Effects of chronic lithium treatment on serotonin binding sites in rat brain

The effects of lithium treatment on serotonin (5-HT) binding sites in the rat brain were investigated. Oral administration of lithium carbonate for 3 weeks did not influence 5-HT2 binding sites in the cerebral cortex. On the other hand, the number of 5-HT1 binding sites labeled with [3H]5-HT was decreased significantly in the hippocampus, but not in the cerebral cortex. While non-5-HT1A sites, defined as specific [3H]5-HT binding in the presence of 100 nM 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were not affected by lithium treatment in either brain region, chronic lithium administration reduced significantly the density of 5-HT1A sites labeled with [3H]8-OH-DPAT only in the hippocampus, but not in the cerebral cortex. These results suggest that 5-HT1A components are responsible for lithium-induced down-regulation of 5-HT1 binding sites in the hippocampus and that 5-HT1A sites in the hippocampus might be connected with the therapeutic efficacy of lithium.     

GABA receptor alterations after chronic lithium administration. Comparison with carbamazepine and sodium valproate.

1. Effects of lithium, carbamazepine, sodium valproate and baclofen on GABA receptors were examined in several regions of the rat brain. 2. [3H]Muscimol (MUS) and [3H] (-)baclofen (BAC) were used to label GABAA and GABAB receptors, respectively, in synaptic membranes from rat brain. 3. Single treatment with lithium chloride, carbamazepine or sodium valproate did not change [3H]MUS or [3H]BAC binding in the frontal cortex, hippocampus and thalamus. 4. Following chronic treatment with lithium, carbamazepine or sodium valproate, [3H]BAC binding was significantly increased in the hippocampus but not in the frontal cortex, thalamus or striatum. 5. [3H]Muscimol binding did not change in any region examined after chronic treatment with lithium, carbamazepine or sodium valproate. 6. Single and chronic administration of baclofen did not change [3H]MUS or [3H]BAC binding. 7. One common mechanism of action of mood stabilizers may be mediated by GABAB receptors in the hippocampus.     

Short-term lithium treatment enhances responsiveness of postsynaptic 5-HT1A receptors without altering 5-HT autoreceptor sensitivity: an electrophysiological study in the rat brain

Short-term lithium administration to rats has previously been shown to enhance 5-HT neurotransmission through a modification of 5-HT neuron properties. In the first part of the present study, the effect of lithium on the function of terminal 5-HT autoreceptors was assessed by comparing in controls and lithium-treated rats the differential effect of two frequencies of stimulation (0.8 and 5 Hz) and that of methiothepin, a terminal 5-HT autoreceptor antagonist, on the effectiveness of the electrical activation of the ascending 5-HT pathway in suppressing dorsal hippocampus pyramidal neuron firing activity. Both procedures produced similar effects in controls and lithium-treated rats. In the second part of the study, the function of somatodendritic 5-HT autoreceptors was studied. The effect of intravenous LSD, an agonist of the somatodendritic 5-HT autoreceptor, on the firing activity of 5-HT neurons was not modified by the lithium treatment, whereas that of intravenous 8-OH-DPAT, a 5-HT1A receptor agonist, was increased two-fold. However, lithium did not alter the responsiveness of 5-HT neurons to direct microiontophoretic applications of 8-OH-DPAT as well as of LSD and 5-HT. It is concluded that short-term lithium treatment does not alter the function of terminal and somatodendritic 5-HT autoreceptors and that it enhances the sensitivity of a subset of postsynaptic 5-HT1A receptors involved in controlling 5-HT neuron firing activity, presumably through a feedback loop.     

Changes in dopamine2 and serotonin2 receptors in rat brain after long-term verapamil treatment: comparison of verapamil and lithium.

Rat brain 5-HT2 and dopamine2 receptors were assessed following a chronic (3 weeks) administration of verapamil, lithium, and a combination of these two drugs. A significant increase in the number of 5-HT2 receptors was observed in the frontal cortex after the verapamil treatment, but the lithium and combined treatment had no effect on the densities of either binding sites. These data suggest that one or more of the mechanisms of the antimanic effect of verapamil may be involved in the change in 5-HT2 binding sites in a manner that is different from that of lithium.     

