Increased sensitivity to serotonergic agonists after repeated electroconvulsive shock in rats

The effect of single and repeated electroconvulsive shock (ECS) (once daily for 7 days) on head twitches produced by 5-HT agonists (LiCl, 5-hydroxytryptophan; 5-HTP and 5-methoxytryptamine; 5-MT) was investigated 1 hr, 24 hr, 5 days and 10 days after the last ECS, while locomotor activity induced by serotonergic agonists (fenfluramine, 3-chlorophenylpiperazine; m-CPP) and antagonists (metergoline, cyproheptadine) was only investigated after 24 hr. 5HT and 5-HIAA concentrations were measured 0.5, 1 and 24 hr after a single ECS and up to 10 days after repeated ECS. Head twitches induced by LiCl were significantly depressed 1 hr after both single and repeated ECS. The number of head twitches produced by LiCl, 5-HTP or 5-MT given 24 hr after single or repeated ECS did not change but it rose significantly 5 and 10 days after the last shock. Repeated ECS increased locomotor activity 24 hr after the last shock. This increase was significantly enhanced by serotonergic antagonists. Biochemical assays showed that a single ECS did not significantly change brain 5-HT and 5-HIAA concentrations 0.5, 1 or 24 hr after the ECS. On the other hand, repeated ECS raised brain 5-HIAA 0.5, 1 and 24 hr or 5 and 10 days and 5-HT 0.5 hr after the final ECS. It is concluded that a single or repeated ECS both depress the serotonergic system response to LiCl but repeated ECS facilitates the response to serotoninomimetics.     

Neurochemical effects of electrically and chemically induced seizures: an in vivo microdialysis study in the rat hippocampus.

This study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), acetylcholine and choline, and the dopamine metabolite homovanillic acid (HVA) in the hippocampus of freely moving rats using online brain microdialysis. The effects of ECS on 5-HT, 5-HIAA, and HVA were compared to the effects of seizures induced by the convulsant agent flurothyl. Interstitial concentrations of 5-HT increased several fold in response to ECS and this increase was accompanied by a significant increase in the concentration of HVA. Acetylcholine and choline concentrations were also increased significantly by ECS. The ECS-induced increase in interstitial 5-HT was markedly reduced when the voltage-dependent sodium channel blocker tetrodotoxin (1 mumol/L) was added in the perfusion solution, indicating that the observed increase was of neuronal origin. Interstitial concentrations of 5-HT also increased in response to flurothyl-induced seizures and this increase was accompanied by a significant increase in the concentration of HVA. These results provide direct in vivo evidence that interstitial concentrations of 5-HT increase several fold in response to both ECS- and flurothyl-induced seizures. These observations are discussed in relation to the hypothesized role of 5-HT in ECS-induced memory deficits.     

Further observations on the effect of repeated electroconvulsive shock on the behavioural resposes of rats produced by increases in the functional activity of brain 5-hydroxytryptamine and dopamine

Following repeated electroconvulsive shocks (ECS) (once daily for 10 days), rats display enhanced hyperactivity responses to tranylcypromine and l-tryptophan, a procedure which increases brain 5-hydroxytryptamine (5-HT) concentrations, or to the suggested 5-HT agonist quipazine. The enhanced responses last for about 6 days following the last shock. Repeated sub-convulsive shocks did not produce this behavioural enhancement.Administration of indomethacin (2 mg/kg) 25 min before the ECS did not prevent the enhanced 5-HT response suggesting that the enhanced response is not the result of the reported rise in prostaglandins F following ECS.Repeated ECS shortened the time to loss of righting following pentobarbital (50 mg/kg) but did not alter the total sleeping time.Repeated ECS enhances locomotor activity produced by methamphetamine. It also enhances circling produced by methamphetamine and apomorphine in unilateral nigrostriatal lesioned rats, suggesting an enhanced postsynaptic response.No evidence was found for ECS altering the response of striatal adenylate cyclase to dopamine nor for any alteration of striatal cyclic AMP concentration.These data taken with our previous study reinforce the suggestion that electroconvulsive therapy (ECT) produces increased responses to 5-hydroxytryptamine and dopamine receptor stimulation.     

