Memory disturbances in ”Ecstasy” users are correlated with an altered brain serotonin neurotransmission

Rationale: Methylenedioxymethamphetamine (MDMA) is known to damage brain pre-synaptic serotonin (5-HT) neurons. Since loss of 5-HT neurons has been implicated in memory loss, it is important to establish whether MDMA use may produce changes in postsynaptic 5-HT receptors and memory function in humans. Objectives: To investigate whether MDMA use leads to compensative alterations in post-synaptic 5-HT_2A receptors and whether there is a relation with memory disturbances. Methods: Brain cortical 5-HT_2A receptor densities were studied with [¹²³I]-5-I-R91150 SPECT in five abstinent MDMA users and nine healthy controls. Memory performance was assessed using RAVLT. Results: [¹²³I]-5-I-R91150 binding ratios were significantly higher in the occipital cortex of MDMA users than in controls, indicating up-regulation. Mean cortical 5-HT_2A receptor binding correlated positively with RAVLT-recall in MDMA users. Conclusion: Our preliminary results may indicate altered 5-HT neuronal function with correlated memory impairment in abstinent MDMA users. Received: 20 August 1999 / Final version: 25 November 1999     

Mapping serotonergic dysfunction in MDMA (ecstasy) users using pharmacological MRI

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [(123)I]β-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction.     

Increased anxiety 3 months after brief exposure to MDMA ("Ecstasy") in rats: association with altered 5-HT transporter and receptor density.

Male Wistar rats were treated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") using either a high dose (4 x 5 mg/kg over 4 h) or low dose (1 x 5 mg/kg over 4 h) regimen on each of 2 consecutive days. After 10 weeks, rats were tested in the social interaction and emergence tests of anxiety. Rats previously given either of the MDMA dose regimens were significantly more anxious on both tests. After behavioral testing, and 3 months after the MDMA treatment, the rats were killed and their brains examined. Rats given the high-, but not the low-, dose MDMA treatment regimen exhibited significant loss of 5-hydroxytryptamine (5-HT) and 5-HIAA in the amygdala, hippocampus, striatum, and cortex. Quantitative autoradiography showed loss of SERT binding in cortical, hippocampal, thalamic, and hypothalamic sites with the high-dose MDMA regime, while low-dose MDMA only produced significant loss in the medial hypothalamus. Neither high- nor low-dose MDMA affected 5HT(1A) receptor density. High-dose MDMA increased 5HT(1B) receptor density in the nucleus accumbens and lateral septum but decreased binding in the globus pallidus, insular cortex and medial thalamus. Low-dose MDMA decreased 5HT(1B) receptor density in the hippocampus, globus pallidus, and medial thalamus. High-dose MDMA caused dramatic decreases in cortical, striatal, thalamic, and hypothalamic 5HT(2A)/(2C) receptor density, while low-dose MDMA tended to produce similar effects but only significantly in the piriform cortex. These data suggest that even brief, relatively low-dose MDMA exposure can produce significant, long-term changes in 5-HT receptor and transporter function and associated emotional behavior. Interestingly, long-term 5-HT depletion may not be necessary to produce lasting effects on anxiety-like behavior after low-dose MDMA.     

Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users

Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive function. Because 5-HT transporters play a key element in the regulation of synaptic 5-HT transmission it may be important to control for the potential covariance effect of a polymorphism in the 5-HT transporter promoter gene region (5-HTTLPR) when studying the effects of MDMA as well as cognitive functioning.The aim of the study was to investigate the effects of moderate and heavy MDMA use on cognitive function, as well as the effects of long-term abstention from MDMA, in subjects genotyped for 5-HTTLPR. A second aim of the study was to determine whether these effects differ for females and males. Fifteen moderate MDMA users (<55 lifetime tablets), 22 heavy MDMA+ users (>55 lifetime tablets), 16 ex-MDMA+ users (last tablet > 1 year ago) and 13 controls were compared on a battery of neuropsychological tests. DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods.A significant group effect was observed only on memory function tasks (p = 0.04) but not on reaction times (p = 0.61) or attention/executive functioning (p = 0.59). Heavy and ex-MDMA+ users performed significantly poorer on memory tasks than controls. In contrast, no evidence of memory impairment was observed in moderate MDMA users. No significant effect of 5-HTTLPR or gender was observed.While the use of MDMA in quantities that may be considered "moderate" is not associated with impaired memory functioning, heavy use of MDMA use may lead to long lasting memory impairments. No effect of 5-HTTLPR or gender on memory function or MDMA use was observed.     

