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.     

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.     

Effects of amitriptyline and isocarboxazid on 5-hydroxytryptophan induced head twitches in mice

Effects of amitriptyline and isocarboxazid on brain 5-HT and 5-HIAA were examined in relation to their action on 5-HTP induced head twitches. Amitriptyline reduced 5-HTP induced head twitches but isocarboxazid increased them. Both amitriptyline and isocarboxazid caused a significant increase of brain 5-HT concentration in 5-HTP treated mice. Amitriptyline also caused a significant increase of 5-HIAA concentration, while isocarboxazid reduced 5-HIAA concentration in the brains of 5-HTP treated mice. Probenecid, which significantly increased 5-HIAA concentration without affecting brain 5-HT concentration in 5-HTP treated mice, reduced 5-HTP induced head twitches. These results suggest that 5-HTP induced head twitches might be induced by an increase of 5-HT concentration, and reduced by an increase of 5-HIAA or a decrease of 5-HT concentration in the brains of mice.     

Effects of electroconvulsive shock on monoaminergic systems in the rat brain. Thesis

The effects of single or repeated electroconvulsive shock (ECS) (once daily for 7 days) on rat behavior and on the level, utilization and uptake of biogenic amines in rat brain were studied between one and ten days after the last ECS. It has been found that a single ECS caused catalepsy and analgesia, depressed locomotor activity and locomotor hypermotility produced by amphetamine and nomifensine (but not by apomorphine) and decreased the frequency of head twitch response evoked by LiCl. Repeated ECS also induced catalepsy and analgesia but enhanced both the spontaneous locomotor activity and amphetamine, nomifensine and apomorphine-induced hypermotility, and increased the frequency of head twitch response produced by LiCl, 5-HTP and 5-methoksytryptamine. Single and repeated ECS did not change exploratory motility or stereotyped behavior induced by apomorphine, but enhanced haloperidol-induced catalepsy and altered dopamine and serotonin levels in the rat brain. The utilization of NA and DA was not changed by repeated ECS, whereas the uptake of these amines was slightly reduced. The present results provide evidence that a single ECS depresses but repeated ECS augments some behavioral responses to dopaminergic and serotonergic agonists. The possible biochemical mechanisms involved in these effects of ECS are discussed.     

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.     

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.     

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.     

Increased sensitivity to dopaminergic agonists after repeated electroconvulsive shock (ECS) in rats

The effects of single or repeated electroconvulsive shock (once daily for 7 days) on spontaneous locomotor activity and dopamine agonist-induced hyperactivity were investigated 1 hr, 1, 5 and 10 days after the last shock. Apomorphine-induced stereotyped behaviour was also measured. One hour after a single ECS both the spontaneous locomotor activity and locomotor stimulation produced by d-amphetamine or nomifensine were depressed but the stimulant effect of apomorphine was not altered. One hour, 1, 2, 3 and 5 days following repeated ECS, the rats displayed enhanced spontaneous loco- motor activity and d-amphetamine, nomifensine or apomorphine stimulated motor activity. This last effect was also observed 10 days after ECS was terminated. Apomorphine-induced stereotyped behaviour was not changed at these times. These results indicate that in rats repeated ECS increased behavioural sensitivity to dopaminergic stimuli in the mesolimbic system.     

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.     

Time-related response of central serotonergic function to lithium administration

The possibility of "acute" (1 hr) changes in serotonergic function by lithium chloride (LiCl) administration was investigated in the rat corpus striatum and frontal cerebral cortex: an increase in 5-HT biosynthesis in vivo and 5-HIAA levels was observed in both areas. After chronic LiCl treatment (14 days) only cortical 5-HIAA levels were reduced. These changes were not correlated with plasma lithium levels. Consequently, LiCl "acutely" (1 hr) probably enhances striatal and cortical serotonergic transmission, this response varying with time of treatment as a result of possible neuronal compensatory mechanisms.     

l-5-Hydroxytryptophan: Correlation between anticonvulsant effect and increases in levels of 5-hydroxyindoles in plasma and brain

The effect of l-5-hydroxytryptophan (5-HTP) on the threshold for maximal electroconvulsions was compared with concomitant changes in levels of 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in plasma and brain of rats. A single injection of 5-HTP (100 $\text{mg}\text{kg}$, i.p.) caused significant elevation in seizure threshold which was markedly intensified by pretreatment with the decarboxylase inhibitor carbidopa (10 $\text{mg}\text{kg}$, i.p., 0.5 hr previously). Pretreatment with carbidopa also resulted in behavioural changes, i.e. the characteristic “wet-dog shake” behaviour became much more prominent. Biochemically, administration of 5-HTP gave rise to significant elevation of levels of 5-HTP, 5-HT and 5-HIAA in plasma and brain. Carbidopa increased levels of 5-HTP in the brain, decreased 5-HIAA in the periphery but did not alter the elimination rate of 5-HTP in plasma. In both naive rats and rats pretreated with carbidopa, a significant correlation was found between levels of 5-HTP and 5-HIAA in plasma and brain following injection of 5-HTP. Furthermore, in the absence of carbidopa, the increases of levels of 5-HT in plasma and brain induced by 5-HTP were correlated in a significant fashion. When the changes in the electroconvulsive threshold were compared with respective changes in levels of 5-hydroxyindoles, a significant correlation was obtained between threshold elevations and increases of 5-HTP and 5-HT in the brain. In rats treated with 5-HTP, without decarboxylase inhibitor, a significant correlation was found between increases in 5-HT in plasma and the seizure threshold. The results suggest that analysis of 5-hydroxyindoles in plasma may represent a useful tool for the estimation of 5-HT metabolism in brain.     