Enhanced 5-hydroxytryptamine and dopamine-mediated behavioural responses following convulsions—III the effects of monoamine antagonists and synthesis inhibitors on the ability of electroconvulsive shock to enhance responses

Repeated electroconvulsive shock (ECS) administration to rats resulted in enhanced 5-hydroxytryptamine 5-HT) and dopamine (DA) mediated behavioural responses. Pretreatment with p-chlorophenylalanine before the course of ECS (over 10 days) abolished the enhancement of 5-HT mediated responses but not the enhancement of DA-mediated responses. Pretreatment of rats just before each ECS with either of the 5-HT antagonists (?)-propranolol (20 mg/kg) or methergoline (5 mg/kg) also abolished the enhancement of 5-HT but not DA-mediated responses. In contrast, pretreatment with haloperidol (0.5 mg/kg) before each ECS did not inhibit the enhancement of 5-HT or DA-mediated responses. α-Methyl p-tyrosine administration during the course of ECS administration abolished both the enhancement of 5-HT and DA-mediated responses. Specific depletion of the brain noradrenaline content by neurotoxin lesioning did not alter the behavioural responses to either the 5-HT agonist quipazine or the dopamine agonist apomorphine. However, following ECS, lesioned animals did not show the enhanced response to these agonists that was seen in the sham operated rats.The data therefore suggest that intact 5-HT synthesis and release is important for ECS to enhance 5-HT mediated responses, but not to enhance DA-mediated responses. Electroconvulsive shock-induced enhancement of DA-mediated responses does not require intact brain DA synthesis, consistent with other published data, and intact brain NA systems (α-methyl p-tyrosine and lesioning results) are required for ECS to produce enhanced responses of both 5-HT and DA-mediated behavioural resnonses.     

Stimulation of prostaglandin biosynthesis by drugs: effects in vitro of some drugs affecting gut function.

1 A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5-hydroxyindoleacetic acid (5-HIAA) but did not alter brain 5-hydroxytryptamine (5-HT) or tryptophan concentrations 3 h later. 2 A single ECS decreased 5-HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS-treated rats did not show greater hyperactivity produced by the increased brain 5-HT accumulation following administration of L-tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5-HT functional activity. 3 Twenty-four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and L-tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increases 5-HT functional activity. Brain concentrations of 5-HT, 5-HIAA and tryptophan were then unchanged by ECS. 5-HT synthesis and accumulation of 5-HT following tranylcypromine and L-tryptophan were not altered by ECS. 4 The hyperactivity following administration of the 5-HT agonist 5-methoxy N,N-dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post-synaptic responses to 5-HT receptor stimulation. 5 Repeated ECS enhanced locomotor activity following tranylcypromine and L-DOPA. It did not alter brain noradrenaline or dopamine concentrations. 6 The latent period before a pentylenetetrazol-induced convulsion was shortened by repeated ECS. 7 Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect.     

Effect of single and repeated electroconvulsive shock on serotonergic system in rat brain--I. Metabolic studies

Effect of single and repeated (once daily for 10 days) electroconvulsive shock (ECS) (150V, 0.4 sec) on 5-hydroxyltryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels under various pharmacological conditions in the hypothalamus (HTh) and forebrain (F) of the rat brain was investigated. Single and repeated ECS increased significantly the accumulation of 5-HT in both brain regions in iproniazide-, and iproniazide plus l-tryptophan-treated rats after 1 hr, but not after 24 and 48 hr. The disappearance of 5-HT in p-chlorophenylalanine-treated animals was potentiated by both ECS regimens only at 1 hr. Single and repeated ECS increased 5-HIAA levels in both hypothalamus and forebrain in rats pretreated with probenecid, and in rats without any drug treatment. It is concluded that single and repeated ECS increased the synthesis and the catabolism of 5-HT in the rat brain only at 1 hr. There was neither qualitative nor quantitative difference in effects on 5-HT metabolism between both ECS regimens.     

Antidepressant treatments: effects in rodents on dose-response curves of 5-hydroxytryptamine- and dopamine-mediated behaviours and 5-HT2 receptor number in frontal cortex.