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT_2A receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT_2A receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT_2A receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT_2A receptor availability (binding potential, BP_ND) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP_ND and higher 5-HT_2A receptor BP_ND in cortical, but not subcortical regions. Decreased SERT BP_ND was regionally associated with upregulated 5-HT_2A receptor BP_ND. In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.     

3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced egr-1 mRNA in rat brain: pharmacological manipulation

Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3, 4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N-methyl-D-aspartate (NMDA) receptor, dopamine D(1) receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT(2A) receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine ((+)-MK801; 1 mg/kg), dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT(2A) receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D(1) receptor and 5-HT transporter.     

The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA (‘ecstasy’) when housed at high ambient temperature

Rationale Administration to rats of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an impairment in thermoregulation which is reflected in a prolonged hyperthermic response to a subsequent dose of MDMA given to rats housed at high ambient temperature.Objective We wished to examine whether the impaired thermoregulation was associated with decreased cerebral 5-HT content produced by the prior neurotoxic dose of MDMA.Methods Rats were injected with drugs decreasing 5-HT function [the tryptophan hydroxlase inhibitor p-chlorophenylalanine (PCPA), and 5-HT receptor antagonists] and rectal temperature was measured after administering MDMA to rats housed at 30°C.Results PCPA pretreatment decreased 5-HT and 5-HIAA concentrations in cortex, hippocampus and striatum by >80% and prolonged the hyperthermia induced in rats housed at 30°C by administering MDMA (5 mg/kg i.p.). A similar prolongation of the hyperthermic response to MDMA was seen when rats were pretreated with methysergide (10 mg/kg i.p.) or the 5-HT_1A antagonist WAY100635 (0.5 mg/kg s.c.).Conclusions Decreasing 5-HT function in diverse ways enhanced the hyperthermic response to MDMA given to rats housed at high ambient temperature. This suggests that loss of 5-HT acting on 5-HT_1A receptors leads to impaired thermoregulation in rats and suggests that the impairment seen in MDMA pretreated rats housed at high ambient temperature is due to a loss in 5-HT function. These data could have implications for recreational users of MDMA, who may have damaged serotoninergic neurons because of prior heavy or frequent use of the drug, when taking further doses of MDMA in hot environments such as dance clubs.     

Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors.

The present study examined short- and long-term effects of MDMA (3,4-methylene-dioxymethamphetamine) on serotonin (5-HT2 and 5-HT1c) receptors in the brain of the rat. N1-Methyl-2-[125I]lysergic acid diethylamide ([125I]MIL) was used to label these receptors in vitro and in vivo. The usefulness of [125I]MIL for in vivo detection of changes in 5-HT2 receptors was confirmed in preliminary experiments in which rats were treated chronically with mianserin (5 mg/kg, once daily for 10 days). Decreases in specific in vivo binding of [125I]MIL, after treatment with mianserin were found to be of the same magnitude as those determined by others, using in vitro methods. The MDMA (8 doses; 5-20 mg/kg each) was administered to rats over a period of 4 days. At various times after administration of the last dose of MDMA, the binding of [125I]MIL was measured. Acutely, treatment with MDMA (20 mg/kg) reduced specific in vivo binding of [125I]MIL in all regions of brain studied. For example, in the frontal cortex, specific binding of [125I]MIL was decreased by 80% at 6 hr and by 62% at 24 hr, after cessation of treatment with MDMA. Twenty-one days after administration of MDMA however, the number of binding sites for [125I]MIL was back to control levels. Reductions in in vivo binding of [125I]MIL in frontal cortex were dependent on the dose of MDMA injected and were associated with decreases in the number of binding sites for [125I]MIL (Bmax values) in tissue homogenates of the same area. Autoradiographic studies of MDMA-treated rats confirmed the decreased density of 5-HT2 receptors and also suggested that the 5-HT1c receptor of the choroid plexus was not affected. These results indicate that repeated administration of MDMA caused transient down-regulation of 5-HT2 receptors in the brain of the rat. Further, they demonstrated that [125I]MIL is a suitable radioligand for labeling 5-HT2 receptors, both in vitro and in vivo. Once labeled with an appropriate radionuclide for SPECT (single photon emission computed tomography) or PET (positron emission tomography), MIL should prove useful for monitoring changes in the density of serotonin receptors in the living mammalian brain.     

MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus

The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10 mg/kg, i.p. at 2 h intervals) resulted in a 2–3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100 μM) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus.     

