocornine increased the 5-HT receptor activity independent of presynaptic 5-HT stores and that it didnot have any effects on uptake, retention and spontaneous overflow of 3-H-5-HT in vitro but reduced the fiedl stimulation-induced release of 3-H-5-HT in vitro. Therefore, it is suggested that ergocornine is a 5-HT recpetor-stimulating agent, an effect which may lead to reduction of nervous impulse flow in the 5-HT neurons and subsequently of 5-HT release and turnover. MPME, on the other hand, seems to increase 5-HT receptor release of 5-HT stores, mainly from extragranular sites. Thus, the increase in extensor reflex activity found after MPME was reduced by reserpine and H 22/54 and enhanced by nialamide and in vitro MPME markedly increased 3-H-5-HT overflow in cortical slices of nialamide-pretreated rats and inhibited uptake and retention of 3-H-5-HT (EC50 equals 1.6 times 10-minus 6 M) in cortical slices of normal rats. Inhibition of the 5-HT membrane pump does not seem to be of any major importance, since chlorimipramine was only weakly active on the extensor reflex in the pharmacological models used and since MPME did not block but rather enhanced the 5-HT depletion caused by 4-methyl-alpha-ethyl-m-tyramine. It is suggested that MPME is a releaser of extragranular 5-HT stores leading to increased 5-HT receptor activity and reduction of 5-HT turnover in the same way as indicated for ergocornine. This new ergolene derivative may represent a new class of antidepressant drugs acting via release of extragranular 5-HT stores.     

DSP-4 lesioning prevents the enhancement of dopamine and 5-hydroxytryptamine mediated behavioural changes by repeated electroconvulsive shock

DSP-4 (N-(2-chloroethyl)-ethyl-2-bromobenzylamine) a novel neurotoxin which destroys central noradrenaline neurones after peripheral injection was administered to rats (50 mg/kg X 2). This procedure did not alter activity responses to quipazine (7.5 mg/kg) or apomorphine (0.2 mg/kg) but prevented their enhancement by repeated electroconvulsive shocks (ECS X 10). This confirms that intact noradrenergic function is required for ECS-induced enhancement of 5-HT and dopamine mediated responses. Furthermore, DSP-4 is shown to provide a simple, effective alternative to centrally injected 6-hydroxydopamine for noradrenergic lesioning.     

On the action of nicotine and cotinine on central 5-hydroxytryptamine neurons.

The actions of nicotine, and its main metabolite cotinine, on 5-hydroxytryptamine (5-HT) neurons in the brain of the rat have been assessed biochemically (on turnover, uptake, release, overflow and binding of 5-HT in brain) and functionally (on extensor reflex activity, which is 5-HT dependent). Nicotine and cotinine in repeated doses of 2 mg/kg caused a reduction of brain 5-HT turnover, which was not blocked by pretreatment with mecamylamine, and nicotine sifnificantly inhibited the effects of norfenfluramine and 5-methoxydimethyltryptamine on extensor reflex activity, effects counteracted by mecamylamine. In low concentrations cotinine weakly inhibits the uptake and retention of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT turnover caused by high doses of nicotine are mediated, at least in part, by its main metabolite cotinine. The experiments on extensor reflexes indicate that nicotine can block the functional expression of 5-HT receptor activity in the spinal cord by an action beyond the 5-HT receptor at nicotine-like cholinergic receptors whose location is also discussed.     

The binding of haloperidol to human blood platelets and interactions with 5-hydroxytryptamine and dopamine.

1 The binding of [3H]-5-hydroxytryptamine ([3H]-5-HT), [3H]-haloperidol and [3H]-dopamine to human blood platelets was investigated and the effects of unlabelled haloperidol on [3H]-5-HT binding and (+)- and (-)-butaclamol on [3H]-haloperidol were studied. 2 Scatchard analysis did not show any specific binding of [3H]-haloperidol or [3H]-dopamine to platelets, but two binding sites were identified for binding of [3H]-5-HT. 3 Unlabelled haloperidol reduced the binding of 5-HT in concentrations comparable to those inhibigint 5-HT-induced platelet aggregation; (+)- and (-)-butaclamol did not affect the binding of [3H]-haloperidol. 4 It is concluded that haloperidol binding represents saturation of the platelet membrane, and that the platelet is not a suitable model for investigation of dopamine-drug interactions.     