The effects of repeated electroconvulsive shock (ECS) administration, repeated desmethylimipramine injection (5 mg kg-1, twice daily for 14 days) and acute administration of the beta-adrenoceptor, clenbuterol, on 5-hydroxytryptamine (5-HT)- and dopamine-mediated behaviours in mice have been examined. All three treatments enhanced the carbidopa/5-hydroxytryptophan (5-HTP)-induced head-twitch response at all doses of 5-HTP examined, producing a parallel shift in the dose-response curve. A single ECS administration or single dose of desmethylimipramine had no effect. Only repeated ECS enhanced the locomotor response to injection of apomorphine. The dose-response curve shift was not parallel. A single ECS had no effect. A 6-hydroxydopamine lesion of brain dopamine terminals also enhanced the apomorphine response, but again did not produce a parallel shift in the dose-response curve. Both repeated ECS and repeated desmethylimipramine administration to rats increased the number of 5-HT2 receptor sites in rat brain. Clenbuterol had no effect. The enhancing effects of repeated ECS and clenbuterol administration on the 5-HTP-induced head-twitch response were additive. Enhanced 5-HT-mediated behavioural responses are seen in both mice and rats after these treatments. If it is assumed, therefore, that similar receptor changes occur in both species it appears that there is no relationship in either behavioural system between the ability of the treatment to alter receptor number and the change in the dose-response curve (parallel or non-parallel). All three antidepressant treatments (ECS, a tricyclic and a beta-adrenoceptor agonist) increase 5-HT-mediated behavioural responses although clenbuterol did not increase 5-HT2 receptor number. Only ECS increased dopamine-mediated responses.     

Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine.

Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT(2A) receptor binding sites. However, the effects of antidepressants on 5-HT(2A) receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT(2A) receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT(2A) receptors were consistent with 5-HT(2A) receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT(2A) receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex.     

Enhancement of serotonin(1A) receptor function following repeated electroconvulsive shock in young rat hippocampal neurons in vitro

Effects of repeated electroconvulsive shock (ECS) treatment on 5-hydroxytryptamine (5-HT) response were investigated to elucidate the ECS-induced changes, which may be related to antidepressant effects, using electrophysiological methods with hippocampal slices in vitro. ECS was applied to Wistar rats once daily for 14 d from 3 wk of age (ECS group). Control animals did not receive ECS (control group). Twenty-four hours after the final ECS treatment, hippocampal slices were prepared for intracellular recording analysis. Application of 5-HT (0.1-30 μm) caused a dose-dependent hyperpolarization in hippocampal CA1 neurons. 5-HT-induced hyperpolarization in the ECS group was significantly greater than that in the control group. Furthermore, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], a 5-HT(1A) receptor agonist, also induced significantly larger hyperpolarization in the ECS group than in the control group. These results suggest that repeated ECS treatment enhances function of the 5-HT(1A) receptor for 5-HT. This supports the hypothesis that enhanced 5-HT(1A) receptor function, at least in part, contributes to the effectiveness of ECS treatment for depression directly and/or indirectly.     

The effects of single and repeated electroconvulsive shock administration on the release of 5-hydroxytryptamine and noradrenaline from cortical slices of rat brain.

1 A method is described of measuring the K+-evoked release of endogenous 5-hydroxytryptamine (5-HT) and noradrenaline (NA) from slices prepared from rat cortex. 2 There was no difference in either the spontaneous (basal) or K+-evoked release of 5-HT or NA from cortical slices prepared from handled animals and those given a single electroconvulsive shock (ECS) either 30 min or 24 h earlier. 3 In chronic studies, rats were either handled or given an ECS 5 times over 10 days and cortical slices prepared. There was no difference in 5-HT or NA release between the groups 30 min after the last treatment other than a modest attentuation of spontaneous NA release following ECS treatment. However 24 h after the last treatment K+-evoked release (above basal release) of 5-HT and NA was inhibited by 84% and 48%, respectively. 4 These data demonstrate that following a single ECS, normal 5-HT and NA release is seen at a time when GABA release is markedly inhibited. After repeated ECS the release of both monoamines was markedly inhibited. These 5-HT changes may be involved in the enhanced 5-HT-receptor function seen after repeated ECS.     