Methylenedioxymethamphetamine induces spontaneous tail-flicks in the rat via 5-HT1A receptors.

In rats lightly restrained in horizontal cylinders, (+/-)-3,4-methylenedioxymethamphetamine (MDMA) dose dependently (0.16-10.0 mg/kg, s.c.) elicited spontaneous tail-flicks; that is, tail-flicks in the absence of extraneous stimulation. In contrast, amphetamine over a similar dose-range was inactive. Selective inhibitors of 5-hydroxytryptamine (5-HT) uptake and carrier-mediated 5-HT release, paroxetine and citalopram, did not induce spontaneous tail-flicks themselves and blocked those induced by MDMA. In distinction, maprotiline and bupropion, selective inhibitors of noradrenaline and dopamine uptake, respectively, failed to modify the action of MDMA. Spontaneous tail-flicks elicited by MDMA were unaffected by the selective 5-HT3 receptor antagonists, ICS 205,930 and GR 38032F. They were attenuated by the mixed 5-HT1/5-HT2 receptor antagonist, methiotepin, the mixed 5-HT1A/5-HT1B receptor antagonist, (-)-alprenolol and the mixed 5-HT1A/5-HT2 receptor antagonist, spiperone, but not by the selective 5-HT1C/5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ketanserin. The novel 5-HT1A receptor antagonists, BMY 7378 and NAN-190, each abolished MDMA-evoked spontaneous tail-flicks. Selective D1, D2, alpha 1, alpha 2, beta 1 and beta 2 antagonists had little influence upon induction of spontaneous tail-flicks by MDMA. These data indicate that MDMA evokes spontaneous tail-flicks in the rat via a release of 5-HT which acts at 5-HT1A receptors. Thus, 5-HT1A receptors appear to be involved in the acute functional actions of MDMA.     

Selective reduction of striatal type II glucocorticoid receptors in rats by 3,4-methylenedioxymethamphetamine (MDMA)

A single 20 mg/kg dose of 3,4-methylenedioxymethamphetamine (MDMA) administered to rats markedly decreased serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in hippocampus, frontal cortex and striatum seven days following injection. MDMA also significantly decreased type II glucocorticoid receptor levels in the striatum, but not in hippocampus or frontal cortex. Since no difference in basal serum corticosterone levels was observed between the two groups, MDMA may decrease striatal type II glucocorticoid receptors via a corticosterone-independent mechanism.     

Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour.

1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.     

Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement

RATIONALE: Responding for conditioned reinforcement is increased by the dopamine releasing agent amphetamine, but reduced by drugs that enhance serotonin (5-HT) function. The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) releases both monoamines. OBJECTIVES: The primary purpose of this study was to examine the effects of MDMA on responding for conditioned reinforcement as well as on locomotor activity. The roles of several 5-HT receptor sub-types in mediating these behavioural effects of MDMA were also examined. METHODS: Locomotion was measured in photocell activity monitors. For conditioned reinforcement experiments thirsty rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were available; responding on one lever delivered the CS, while responding on the second lever had no consequences. Drug effects on this operant response were measured. RESULTS: MDMA dose-dependently increased locomotion but reduced responding for conditioned reinforcement. This latter effect differs from that induced by amphetamine, which potentiates conditioned reinforcement responding. The stimulant effect of MDMA was attenuated by GR127935 and ketanserin, indicating facilitatory roles of 5-HT(1B) and 5-HT(2A) receptors in mediating this effect. The 5-HT(2C) antagonist SB242084 enhanced the stimulant effect of MDMA. Only SB242084 attenuated the suppressant effect of MDMA on responding for conditioned reinforcement. CONCLUSIONS: The results show that 5-HT(2A) and 5-HT(1B/1D) receptors play a facilitatory role in mediating the stimulant effect of MDMA, whereas 5-HT(2C) receptors are inhibitory. Activation of 5-HT(2C) receptors also contributes to the deficit in operant responding. Multiple 5-HT receptor sub-types appear to contribute to the behavioural effects of MDMA.     