Studies with new ergoline derivatives on the effects of central and peripheral 5-hydroxytryptamine receptors.

The antiserotonin properties of a series of new ergoline derivatives were investigated in several pharmacological test systems which have been proposed for the characterization of putative antagonists at central and peripheral 5-HT2 receptors. In radioligand binding studies with [3H]ketanserin among the new ergolines only 1-methyl-2-brom-9,10-dihydrolysergic acid-bis(beta-acetoxyethyl)-amide (AWD 52-336) showed high affinity at cortical 5-HT2 receptors (Ki-5.4 nmol/l). In 5-HT-amplified ADP-induced aggregation of human platelets 6-nor-6-propyl-9,10-dihydro ergometrine (AWD 52-227) and 9,10-dihydrolysergic acid-di-ethanol-amide (AWD 52-302) were potent inhibitors of 5-HT response. Comparison of this two in vitro tests demonstrated a significant correlation (r = 0.636; p < 0.05) between the ability of the ergolines to block the 5-HT aggregation mediated by platelet 5-HT2 receptors and their affinity to [3H]ketanserin-labelled binding sites in rat cortical membranes. In the used in vivo tests (tryptamine tremor, 5-HTP-induced head twitches) 1-methyl-9,10-dihydrolysergic acid-bis(beta-acetoxyethyl)-amide (AWD 52-83) and AWD 52-336 were found to antagonize the behavioural responses with comparatively moderate potency. The results suggest, therefore, that AWD 52-83 and AWD 52-336 may be both central and peripheral acting 5-HT2 antagonists, whereas AWD 52-227 and AWD 52-302 seem to be potent blockers at peripheral 5-HT2 receptors. Furthermore, the obtained results allow to reveal structure-activity relationships of ergolines. Substitution in position 1 in the tetracyclic ergoline ring system may be important with respect to the efficacy at central 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of lithium on central metabolism of 5-hydroxytryptamine

The administration of lithium carbonate for 5 days to rats increased the synthesis rate of brain serotonin, without modifying the brain level of the amine. This increase was not due to a modification of the free tryptophan in the blood. The level of serotonin and 5 HIAA remained unchanged in seven areas of brain. These results are discussed in comparison with the results of the other authors on the same subject.Attachée de recherche INSERM.     

The central vasomotor effects of 5-hydroxytryptamine

In the dog, injection of 5-hydroxytryptamine into the cerebral ventricles caused hypotension, inhibition of the pressor response to occlusion of the carotid artery and inhibition of the pressor or depressor response evoked by electrical stimulation of the central end of the cut vagus. Hypotension and inhibition of the vagal vasomotor response also occurred in dogs in which the carotid sinuses had been denervated and the vagi cut. The site of action was central. Local cerebral vascular changes could not have been responsible for the action. The central vasomotor effects of 5-hydroxytryptamine are mediated through the sympathetic outflow. Implications of these findings are discussed in relation to the effects of intravenous 5-hydroxytryptamine and the mechanism of action of reserpine.     

Dexfenfluramine-induced prolactin release as an index of central synaptosomal 5-hydroxytryptamine during treatment with fluoxetine