Failure of repeated electroconvulsive shock treatment on 5-HT4-receptor-mediated depolarization due to protein kinase A system in young rat hippocampal CA1 neurons

We previously demonstrated that repeated electroconvulsive shock (ECS) treatment enhanced serotonin (5-HT)(1A)- and 5-HT(3)-receptor-mediated responses in hippocampal CA1 pyramidal neurons. The electrophysiological studies were performed to elucidate the effects of ECS treatment on depolarization, which was an additional response induced by 5-HT, and the second messenger system involved in this depolarization of hippocampal CA1 neurons. Both application of 5-HT (100 microM) induced depolarization of the membrane potential in the presence of 5-HT(1A)-receptor antagonists. This depolarization was mimicked by 5-HT(4)-receptor agonists, RS 67506 (1-30 microM) and RS 67333 (0.1-30 microM), in a concentration-dependent manner. 5-HT- and RS 67333-induced depolarization was attenuated by concomitant application of RS 39604, a 5-HT(4)-receptor antagonist. H-89, a protein kinase A (PKA) inhibitor, inhibited 5-HT-, RS 67506-, and RS 67333-induced depolarizations, while forskolin (10 microM), an activator of adenylate cyclase, induced depolarization. Furthermore, RS 67333-induced depolarization was not significantly different between hippocampal slices prepared from rats administered ECS once a day for 14 days and those from sham-treated rats. These findings suggest that 5-HT(4)-receptor-mediated depolarization is caused via the cAMP-PKA system. In addition, repeated ECS-treatment did not modify 5-HT(4)-receptor functions in contrast to 5-HT(1A)- and 5-HT(3)-receptor functions.     

Effect of single and repeated electroconvulsive shock on serotonergic system in rat brain—II behavioural studies

Effect of single and repeated (once daily, for 10 days) ECS (150 V, 0.4 sec) on head twitch behaviour (HTB) induced by 5-HT (i.v.t.) or 5-HTP (i.p.) in tranylcypromine-treated rats was investigated. Single ECS did not change the frequency of head twitch evoked by both serotonergic agents at any time studied (1, 24 and 48 hr). Repeated ECS, having no effect at 1 hr, increased significantly the frequency of head twitch induced by both 5-HT (i.v.t.) and 5-HTP (i.p.) by approximately 100% at 24 and 48 hr after the last shock. It is concluded that repeated ECS increases the sensitivity of central 5-HT receptors.     

Some anticonvulsant drugs alter monoamine-mediated behaviour in mice in ways similar to electroconvulsive shock; implications for antidepressant therapy.

The effects in mice of administration of the anticonvulsants, progabide, sodium valproate, diazepam, carbamazepine and phenytoin on 5-hydroxytryptophan (5-HTP)-induced head-twitch, apomorphine-induced locomotion, clonidine-induced sedation, and beta-adrenoceptor and 5-HT2 receptor number have been examined. Repeated progabide administration (400 mg kg-1, i.p. twice daily for 14 days) enhanced the head-twitch response the effect lasting for over 8 days after the last dose, and also increased 5-HT2 receptor number in frontal cortex. Progabide (400 mg kg-1, i.p.) enhanced the head-twitch response when given once daily for 10 days and when given intermittently (5 times over 10 days) but not after 1 day of administration. Repeated Na valproate (400 mg kg-1, i.p.) also increased the 5-HTP-induced head-twitch response and 5-HT2 receptor number in the frontal cortex when given twice daily for 14 days, but no behavioural enhancement was seen after 10 days' treatment. Diazepam (1.25 mg kg-1, i.p.) twice daily for 14 days increased the head-twitch response and 5-HT2 receptor number. Repeated progabide and valproate (but not diazepam) administration attenuated the sedation response to the alpha 2-adrenoceptor agonist, clonidine (0.15 mg kg-1) but neither drug altered beta-adrenoceptor number in the cerebral cortex. No changes in apomorphine-induced locomotor behaviour were seen after progabide, valproate or diazepam. Repeated carbamazepine (20 mg kg-1) or phenytoin (40 mg kg-1) administration failed to alter any of the biochemical or behavioural parameters listed above. Like repeated electroconvulsive shock (ECS), progabide altered the head-twitch response, clonidine-induced sedation response and 5-HT2 receptor number. Unlike repeated ECS, it did not alter beta-adrenoceptor number or the apomorphine-induced locomotor response. These data suggest that ECS may produce some changes in monoamine function by altering GABA metabolism as has previously been postulated.     