Comparison of regional brain 5-HT and 5-HIAA content in flexor and extensor rats

Hindlimb extension (HLE) induced by maximal electroshock seizures (MES) can be markedly affected by drugs which affect CNS 5-hydroxytryptamine (5-HT). Consequently, it has been proposed that the natural resistance of certain rats (flexor rats) to HLE is due to elevated levels of 5-HT. We have tested the hypothesis that the increased resistance of flexor rats to MES-induced HLE is due to elevated serotonergic levels in some region(s) of the CNS by examining 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in 8 regions of the CNS in rats classified by MES as either flexors or extensors. Furthermore, we compared the in vivo synthesis rate of 5-HT between flexor and extensor rats in 6 regions of the brain by measuring the accumulation of 5-HTP following aromatic amino acid decarboxylase inhibition with NSD-1015. All neurochemical analyses were carried out on rats sacrificed one week after their last seizure test. No differences in 5-HT, 5-HIAA or 5-HTP synthesis rate were detected between flexor and extensor rats for any of the regions examined, suggesting that enhanced serotonergic levels are not responsible for the unusual resistance of flexor rats to HLE.     

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.     

Differential uptake, metabolism and behavioral effects of the D and L isomers of 5-hydroxytryptophan.

The relative contribution of the D and L isomers of 5-hydroxytryptophan (5-HTP) to the uptake and metabolism of 5-HTP and their associated behavioral effects were investigated. For the metabolic study, an injection of 25 mg/kg of D or L-5-HTP was administered IP and the rats killed 15, 30, 45 or 60 min later. Endogenous levels of 5-HTP, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the telencephalon following D- or L-5-HTP administration. Levels of 5-HTP, 5-HT and 5-HIAA were also measured in the brain stem (including diencephalon) following L-5-HTP administration. In the behavioral study, the effects of IP injections of D-5-HTP, L-5-HTP and D,L-5-HTP upon operant responding on a VI 1 schedule were investigated. Compared to vehicle controls, L-5-HTP significantly increased the levels of 5-HTP, 5-HT and 5-HIAA in the telencephalon and brain stem at all time points investigated. Behaviorally, 25 mg/kg of L-5-HTP and 50 mg/kg of D,L-5-HTP produced similar changes. Following the injection of either compound there was a large decrease in response rate with a duration of about 1 hr which paralleled the neurochemical changes. Injections of D-5-HTP produced an increase in the levels of 5-HTP and 5-HIAA in the telencephalon at 15 min but no change in the level of 5-HT was observed. In the operant situation, following D-5-HTP injections, a brief decrease in responding occurred in some animals which did not correlate with the neurochemical data. It was concluded that the L isomer is mainly responsible for the neurochemical and behavioral effects seen when D,L-5-HTP is administered.     

Electroconvulsive shock reduces the cataleptogenic effect of both haloperidol and arecoline in rats

The cataleptic response of rats following haloperidol administration (1.5 mg kg^?1 i.p.) was measured at various times after a single electroconvulsive shock (ECS × 1), a single ECS daily for 5 days (ECS × 5). a single ECS daily for 10 days (ECS × 10) or 24 hr after a single sub-convulsive shock daily for 10 days (sub-con × 10). The cataleptic response following injection of haloperidol was markedly attenuated 24 hr but not 48 hr after ECS × 1, up to 48 hr after ECS × 5 and 72 hr but not 168 hr (7 days) after ECS × 10. Sub-convulsive shock × 10 did not alter the normal catalepsy response. Attenuation was also not seen 12 hr after ECS × 1. The possible involvement of GABA in these changes is discussed.A reduction in the cataleptic response to the cholinomimetic drug arecoline was also seen following ECS × 1 and ECS × 10 and such changes appeared to have a similar time-course to those seen in neuroleptic-induced catalepsy.Thus, ECS produces changes in these cataleptic responses which can be seen after a single shock and are consolidated and sustained following further treatment. The relevance of these findings to the enhanced monoamine behavioural responses seen in rats after ECS, and the possible relevance of the data to therapeutic mechanism of electroconvulsive therapy (ECT) are discussed.     