Serotonin (5-HT) stimulates prolactin release. In the present study the ability of dexfenfluramine to increase serum prolactin was used as an index of central 5-HT function after acute and chronic pretreatment of volunteers with fluoxetine.Following a single-blind, random design, on each experimental day each volunteer received 60 mg dexfenfluramine taken with 250 ml water at zero time and no other treatment, or pretreatment with 40 mg fluoxetine at -8 h, or pretreatment with 20 mg fluoxetine daily for 14 days, or the dexfenfluramine alone 14 days after cessation of 14 days of fluoxetine treatment.There were no significant differences between the prolactin levels found after dexfenfluramine only, dexfenfluramine after a single dose of fluoxetine, and dexfenfluramine 14 days after cessation of fluoxetine treatment. However, baseline levels and those 3 and 4 h after dexfenfluramine administration were significantly lower after pretreatment for 14 days with fluoxetine compared to the other three regimens. At 5 h the levels were still lower, but not significantly so, as the prolactin level rose approximately 110% compared to the baseline and 4 h values.The reduction in the median basal serum prolactin level by almost two-thirds after 14 days of fluoxetine treatment suggests a decrease in 5-HT turnover. Furthermore, the delayed surge in prolactin release produced by dexfenfluramine with this regimen suggests 5-HT release from a less accessible pool or accumulation of fluoxetine in the neuronal cytosol and consequent competitive inhibition of 5-HT transport out of the nerve terminal.5-HT turnover is reduced in depression. The present results suggest similar impairment of central 5-HT function in normal volunteers treated with fluoxetine. Thus, rather than cause an increase in 5-HT turnover, anti-depressants may correct defects in the 5-HT system. We speculate that anti-depressant treatment which decrease 5-HT turnover may lead to disturbed aggression regulation and violent self-destructive impulses.     

Influence of the selective ligands of dopamine and 5-hydroxytryptamine receptors on the tolerance to global cerebral ischemia

Selective dopamine (D) receptor agonists either slightly improve (D2 and D3) or do not affect (D1 and D4) the tolerance of the brain to global ischemia. As for D and 5-HT (hydroxytryptamine) antagonists, only D1 antagonist SCH 23390 and 5-HT2 antagonist ketanserin produce a small neuroprotective effect, while D2, D4, 5-HT(2B) and 5-HT(2C) antagonists are not active. Simultaneous injection of D2 (raclopride), D3 (GR 103691), and D4 (L 745870) receptor blockers also does not protect the brain. These results are not at variance with a widespread hypothesis that the accumulation of extracellular 5-HT and especially D in the brain causes the neuron damage. The effect of ketanserine is not increased by D2 or D4 blockers, but the introduction of D3 blocker GR 103691 (+88%) and especially the simultaneous injection of D2,3,4 antagonists improve the effect of ketanserine (+134%). The neuroprotective effect of the last combination is not lower but even exceeds that of some neuroleptics. This fact shows the possibility to increase the tolerance to cerebral ischemia by simultaneously blocking D and 5-HT-receptors.     

Effects of tetrahydropapaveroline on dopamine and 5-hydroxytryptamine metabolism in rat brain in vivo.

HVA and 5-HIAA levels have been assayed in the rat brain at different time intervals after acute or chronic i.p. administration of tetrahydropapaveroline (THP), 8 and 60 mg/kg. In addition, the influence of THP pretreatment on the L-dopa-induced HVA increase in the rat brain as well as the PCPA-induced 5-HIAA decrease have been studied. The results support the possibility that THP may displace brain monoamines in vivo. This property of THP may be related to certain side effects of L-dopa long-term therapy in parkinsonism.     

Increased central 5-hydroxytryptamine receptor mechanisms in rats after chronic neuroleptic treatment

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.

2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and `wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals.

3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats.

4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats.

5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals.

6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals.

7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.

     

Some central effects of repeated treatment with fluvoxamine

We investigated the effect of repeated treatment with fluvoxamine, a selective serotonin uptake inhibitor, on behavioral effects of dopaminomimetics and methoxamine and on the animal behavior in the "behavioral despair" test. A repeated treatment with fluvoxamine (twice daily for 14 days) potentiated in mice and in rats (weaker) the amphetamine-induced hyperactivity. The hyperactivity induced by nomifensine in mice remained unaffected by fluvoxamine. The stimulation of locomotor activity by intracerebroventricularly administered methoxamine was not affected by repeated treatment with fluvoxamine. Given three times fluvoxamine had no effect on the immobilization time in the "behavioral despair" test in rats. The results indicate that fluvoxamine given repeatedly acts differently than citalopram, another selective serotonin uptake inhibitor, and differs also from other antidepressant drugs.