MDMA use is associated with increased spatial BOLD fMRI visual cortex activation in human MDMA users

Previous animal studies have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) exposure causes serotonin axotomy that is greatest in occipital cortex (including primary visual cortex) where serotonergic axons innervate neurons and blood vessels. Human MDMA users have altered serotonergic function and reduced gray matter density in occipital cortex. The fMRI BOLD method is potentially sensitive to both the neuronal and vascular consequences of MDMA-induced serotonin toxicity. To test the hypothesis that MDMA users have altered visual system function, we used the fMRI BOLD technique to assay visual cortical activation after photic stimulation in a group of adult MDMA users. Because MDMA users worldwide are polydrug users and therefore difficult to match to comparison groups in terms of polydrug exposure, we conducted a primary within-group analysis examining the correlation between lifetime episodes of MDMA exposure and measures of visual cortical activation. The within-group correlational analysis in the MDMA user group revealed that the degree of prior MDMA exposure was significantly positively correlated with the number of activated pixels for photic stimulation (r=0.582, p=0.007). A secondary between-group comparison of MDMA users with non-MDMA users found overall greater levels of polydrug exposure in the MDMA user cohort but no significant differences in visual cortical activation measures between the two groups. Additional research is needed to clarify the origin and significance of the current findings.     

Acute and chronic effects of MDMA on molecular mechanisms implicated in memory formation in rat hippocampus: surface expression of CaMKII and NMDA receptor subunits

Acute 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") treatment induces learning deficits in different animal models. In a passive avoidance learning task in rats, previous studies suggested a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) and N-methyl-D-aspartate (NMDA) receptors in the acute learning impairment. As cognitive deficits by "ecstasy" in humans have been only reported in frequent recreational users, we examined whether a repeated MDMA treatment could induce in rats lasting molecular changes related to memory consolidation of passive avoidance. In rats with a pronounced 5-HT depletion by MDMA, the effect of another drug challenge was also examined. The surface expression in the hippocampus of NMDA receptor subunits, the scaffolding postsynaptic density protein PSD-95, phosphorylated CaMKII and protein phosphatase 1 (PP1) was measured. In rats repeatedly treated with MDMA (10 mg/kg) twice daily for 4 consecutive days, hippocampal 5-HT levels were markedly reduced 1 week later. At this time, neither learning performance was affected nor changes in membrane levels of NMDA receptor subunits, PSD-95, CaMKII and PP1 were found. In these rats, however, another drug challenge produced a rapid reduction in PSD-95 immunoreactivity and prevented the learning-specific increase in the NMDA receptor NR1 subunit and phosphorylated CaMKII. The results show no lasting change in learning-associated molecular events after a neurotoxic MDMA treatment. This drug only produces transient effects on early molecular events involved in memory consolidation, which do not appear to depend on endogenous 5-HT levels.     

Effect of chronic lithium treatment on glucocorticoid and 5-HT1A receptor messenger RNA in hippocampal and dorsal raphe nucleus regions of the rat brain

The therapeutic mechanism of action of lithium in the treatment of bipolar disorder is not well understood. Dysfunction of both 5-HT(1A) receptor mediated neurotransmission and the glucocorticoid receptor is associated with mood disorders, and preclinical studies suggest that lithium treatment can modulate these receptor subtypes. In this study, we investigated the effect of chronic lithium treatment on 5-HT(1A) receptors and glucocorticoid receptors in the rat brain. Male Sprague-Dawley rats were treated with lithium (3 mmol/kg/day) or saline for 28 days via subcutaneous implanted mini-osmotic pumps. After 28 days of treatment, the expression of mRNA for 5-HT(1A) receptors and glucocorticoid receptors in the rat hippocampus and dorsal raphe nucleus was determined by in situ hybridization histochemistry. Chronic administration of lithium decreased mRNA coding for post-synaptic 5-HT(1A) receptors in hippocampal subregions but not for somatodentritic 5-HT(1A) receptors in the dorsal raphe nucleus. Chronic administration of lithium did not affect mRNA coding for glucocorticoid receptors in hippocampal subregions or in the dorsal raphe nucleus. Mean plasma lithium levels in the lithium-treated group were 0.50 +/- 0.03 mmol/l; all animals appeared healthy and maintained a normal increase in body weight. Given recent reports implicating hypersensitive post-synaptic 5-HT(1A) receptors in bipolar manic patients, the present study suggests that down-regulation of this receptor population may be important in the therapeutic mechanism of action of lithium.     

