Lucy Rényi

Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT.

The effects of repeated treatment of rats with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Ejaculations induced by p-chloroamphetamine in the rat☆

The ejaculatory response following acute injections of p-chloroamphetamine (PCA) and several other drugs was measured by weighing the compact seminal material accumulated over 2 hr. p-Chloroamphetamine caused a dose-dependent ejaculatory response that was inhibited by the inhibitor of the synthesis of 5-hydroxytryptamine (5-HT), p-chlorophenylalanine (PCPA), neurotoxic doses of PCA, reserpine, DSP 4 a selective noradrenergic neurotoxin given 48 hr before PCA, the inhibitor of synthesis of noradrenaline (NA) FLA 63, the specific inhibitors of uptake of 5-HT, alaproclate, fluoxetine and norzimeldine and the selective inhibitor of the uptake of NA, CPP 199, the E form of norzimeldine. The doses of several receptor antagonists producing a 50% decrease in the weight of seminal material were determined. The non-selective 5-HT receptor antagonists, metitepine and methergoline, the selective alpha 1-adrenoreceptor antagonists, prazosin and phenoxybenzamine and the non-selective alpha-adrenoreceptor antagonist, phentolamine, had strong effects, followed by the selective 5-HT2 antagonists, ketanserin and pirenperone. Yohimbine, an alpha 2-adrenoreceptor antagonist and atropine, a muscarinic receptor antagonist, only produced a partial blockade. The rank order of potency for some dopamine (DA) receptor antagonists was chlorpromazine, domperidone, haloperidol, pimozide. Remoxipride, a selective DA2 receptor antagonist and the selective DA1 antagonist, Sch 23390, had no effect. The following drugs had no effect: propranolol, naloxone, picrotoxin, cimetidine and mepyramine. The 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT 3 mg/kg, i.p.) produced a small effect on the weight of seminal material, although 72% of the rats ejaculated. d-Amphetamine did not induce ejaculation at 5 mg/kg but had a marked effect at 15 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

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

1 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. 2 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. 3 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. 4 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. 5 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.

N-Methyl-D-aspartate receptor antagonists counteract the long lasting 5-HT1A receptor-induced attenuation of postsynaptic responses in the rat in vivo

SummaryThe effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine and phencyclidine, the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) and the antagonist at the glycine modulatory site of the NMDA receptor, 3-amino-l-hydroxy-2-pyrrolidone (HA-966) on the long lasting attenuation of some postsynaptic 5-HT1A receptor-mediated responses in rats (increased corticosterone secretion and inhibition of the cage leaving response) produced by a single injection of the 5-hydroxytryptamine1A 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied. It was found that these antagonists counter-acted the attenuation of these responses at dose levels known to block the NMDA receptor-ion channel complex in vivo. It is concluded that the long lasting attenuation of postsynaptic responses after a 5-HT1A receptor agonist is initiated through stimulation of glutamate NMDA receptors indicating a functional interaction between the 5-HT and glutamate systems in at least two different models.

The non-competitive NMDA receptor antagonist (+)MK-801 counteracts the long-lasting attenuation of the hypothermic response induced by acute doses of 8-OH-DPAT in the rat ☆

The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothermic response, induced by a challenge dose of 8-OH-DPAT, were examined in rats. Acute doses of 8-OH-DPAT (1.0 or 0.5 mg/kg, s.c.) significantly attenuated the hypothermic response induced by 8-OH-DPAT (0.05 mg/kg, s.c.). The response to 8-OH-DPAT was almost abolished between 4 hr and 4 days and the attenuation of the response lasted for 21 days. On day 28 the response had returned to the control level. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine [(+)MK-801], blocked this long-lasting attenuation of the 8-OH-DPAT-induced hypothermic response. Given on its own, (+)MK-801 did not reduce body temperature, at the doses used in the experiments but the drug did block the acute effects of 8-OH-DPAT, at the same doses which blocked the attenuation of the hypothermic response. The present data suggest that stimulation of glutamate NMDA receptors may underlie the long-lasting effect of acute injections of 8-OH-DPAT.

The inhibition of the cage-leaving response—A model for studies of the serotonergic neurotransmission in the rat

It was observed that rats that had been given drugs that enhance serotonergic neurotransmission,e.g. the serotonin releasing compounds p-chloroamphetamine (PCA) and fenfluramine, the MAO-A inhibitors and serotonin releasing agents amiflamine andα-ethyltryptamine and the serotonin agonists 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT), m-chlorophenyl piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl)1H-indole (RU 24969), did not leave their home-cages when the grid-covers were removed in contrast to normal rats who almost immediately left the cages. The association between the serotonin neurotransmission and the inhibitory effect of PCA on the cage-leaving response was indicated by the findings that 1. Serotonin uptake inhibitors (alaproclate and citalopram) antagonized the effect of PCA. 2. High, neurotoxic doses of PCA antagonized the effect of PCA when tested one week after the former administration. The serotonin uptake inhibitor zimeldine counteracted the effect of neurotoxic PCA. 3. Depletion of brain serotonin with p-chlorophenylalanine counteracted the effect of acute PCA. 4. Repeated treatment of rats for 7 days with zimeldine, amiflamine,α-ethyltryptamine or clorgyline plus a low dose of PCA counteracted the effect of acute PCA probably due to a functional downregulation at postsynaptic receptors. Clorgyline or a low dose of PCA by themselves had no effect. 5. Compounds interacting with dopamine or noradrenaline mechanisms,e.g. α-methyltyrosine, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP 4), pimozide, remoxipride and prazosin did not antagonize the effect of PCA nor did (+)-amphetamine inhibit the cageleaving response. None of the serotonin receptor antagonists (cinanserin, ketanserin, metergoline, methysergide, metitepine, mianserin, pirenperone) blocked the inhibition of the cage-leaving response produced by PCA, indicating that the receptors involved may not be of the S1 and S2-types. Observation of the cage-leaving response may be a valuable technique in studies of drugs that enhance the serotonin neurotransmission in the rat brain.