Acute and long-term effects of 17beta-estradiol on G(i/o) coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [35S]GTPgammaS binding

Estrogens exert effects on mood, mental state, memory and other central nervous system (CNS) functions by modulating neurotransmitter receptor systems in the brain. Studies were designed to investigate the effect of 17beta-estradiol (E(2)) on agonist-stimulated [35S]GTPgammaS binding in membranes to assess the first step in the intracellular signal transduction cascade in a functional assay following: (1) an acute, one-time bolus subcutaneous injection, or (2) 14-day continuous exposure by a slow-release pellet implanted subcutaneously. In rats treated with E(2) acutely, the maximal response produced by activation of serotonin(1A) (5-HT(1A)) receptors was decreased approximately 25% in the hippocampus, cortex, and amygdala. Similarly, acute E(2) administration desensitized 5-HT(1B) and GABA(B) receptors in hypothalamus and cerebellum, respectively, and cannabinoid receptors in hippocampus and cortex. Although the maximal responses were decreased, acute E(2) treatment did not alter the EC(50) of any of the aforementioned receptors. The incubation of membranes prepared from the cortex of ovariectomized (OVX) rats with E(2) (1 microM) in vitro did not alter 5-HT(1A) or cannabinoid receptor-mediated [35S]GTPgammaS binding. By contrast to acute treatment in vivo, 14-day E(2) administration to OVX rats did not alter the maximal responses produced by activation of 5-HT(1A), 5-HT(1B), GABA(B), or cannabinoid receptors in any of the brain regions examined. Thus, it is concluded that acute E(2) administration in vivo modulates multiple G(i/o) coupled receptors in various regions of the female rat brain. Because these effects are observed only in vivo, it is concluded that cytosolic, nuclear and/or extraneuronal factors are required.     

The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels

The reported increase in brain-derived neurotrophic factor (BDNF) mRNA expression after antidepressant treatment is a cornerstone of the BDNF hypothesis of antidepressant action. However, if this increase becomes manifest on the BDNF protein level is unknown. In the present study we performed parallel measurements of BDNF mRNA and protein expression in the frontal cortex and hippocampus of the rat after chronic treatment with electroconvulsive seizures (ECS), lithium, desipramine or escitalopram. ECS increased BDNF mRNA and protein in the hippocampus and BDNF protein in the frontal cortex. Desipramine moderately increased BDNF mRNA expression in the dentate gyrus but did not change BDNF protein in neither region. Escitalopram did not affect BDNF mRNA expression, but decreased BDNF protein in the frontal cortex and the hippocampus. Lithium increased BDNF protein levels in the hippocampus and frontal cortex, but overall decreased BDNF mRNA expression. Thus, here we report a striking non-correspondence between changes in BDNF mRNA and protein expression induced by the antidepressant treatments and lithium. Further, increased expression of BDNF mRNA or protein was not a common action of the treatments. We also investigated if treatment-induced modulations of the tissue contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxy-indoleacetic acid (5-HIAA), were related to changes in BDNF mRNA or protein expression. No correlation was found. However, all treatments increased 5-HT levels in the hippocampus.     

In vivo study of central serotoninergic receptors in man using positron tomography