Decreased social behaviour following 3,4-methylenedioxymethamphetamine (MDMA) is accompanied by changes in 5-HT2A receptor responsivity

This study examined the involvement of the 5-HT(2A) receptor in the long-term anxiogenic effect of a brief exposure of young rats to 3,4-methylenedioxymethamphetamine (MDMA) using the social interaction and elevated plus-maze paradigms. Wistar rats (post-natal day (PND) 28) received either MDMA (5 mg/kg i.p.) or saline (1 ml/kg i.p.) hourly for 4 h on 2 consecutive days. Locomotor activity was measured for 60 min after the first injection and core body temperature was recorded at regular intervals over 4 h. On PND 84, without further drug administration, social interaction was assessed between treatment-matched rat pairs derived from separate litters. On PND 86, rats received either the 5-HT(2A/2C) receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg i.p.) or saline and locomotor activity, wet-dog shakes and back muscle contractions were monitored. The change in elevated plus-maze behaviour was assessed following the same injection on PND 87. Acutely, MDMA produced a significant hyperlocomotion and hyperthermia (p<0.01). Following 55 days of abstinence, social interaction was reduced by 27% in MDMA pre-treated rats compared with that in controls (p<0.01). On the elevated plus-maze, pre-treatment with MDMA prevented the anxiogenic effect of DOI. On PND 92, hippocampal, frontal cortical and striatal 5-hydroxytryptamine (5-HT) was significantly reduced in MDMA pre-treated rats by between 16% and 22%, without any accompanying change in [(3)H]paroxetine binding in cortical homogenates. In conclusion, exposure of young rats to repeated MDMA caused serotonin depletion and induced 'anxiety-like' behaviour in the social interaction test accompanied by a long-lasting reduction in specific 5-HT(2A) receptor mediated behaviour.     

Effect of 3,4-methylenedioxymethamphetamine on [3H]paroxetine binding in the frontal cortex and blood platelets of rats.

The effects of single or repeated administration of the racemic mixture of 3,4-methylenedioxymethamphetamine (MDMA; 20 mg/kg, s.c.) on the number (Bmax) of serotonin (5-HT) uptake sites as determined by [3H]paroxetine binding and the concentration of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the frontal cortex and blood platelets of rats 1 and 7 days following its administration. A single injection of MDMA significantly (P less than 0.05) decreased the number of [3H]paroxetine binding sites as well as the concentrations of 5-HT and 5-HIAA in the frontal cortex but not in platelets 7 days following administration. Repeated injections of MDMA (twice daily for 4 days) significantly (P less than 0.05) decreased the number of 5-HT uptake sites and the concentration of 5-HT and 5-HIAA in the frontal cortex but not in platelets 7 days following administration. Pretreatment with the 5-HT2/5-HT1C antagonist, ketanserin, inhibited the MDMA-induced decrease in 5-HT and 5-HIAA concentrations and the number of [3H]paroxetine binding sites in the frontal cortex 7 days following a single administration. These data are suggestive that blood platelets are less sensitive than brain tissue to the 5-HT-depleting effects of MDMA. The ability of ketanserin pretreatment to block MDMA-induced decreases in [3H]paroxetine binding sites in the frontal cortex is suggestive that 5-HT2/5-HT1C receptors may be involved in the neurotoxic effects of MDMA.     

Chronic treatment with a serotonin(2) receptor (5-HT(2)R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA

3,4-Methylenedioxymethamphetamine [MDMA; ecstasy] evokes a multifaceted subjective experience in human users which includes stimulation, feelings of well-being, mood elevation, empathy towards others as well as distortions in time, sensation and perception. Aspects of this unique psychopharmacology of MDMA are thought to be related to its potent actions to release serotonin (5-HT) and indirectly stimulate the 5-HT(2A) receptor (5-HT(2A)R). In the present studies, we examined the interrelationship between down-regulation of 5-HT(2A)R expression and the behaviorally stimulatory effects generated by acute administration of (+)-MDMA, the most potent enantiomer of (+/-)-MDMA. Male Sprague-Dawley rats were chronically treated with the preferential 5-HT(2A)R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) which has been shown to down-regulate expression of the 5-HT(2A)R, but not the closely related 5-HT(2C)R. While chronic DOI treatment did not alter the functional sensitivity of either the 5-HT(2A)R or 5-HT(2C)R, this regimen enhanced (+)-MDMA-evoked hyperactivity. Subsequent analysis of c-Fos and 5-HT(2A)R immunoreactivity in brain sections demonstrated that DOI treatment decreased the number of (+)-MDMA-induced c-Fos immunopositive nuclei and 5-HT(2A)R immunostaining in select cortical and striatal areas. These results indicate that chronic DOI exposure results in an enhanced behavioral response to (+)-MDMA and in a pattern of neuronal activation which resembles that seen in psychostimulant sensitization. These data also suggest that expression of the 5-HT(2A)R in the NAc and PFC may play a role in the sensitivity to the locomotor-stimulating effects of (+)-MDMA and in the processes of neural regulation upon repeated psychostimulant administration.     

Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA

Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.