Opposite effects of antidepressants and corticosterone on the sensitivity of hippocampal CA1 neurons to 5-HT1A and 5-HT4 receptor activation

Using extracellular and intracellular ex vivo recording techniques we studied changes in the reactivity of hippocampal pyramidal CA1 neurons to serotonin (5-HT) and to the 5-HT1A- and 5-HT4 receptor agonists (+/-)-2-dipropylamino-8-hydroxy- 1,2,3 ,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, evoked by repeated electroconvulsive shock (ECS), imipramine and corticosterone treatments. Rats were subjected to ECS for 1 or 10 days, treated with imipramine for 1, 7, 14 or 21 days (10 mg/kg p.o., twice daily) and with corticosterone for 7 days (10 mg/kg s.c., twice daily). Hippocampal slices were prepared 2 days after the last treatment. Activation of 5-HT1A receptors decreased the amplitude of population spikes evoked by stimulation of the Schaffer/collateral-commissural pathway and hyperpolarized CA1 cells. Activation of 5-HT4 receptors increased the population spike amplitude and decreased the amplitude of slow afterhyperpolarization. Both repeated ECS and imipramine enhanced the effects related to 5-HT1A receptor activation and attenuated the effects of 5-HT4 receptor activation. The action of imipramine was significant after a 7-day treatment and reached a maximum after 14 daily applications, remaining at the same level in a group of animals treated for 21 days. Repeated corticosterone attenuated the inhibitory effect of 5-HT and 8-OH-DPAT on the population spike amplitude and enhanced the increase in population spike amplitude induced by zacopride. These findings indicate that antidepressant treatments and repeated corticosterone have opposite effects on hippocampal responsiveness to 5-HT1A and 5-HT4 receptor activation. In consequence, antidepressants enhance, whereas corticosterone reduces the 5-HT-mediated inhibition of hippocampal CA1 cells, which may be relevant to the antidepressant and pro-depressant effects of either treatment, respectively.     

Effect of repeated electroconvulsive shocks on serotonergic neurons.

The hypothermia induced by the serotonin (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was attenuated in rats that had received a course of six electroconvulsive shocks (ECS) over a two-week period. The firing activity of dorsal raphe 5-HT neurons, as well as their responsiveness to microiontophoretic applications of 5-HT and 8-OH-DPAT, was unaltered in ECS-treated rats. The electrically evoked overflow of [3H]5-HT from preloaded slices of guinea pig hypothalamus was unchanged after the same ECS treatment. The concentration-effect curves of the 5-HT autoreceptor agonist 5-carboxyamidotryptamine (0.1-100 nM) were similar in slices prepared from control and ECS-treated guinea pigs. In addition, the reduction in the evoked [3H]5-HT overflow obtained by increasing the stimulation frequency from 1 to 5 Hz, which is due to a greater activation of terminal 5-HT autoreceptors at the higher frequency, was not altered by the ECS treatment. The enhancing effects of the 5-HT autoreceptor antagonist methiothepin (0.1-1 microM) and of the 5-HT3 agonist 2-methyl-5-HT (0.1-1 microM) on the evoked [3H]5-HT overflow were unaltered by the ECS treatment. These results thus indicate that repeated ECS attenuates the 8-OH-DPAT-induced hypothermia in rats, as previously reported, but does not affect the firing activity of 5-HT neurons and the sensitivity of their somatodendritic 5-HT1A autoreceptors in the dorsal raphe. The function of 5-HT terminals in the guinea pig hypothalamus was also unaffected by repeated ECS. In conclusion, repeated ECS does not affect the function of 5-HT neurons at the cell body and nerve terminal.     

Increased 5-HT2 receptor number in brain as a probable explanation for the enhanced 5-hydroxytryptamine-mediated behaviour following repeated electroconvulsive shock administration to rats.

Following electroconvulsive shock (ECS) administration daily for 10 days there was an increase (35%) in 5-hydroxytryptamine2 (5-HT2) receptor number in rat frontal cortex 24 h after the last ECS, compared with handled controls. A similar increase was seen after intermittent ECS administration (5 ECS over 10 days) given during halothane anaesthesia, compared with halothane-treated controls. The dissociation constant was also increased at this time. A single ECS had no effect. Treatment of rats with pentylenetetrazol, p-chlorophenylalanine or alpha-methyl p-tyrosine during the intermittent ECS administration abolished the increase in 5-HT2 receptor binding. Since enhanced 5-HT-mediated behavioural responses are seen after repeated ECS but not when the ECS is given with the drug treatments outlined above, it is suggested that ECS-induced enhancement of 5-HT-mediated behaviour results from an increase in 5-HT2 receptor number.     