In an attempt to characterize in vivo the central serotonergic (5-HT2) receptors in humans with positron emission tomography (PET), we have used 11C-labeled-ketanserin, a seratonergic antagonist that has high affinity and selectivity for the 5-HT2 receptors in vitro. Earlier in vivo studies in rats had demonstrated a preferential accumulation of 3H-ketanserin in the frontal cortex relative to cerebellum, in accordance with known differences in density of 5-HT2 receptor in these two brain structures (5-HT2 receptors are dense in frontal cortex and sparse or absent in cerebellum). In rats, tracer accumulation in frontal cortex represented specific binding of 3H-ketanserin to 5-HT2 receptors in vivo as demonstrated by inhibition, saturation, and displacement studies. In 5 control subjects, we found a statistically significant retention of 11C-ketanserin in frontal cortex relative to cerebellum after intravenous injection of a tracer dose of the radioligand, suggesting specific in vivo binding of 11C-ketanserin to frontal cortex. To substantiate this hypothesis, we studied 4 subjects administered unlabeled chlorpromazine (CPZ) intramuscularly in therapeutic amounts (75 mg) two hours before the PET study. Pretreatment with CPZ decreased significantly the retention of 11C-ketanserin by the frontal cortex, indicating that almost total occupation of the ketanserin receptors by CPZ had been achieved prior to the injection of the radioligand. Despite these positive results, both the duration and the magnitude of tracer retention by frontal cortex in control subjects were much smaller than was reported in rats, presumably indicating lower specific binding, higher nonspecific binding, and faster drug metabolism in humans.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain.

Repeated treatment with fluoxetine and citalopram, which are potent 5-HT reuptake inhibitors, resulted in different regulation of 5-HT1A and 5-HT2 receptors in the rat brain. Their effects were compared with those of other antidepressants: imipramine, mianserin and levoprotiline. The density of 5-HT1A receptors, labelled with [3H]8-OH-DPAT, in the rat hippocampus was enhanced after citalopram, imipramine, mianserin and levoprotiline, but not altered after fluoxetine administration. [3H]Ketanserin binding sites, which label 5-HT2 receptors, were increased after fluoxetine and levoprotiline, but decreased after citalopram, imipramine and mianserin in the rat cerebral cortex. Acute administration of fluoxetine, but not citalopram, resulted in a decreased density of 5-HT1A receptors. 5-HT2 receptors were not changed by acute administration of either fluoxetine or citalopram. The obtained results indicate that besides 5-HT reuptake inhibiting properties of both compounds, there may exist an additional mechanism(s) of their action, which leads to different regulation of 5-HT1A and 5-HT2 receptors.     

Regional changes in brain 5-HT1A serotonin receptors in the rat model of persistent spasmodic dyskinesias induced by iminodipropionitrile

Chronic injection of iminodipropionitrile (IDPN) to rats causes persistent motor abnormalities such as hyperactivity, lateral and vertical dyskinesia of the neck, and random circling. These behavioral changes are very similar to those observed after the acute administration of serotonin (5-HT) agonists in rodents. Moreover, some aspects of this syndrome are reproduced by stimulation of 5-HT1A receptors. The present quantitative autoradiographic study revealed a number of changes in 8-hydroxy-2-[di-n-propylamino-3H]tetralin (8-OH[3H]DPAT)-labeled 5-HT1A receptors in the brains of IDPN-treated rats. There were significant increases of 8-OH[3H]DPAT binding in the frontal cortex and in the caudate-putamen. In contrast, there were significant decreases in the interpeduncular nucleus, the pyramidal layer of the CA3 field of hippocampus, the superior colliculus and the pars reticulata of the substantia nigra. These results provide further evidence for the involvement of the 5-HT system in the development of the IDPN-induced dyskinetic syndrome.     

Delayed effects of spiperone on serotonin1A receptors in the dorsal hippocampus of rats.