Association between brain indole levels and severity of posthypoxic myoclonus in rats

We have previously reported the presence of posthypoxic, audiogenic myoclonus in rats after cardiac arrest and the ability of the 5-HT precursor, 5-HTP, to attenuate these muscle jerks. In addition, we have recently shown that 5-HT₂ and 5-HT₃ agonists can reduce the severity of myoclonus in these animals, suggesting a deficiency in serotonergic neurotransmission. In the present study, the levels of 5-HTP, 5-HT, and 5-HIAA were measured in seven regions of the brain in myoclonic and normal rats to identify the areas of the brain in which a serotonergic dysfunction resides. Similar to previous studies, we observed pronounced posthypoxic, audiogenic myoclonus 3 and 14 days after resuscitation from cardiac arrest, with a resolution of the abnormal movements by 45 days postarrest. HPLC measurements revealed significant changes in indole levels in the following areas of the brain: cortical 5-HIAA, striatal 5-HT, striatal 5-HIAA, hippocampal 5-HT, mesencephalic 5-HIAA, myelencephalic 5-HT, myelencephalic 5-HIAA, cerebellar 5-HTP, and cerebellar 5-HT. The changes in striatal 5-HT, cortical 5-HIAA, and mesencephalic 5-HIAA appear most relevant to the pathophysiology of posthypoxic myoclonus because regression analyses showed significant correlations between the myoclonus scores of the animals and the levels of these indoles. Based on the observed pattern of results, we postulate a dysfunction in serotonergic lateral (cortical) and far lateral (extrapyramidal) ascending pathways in posthypoxic myoclonus.     

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.     

Effects of single and repeated electroconvulsive shock on the social and agonistic behaviour of resident rats

The aim of this study was to determine whether electroconvulsive shock (ECS, an established antidepressant treatment), like acute and chronic antidepressant drug treatments, produces similar differential effects on the behavioural profile of resident rats expressed during social encounters with unfamiliar intruder conspecifics (resident-intruder paradigm). Thirty minute pretreatment with a single ECS suppressed both investigation and aggression directed at intruders concomitant with increased flight behaviour and marked sedation. Behavioural disruption subsided over the following 24 h. In contrast, resident rats subjected to bi-daily ECS treatment expressed elevated aggression at days 7 (four shocks) and 14 (eight shocks). Eight days after the last ECS treatment the behaviour of the resident rats had returned to pretreatment values. Additional studies showed that bi-daily ECS treatment nearly abolished 5-HT(2C) receptor-mediated hypolocomotion induced by acute m-chlorophenylpiperazine (mCPP, 2.5 mg/kg sc) challenge 24 h following 2 ECSs, while 4 ECSs only enhanced 5-HT(2A) receptor-mediated head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 2.0 mg/kg sc). These studies demonstrate that repeated ECS treatment increases the aggressive behaviour of resident rats which may be associated with adaptive changes in 5-HT(2C) and 5-HT(2A) receptor-mediated function. It remains to be seen whether adaptive changes in 5-HT(2C) receptor function represent a common mechanism of clinical antidepressant efficacy.     

Circadian variation in the head twitch response produced by 5-methoxy-N1,N1-dimethyltryptamine and p-chloroamphetamine in the mouse

Circadian fluctuations were measured in the head twitch response produced by 5-methoxy-N¹,N¹-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA) in male BK. TO mice. The effects of depleting brain 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) on the 5-MeODMT in the mouse were also studied. Changes in brain 5-HT and 5-hydroxyindoleacetic (5-HIAA) were concomitantly determined. PCPA (400 mg/kg IP twice on consecutive days) significantly increased the number of head twitches induced by 5-MeODMT (5 mg/kg IV) on days 3 and 5 after the initial injection of PCPA when 5-HT and 5-HIAA were also significantly reduced. On day 12, there was no significant difference in the number of head twitches between mice administered PCPA and those given saline, and 5-HT and 5-HIAA levels were nearly back to normal. PCPA, using the same dose schedule, significantly reduced the number of head twitches induced by PCA when PCA was administered 24h after the second injection of PCPA (day 3). Mice maintained on a 12-h light-dark cycle showed a maximum response to the direct 5-HT receptor agonist 5-MeODMT (5 mg/kg IV) towards the end of the dark period, when the 5-HT level was at its lowest. p-Chloroamphetamine, which causes release of 5-HT from pre-synaptic neurones, produced a peak head twitch response in the middle of the light period when 5-HT and 5-HIAA levels were maximal, while the response towards the end of the dark period was significantly less than that at other tines tested. It is concluded that 5-HT receptor response shows a circadian rhythm related to both pre-synaptic availability of 5-HT and post-synaptic receptor sensitivity.     

Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat

In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxy-methamphetamine (MDMA), causes selective, pronouced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr.

Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.