Biochemical and behavioural effects of isamoltane, a β-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain

SummaryThe biochemical and behavioural effects of isamoltane, a \-adrenoceptor and 5-HT1B receptor antagonist that has higher affinity for 5-HT1B receptors than for 5-HTIA receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT1B receptor than for the 5-HT1A receptor (Ki values 21 and 112 nmol/l, respectively). Isamoltane increased the K+-evoked overflow of 3H from 3H-5-HT loaded slices of rat occipital cortex at 0.1 μmol/l, consistent with inhibition of the terminal 5HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the β-adrenoceptor blocking action of isamoltane since the β-adrenoceptor antagonists, (−)-alprenolol, betaxolol or ICI 118,551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT2 receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT2 receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response.

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

1 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. 2 Repeated but not single treatment with 5‐MeODMT reduced strongly but reversibly the ejaculatory response and the behavioural responses. 3 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. 4 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. 5 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, α‐ethyltryptamine, and α‐methyltryptamine reduced markedly the ejaculatory response after both single and repeated treatments. The behavioural responses were blocked only after repeated treatment. 6 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.

Antagonism of 5‐methoxy‐N,N‐dimethyltryptamine‐induced changes in postdecapitation convulsions in rats by repeated treatment with drugs enhancing 5‐hydroxytryptamine neurotransmission

Repeated administration of drugs that increase tryptaminergic neurotransmission antagonized the increase in latency to onset and the duration of postdecapitation convulsions (PDCs) induced by an acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) injection; Zimelidine (2 X 5 mg kg-1), fluoxetine (2 X 5 mg kg-1), amiflamine (2 X 2.5 mg kg-1) and alpha-ethyltryptamine (2 X 2.5 mg kg-1) administered orally over 10 days caused a substantial blockade of the increase in latency to onset and duration of PDCs following 5-MeODMT, whereas alaproclate (2 X 5 mg kg-1), clorgyline (1 X 1 mg kg-1) and pargyline (2 X 2.5 mg kg-1) caused a lesser blockade. Repeated 5-MeODMT (3 X 2 mg kg-1) administration blocked the acute effects of 5-MeODMT (2 and 4 mg kg-1) upon PDCs completely. These findings indicate down-regulation of the 5-hydroxytryptamine receptors which mediate the action of 5-MeODMT on the PDCs and offer a simple model system for studying 5-HT receptor sensitivity changes at the spinal level.

Plasticity Responses After Neonatal Dopamine Lesions Induced With 6-Hydroxydopamine

Selective lesions of mesencephalic dopamine neurons in newborn rats do not lead to the loss of motor function and feeding ability that is seen after similar lesions in adult rats. On the other hand, neonatal dopamine lesions induce changes that mimic certain aspects of the attention deficit and hyperactivity disorder, the Lesch–Nyhan syndrome as well as schizophrenia, e.g., locomotor hyperactivity, cognitive deficits and self-mutilation. A permanent and extensive loss of the nigrostriatal dopamine neurons is seen after neonatal intracerebral 6-hydroxydopamine administration, while other DA projection regions are less affected. The locomotor activity in lesioned rats is dependent on maintained presynaptic dopamine function. Dopamine synthesis in remaining terminals and reduced dopamine reuptake may act together in counterbalancing the lesion, though the response to pharmacological challenge is diminished. An increase in postsynaptic DA mediated behavior is seen after lesioning. D 1 and D 2 receptor binding appear to be unaltered in striatal and limbic regions, whereas D 1 receptor and G s protein stimulated adenylate cyclase activity is increased in striatum. The postsynaptic super sensitivity may therefore be due to alterations remote from DA recognition sites. A collateral sprouting of striatal serotonin fibers occurs after the lesion, indicating a competitive interaction in the development of striatal dopamine and serotonin systems. Treatment with 5-HT 2 receptor antagonists reduces the hyperactivity seen in lesioned rats, while 5-HT 1 A receptor mediated behaviors do not differ in lesioned compared to control rats, d -Amphetamine administration leads to a selective decrease in striatal serotonin metabolite levels in the lesioned rats. The levels of substance P, neurotensin, cholecystokininin are reduced in the basal ganglia following lesioning, while no changes in striatal synaptosomal d -aspartate or choline uptake are seen. Thus, a number of pre-and postsynaptic alterations occur in the DA system as well as in other neuronal systems after neonatal 6-hydroxydopamine lesions of mesencephalic dopamine neurons. These alterations appear to act in conjunction to reduce the consequences of early DA lesions, but they could also be involved in the behavioral changes seen after such lesions.