The effects of 5-HT1A antagonists spiperone, methiothepin and BMY 7378 on [3H]-8-OH-DPAT binding were determined in vitro and ex vivo in rat hippocampus CA3 membrane preparations, and ex vivo in tissue sections of CA1 and CA3 subfields using quantitative autoradiography. In CA3 membranes from rats sacrificed 1 h or 24 h after administration of 5 mg/kg i.p. spiperone or methiothepin, no decrease in [3H]-8-OH-DPAT Bmax values approached statistical significance. Autoradiograms from identically treated rats showed significant increases in Kd values in both CA1 and CA3 hippocampal subfields 24 h but not 1 h after administration of the drugs, while no changes were observed in the dorsal raphe at either time. In vitro co-incubation of membranes with spiperone (200 or 500 nM) or methiothepin (500 nM) resulted in significant decreases in both affinity and Bmax values. In contrast, co-incubation with BMY 7378 (5 nM) increased only Kd values. GTP gamma S produced a concentration-dependent inhibition of specific [3H]8-OH-DPAT binding. At 0.1 mM of GTP gamma S, Kd values were increased three-fold and Bmax values were significantly decreased. When membranes were co-incubated with GTP gamma S and spiperone or BMY 7378, Kd values increased further. Moreover, the effects of spiperone and GTP gamma S on Bmax values were additive. It is concluded that BMY 7378 acts as a competitive antagonist at hippocampal post-synaptic 5-HT1A receptors, whereas spiperone and methiothepin exert their delayed antagonistic effects at these receptors through a non-competitive mechanism of action, possibly affecting the coupling of the receptors to their Gi/o proteins.     

Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain

Long-term administration of the atypical neuroleptic clozapine (CLZ) poses a much lower risk of extrapyramidal side effects (EPS) than does the use of typical neuroleptics such as haloperidol (HAL). To investigate the neural mechanisms of the differing CNS activities of these two drugs, we used quantitative autoradiography to measure changes in dopamine and serotonin receptors in rats after injection with CLZ or HAL for 21 days at clinically relevant dose ratios. Levels of D1, D2, and 5-HT2 receptors were determined in frontal cortex, caudate-putamen, and nucleus accumbens. Rats that received CLZ chronically showed CNS receptor changes markedly different from those in chronic HAL-treated animals. Whereas rats treated chronically with HAL showed enhanced striatal D2 binding (average increase of 42%), those treated with CLZ did not. In contrast, chronic CLZ, but not chronic HAL, induced enhanced striatal D1 binding (average increase of 43%). Finally, CLZ treatment decreased 5-HT2 receptor binding by an average of 37%, while HAL had no significant effect. The effects of chronic HAL or CLZ treatment on receptors were similar in all forebrain areas examined. However, since D1 and 5-HT2 receptors are more abundant than D2 sites in limbic and neocortical areas, the preferential modulation of D1 and 5-HT2 receptors by CLZ suggests a greater impact of this atypical neuroleptic on activity of the limbic system than that achieved by the typical neuroleptic, HAL. These findings suggest that the clinical profile of atypical neuroleptics such as CLZ may be attributed to their effects on a receptor profile differing in pharmacological characteristics and anatomical distribution from that affected by typical neuroleptics.     

Chronic 5-HT2 receptor antagonist treatment alters 5-HT1A autoregulatory control of 5-HT release in rat brain in vivo.

Rats treated chronically (14 days) with the 5-HT2 receptor antagonist ritanserin, show decreased 5-HT2 receptor numbers in the frontal cortex. The present experiments were designed to investigate the effects of acute and chronic ritanserin treatment on the autoregulatory control of the release of 5-HT and its metabolite 5-HIAA in vivo in rats using intracerebral dialysis. Neither acute nor chronic ritanserin treatment altered basal extracellular levels of 5-HT or 5-HIAA, suggesting that 5-HT2 receptors do not directly influence 5-HT release. In the control animals, systemic stimulation of somatodendritic 5-HT1A receptors with the 5-HT1A receptor agonist 8-OH-DPAT, inhibited the release of 5-HT presumably via inhibitory feedback autoregulation; an effect also seen in animals treated acutely with ritanserin. However, in the animals treated chronically with ritanserin, administration of 8-OH-DPAT produced an initial increase in extracellular 5-HT which declined gradually to the end of the experiment. These results suggest that chronic, but not acute, 5-HT2 receptor antagonist treatment attenuates the 5-HT1A receptor-mediated autoregulation of 5-HT release. The underlying mechanisms have yet to be ascertained.     

Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations

OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.     