Warming and response to contractile agents in calf cardiac vein: role of the Ca2+, KCa2+, and Na+ ion channel blockers

The effects of warming (to 41 degrees C) on the serotonin (5-HT, 10(-8)-3 x 10(-3) M)- and carbachol (10(-)9-3 x 10(-4) M)-induced contractions and the role of calcium (Ca2+), potassium (K+), and sodium (Na+) channel blockers, in the warming-induced responses were investigated in the calf cardiac vein. Concentration-response curves to 5-HT and carbachol were isometrically recorded at 37 and 41 degrees C (control). The same procedure was repeated at 41 degrees C in the presence of verapamil (10(-6) M), caffeine (3 x 10(-4) M), tetraethylammonium (TEA, 10(-3)M), flecainide (10(-6) M), and also in the Ca2+-free medium with ethylene glycol bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA). During warming, the sensitivity, but not the maximal response, was significantly higher. Warming to 41 degrees C after treatment with verapamil or flecainide decreased the sensitivity, whereas treatment with caffeine increased the sensitivity significantly. Treatment with TEA did not modify the effect of warming. Furthermore, warming to 41 degrees C after incubation in Ca2+-free solutions with EGTA decreased the sensitivity to 5-HT and carbachol. The results of this study suggest the role for Ca2+ and Na+ ions in the warming-induced changes of cardiac vein treated with 5-HT and carbachol.     

Differences in sensitivity to the specific protein kinase C inhibitor Ro31-8220 between small and large bronchioles of the rat.

1. The involvement of protein kinase C (PKC) in constriction of small bronchioles has never been investigated. In this study we have examined the effects of the specific PKC inhibitors Ro31-8220 and Ro31-7549 and the non-specific inhibitor H7 on carbachol-, 5-hydroxytryptamine (5-HT)- and 4 beta-phorbol dibutyrate (4 beta-PDBu)-induced contractions in large and small bronchioles. 2. The study was performed on isolated bronchioles of the rat with internal diameters of 574 microns +/- 11 (small, n = 128), and 1475 microns +/- 32 (large, n = 93), using a Mulvaney-Halpen small vessel myograph. 3. In these preparations 4 beta-PDBu had no effect if added on its own. However, after precontracting with 30 mM K+, 0.5 microM 4 beta-PDBu caused a contractile response of 110.4 +/- 7.0% TK (TK = maximum response to 75 mM K+ in small and 69.3 +/- 6.5% TK in large bronchioles. Ro31-8220, Ro31-7549 and H7 all showed concentration-dependent inhibition of this response. 4. In small bronchioles 10 microM Ro31-8220 shifted both the carbachol and 5-HT concentration-response curves to the right, and reduced the maximum response. In contrast, 10 microM Ro31-8220 had no significant effect on the EC50 to carbachol of larger bronchioles, although the maximum response was reduced, and had no significant effect on the 5-HT concentration-response curve. 200 microM H7 shifted the carbachol concentration--response curve to the right as well as reducing the maximal response in both small and large bronchioles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat.

The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.     

Responses of developing rats to l-tryptophan plus an MAOI—II. Effects of repeated electroconvulsive shock

Administration of repeated electroconvulsive shock (ECS) to developing rats (× 5 ECS) from days 10 to 20 resulted in a small statistically significant enhancement in behavioural responses to TCP + l-TP injection on day 21 (14% increase). There was also an increase in the total number of recorded movements on the Animex activity meters in the ECS-pretreated group (30%) over controls but this failed to reach statistical significance. Furthermore, responses to the agonist 5-MeODMT were also significantly enhanced (67%). This suggests that a fully developed CNS is not necessary for the induction of these behavioural changes in the rat brain 5-HT system. There were essentially no differences between control and electroshocked groups in brain 5-HT synthesis rate (measured by accumulation of 5-HT following an MAOI), tryptophan concentration or 5-HIAA concentration. The chronic ECS treatment also resulted in a decreased rate of growth of the immature rats.