Methylenendioxyamphetamine produces serotonin nerve terminal loss and diminished behavioural and neurochemical responses to the antidepressant fluoxetine

The effect of prior exposure to methylenedioxyamphetamine (MDA) on behavioural and neurochemical responses to fluoxetine were assessed in a rat model of antidepressant action. MDA (7.5 mg/kg, i.p.) was administered to rats twice daily for 4 consecutive days, and 4 weeks later the behavioural effect of fluoxetine (5 or 20 mg/kg; i.p. x 3) was examined in the modified rat forced-swimming test. In addition, the ability of fluoxetine to reduce serotonin (5-HT) metabolism was measured as an index of its efficacy in inhibiting 5-HT reuptake in vivo. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) produced a characteristic increase in swimming behaviour in the forced-swimming test. In contrast, fluoxetine-induced swimming was markedly attenuated in MDA-treated rats. MDA pretreatment resulted in 5-HT nerve terminal degeneration, indicated by reduced 5-HT and 5-HIAA concentrations in the frontal cortex, amygdala and hippocampus, and reduced [3H]paroxetine binding in the frontal cortex. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) decreased 5-HT metabolism (5-HIAA : 5-HT ratio) in the frontal cortex, amygdala and hippocampus. MDA pretreatment attenuated the ability of fluoxetine to reduce 5-HT metabolism in all brain regions examined. These findings are the first to demonstrate that prior exposure to the methylenedioxy-substituted amphetamine MDA results in diminished responsiveness to the antidepressant fluoxetine.     

Altered 5-HT2A and 5-HT4 postsynaptic receptors and their intracellular signalling systems IP3 and cAMP in brains from depressed violent suicide victims

Serotonin 5-HT2A and 5-HT4 binding parameters and their second messengers 1,4,5-inositol triphosphate (IP3) and cyclic adenosyl monophosphate (cAMP) were studied in the frontal cortex, hippocampus, caudate nucleus and amygdala of 19 control subjects and 19 antidepressant-free, violent suicide victims. A significantly higher number of 5-HT4 receptors and higher second messenger cAMP concentrations were found in the frontal cortex and caudate nucleus of the depressed suicide victims as compared with the control group. Furthermore, significantly increased 5-HT2A binding sites and IP3 concentrations were noted in the caudate nucleus of the suicide victims, together with a significantly reduced number of 5-HT2A binding sites, higher binding affinity and increased IP3 concentrations in the hippocampus. No significant alterations in 5-HT4 and cAMP or in 5-HT2A and IP3 concentrations were observed in the amygdala. The caudate nucleus of depressed suicide victims seems to be the brain region with the highest alteration of the serotonergic system, and hence with the most diagnostic sensitivity. Further studies on suicidality and depression should focus on the functionality of the caudate nucleus.     

Changes in Dopamine 2 and Serotonin Receptors in Rat Brain after Long-Term Verapamil Treatment: Comparison of Verapamil and Lithium

Abstract: Rat brain S-HT₂ and dopamine₂ receptors were assessed following a chronic (3 weeks) administration of verapamil, lithium, and a combination of these two drugs. A significant increase in the number of 5-HT2 receptors was observed in the frontal cortex after the verapamil treatment, but the lithium and combined treatment had no effect on the densities of either binding sites. These data suggest that one or more of the mechanisms of the antimanic effect of verapamil may be involved in the change in 5-HT₂ binding sites in a manner that is different from that of lithium.     

Regional changes in 5-HT1A but not in 5-HT2A receptors in mouse brain after Semliki Forest virus infection: radioligand binding and autoradiographic studies

Dysfunction of brain 5-hydroxytryptaminergic systems has been associated with several neurological and psychiatric diseases which may have a viral aetiology. The effect of Semliki Forest virus (SFV) on 5-hydroxytryptamine (5-HT1A and 5-HT2A) receptors in mouse brain has been assessed by membrane homogenate binding and autoradiography. Adult mice were injected with saline or virus and brains removed 2, 6, 14, 22 and 35 days after infection. 5-HT1A and 5-HT2A receptors were characterised by saturation studies using [3H] 8-OH-DPAT and [3H] Ketanserin respectively. SFV infection increased 5-HT1A receptor numbers by up to 80% in the cortex on days 6, 14, and 22 but had no effect on Bmax in the midbrain, pons/medulla and the hypothalamus. SFV infection did not affect 5-HT2A receptor number in any of the brain regions studied and the affinity (Kd) of either ligand for 5-HT1A or 5-HT2A receptors was unaffected. Autoradiographic mapping of 5-HT1A receptors in SFV-infected brain showed substantially higher binding in nucleus accumbens, tenia tecta, septohippocampal nucleus, septum, medial and basolateral amygdaloid nucleus, anterioventral preoptic nucleus, hippocampus, interpeduncular nucleus, frontal, lateral orbital, and entorhinal cortex and claustrum on days 6 and 14. Elevated binding persisted in tenia tecta, frontal, lateral orbital, entorhinal cortex, and hippocampal formation to day 22. Autoradiography of 5-HT2A receptors using [3H] Ketanserin showed no difference in the binding in SFV-infected brains. A decrease in plasma corticosterone levels in SFV-infected mice was observed on post infection days 6 and 22. These results show SFV infection induces a regionally selective upregulation of 5-HT1A but not 5-HT2A receptors.     

Involvement of the central serotoninergic system in the changes of leu-enkephalin level in discrete rat brain areas

The effects of acute and chronic treatment with LSD and acute treatment with mescaline, m-CPP, citalopram and fenfluramine on leu-enkephalin (LENK) content in rat brain were examined. The acute LSD treatment was found to decrease and chronic treatment to increase the LENK content in the frontal cortex. In the thalamus with hypothalamus the LENK level fell after the administration of LSD, mescaline, citalopram and fenfluramine, while in the striatum it increased significantly, except for fenfluramine treatment. Methergoline and methiothepin prevented the effects of acute and chronic LSD administration. The diminished LENK level was associated with a decrease of 5-HT or 5-HIAA content in the rat brain areas investigated. Therefore, it has been concluded that the serotoninergic system may modulate the LENK pathway.     

Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-Br-LSD

N1-([11C]-Methyl)-2-Br-LSD ([11C]-MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5-HT2 receptors. In vitro receptor binding assays with nonradioactive MBL show high-affinity binding to serotonin 5-HT2 receptors (Ki = 0.5 nM), a secondary interaction of 8-fold lower affinity with dopamine D2 receptors, and low-affinity interactions with alpha 1-adrenergic as well as serotonin 5-HT1 receptors. Intravenous injection of [11C]-MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5-HT2 receptor antagonist. Clinical trials with [11C]-MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52-year-old male to 2.7 for a 30-year-old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5-HT2 receptor levels) was observed in older volunteers. These studies indicate that [11C]-MBL is a selective radioligand that can be used to monitor serotonin 5-HT2 receptor densities in vivo in most regions of the human brain.     

Increased CRE-binding activity and tryptophan hydroxylase mRNA expression induced by 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in the rat frontal cortex but not in the hippocampus

A single administration of either 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") or p-chloroamphetamine (PCA) produced a rapid and marked reduction of serotonin (5-HT) content in rat frontal cortex and hippocampus. In the cortex of MDMA-treated rats, 5-HT levels returned to control values 48 h after drug administration. This recovery was correlated with an induction of CRE-binding activity and an enhanced expression of tryptophan hydroxylase (TPH) mRNA, the rate-limiting enzyme in 5-HT biosynthesis, suggesting that MDMA may up-regulate the TPH gene through a CREB-dependent mechanism. In the cortex of PCA-treated rats, neither a recovery of 5-HT levels nor changes in DNA-binding or TPH mRNA were found at the same time point. In the hippocampus of rats receiving either PCA or MDMA a decrease in TPH mRNA levels was found at all times, along with a reduced CRE-binding at the 8-h time point. The results show region-specific effects of MDMA. In the frontal cortex, the increased TPH expression suggests a compensatory response to MDMA-induced loss of serotonergic function.