Paroxetine Binding Research Articles

3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with major depression before and after treatment with fluoxetine

Serotonin has been involved in major depression and is also related to central and peripheral mechanisms of neuroimmunomodulation. Recently, the uptake of [ 3H]serotonin into human peripheral blood lymphocytes has been reported. We determined the density of serotonin uptake sites by the binding of [ 3H]paroxetine to blood peripheral lymphocyte membrane preparations of controls and of patients with major depression before and after treatment with fluoxetine for six weeks. The severity of depression was assessed by the use of Hamilton Rating Scale for Depression and of Beck Depression Inventory. There was a reduction in the number of sites for [ 3H]paroxetine in patients before administration of the antidepressant respecting controls, and a recovery after the treatment. Affinity was unchanged. No correlation was obtained between the severity of symptoms determined by Hamilton Rating Scale for Depression or by Beck Depression Inventory, and the number of binding sites for [ 3H]paroxetine. The levels of the plasma serotonin metabolite, 5-hydroxyindoleacetic acid, did not differ between the three groups of subjects, but serotonin was lower in patients after treatment respecting controls and in patients before treatment. The significant correlation between specific binding of [ 3H]paroxetine and plasma serotonin levels in controls was not present in the patients. Lymphocyte serotonin transporter is decreased in major depressed patients and is modulated by antidepressant treatment. In addition of counting with a peripheral marker in depression, the study of serotonin system in lymphocytes might contribute to understand the bi-directional interaction between the nervous and the immune systems.

PLATELET PAROXETINE BINDING TO 5-HT UPTAKE SITES IN ELDERLY PATIENTS WITH ALZHEIMER's DISEASE WITH AGITATION AND AGGRESSION

Introduction: Currently a large body of literature supports the relationship between aggression and serotoninergic dysfunction. Furthermore, patients with AD have well-established findings regarding pathology in the serotoninergic system at the Central Nervous System level (Andersson et al. 1991.) The authors' (Mintzer et al.1998) and others (Lanctot et al. 1997) challenge data supports the presence of serotoninergic dysfunction in agitated (Mintzer et al. 1998) and agitated/aggressive AD patients (Lanctot et al. 1997). It is, however, not known if this is a state phenomenon secondary to an AD-related process or a trait phenomenon that is manifested in predisposed AD patients. This study addresses this issue by assessing 5-HT uptake sites in aggressive and nonaggressive AD patients' platelets, an organ not known to be affected by the primary AD process. Objective: Explore possible differences, specifically in binding affinity (Kd) and maximum number of binding sites (Bmax), in 5-HT uptake sites in platelets between patients with AD, AD with behavioral disturbances, and age-matched normal control subjects using [3H]paroxetine platelet binding. Methods: The authors have already recruited, rated, and obtained samples from elderly AD patients without behavioral disturbances (n=6, CMAI: 1), and 8 elderly AD subjects with agitated aggressive behaviors (n=8, CMAI: 2.96). All subjects were objectively rated for cognitive function, depression, anxiety, and behavioral symptoms. Blood samples and paroxetine binding was performed accordingly to Andersson et al. (1991) procedures. Results: All the subjects were able to tolerate the procedure. Preliminary data in the AD/Agitated group (n=5) showed a Bmax of 6,000 fmol/mg and a Kd of 0.08934 nM. In the Nonagitated group (n=4) Bmax was 4,084.5 fmol/mg and Kd was 0.056745 nM. Final data are presented by group (AD with and without behavioral disturbances and controls), and correlations are examined with disease severity.

Platelet serotonergic binding sites in alcohol-dependent patients.

The serotonin (5-hydroxytryptamine, 5-HT) uptake sites assessed with both [3H]imipramine and [3H]paroxetine, and the 5-HT2A receptors were simultaneously measured in platelets from 24 male subjects meeting the American Psychiatric Association's DSM-IV criteria for alcohol dependence and admitted for inpatient detoxification. Blood samples from alcoholic patients were collected during acute alcohol intoxication (day 0), during withdrawal (day 1), and after 2 weeks of abstinence (day 14). All patients met the criteria for type II alcoholism. Alcohol misuse was found to be associated with an increased number and a lower affinity of [3H]paroxetine binding in comparison to the control values. Abstinence from alcohol for 2 weeks (day 14) resulted in a decrease in the number of 5-HT uptake sites labelled with [3H]paroxetine compared to normal values, together with a significant decrease in the number of 5-HT2A binding sites. The present data indicate that altered serotonergic function existing in alcoholic patients is a reversible phenomenon that normalizes after detoxification and withdrawal.

Changes in 5-HT 1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats

The effects of a single rapid-rate transcranial magnetic stimulation (rTMS) exposure on neurotransmitter binding sites in the rat brain 24 h after the stimulation were examined. Quantification by in vitro-autoradiography showed no differences for 3 H -paroxetine binding (5-HT uptake sites) between rTMS-treated, sham and control animals. In contrast, the number of 5-HT 1A binding sites (labeled with 3 H -8-OH-DPAT) were selectively increased in the rTMS-group with significantly higher B MAX values in the frontal cortex, the cingulate cortex, and the anterior olfactory nucleus. A non-specific increase in NMDA binding sites (labeled with 125 I -MK-801) in rTMS and sham animals was observed in the hippocampal formation. A selective increase of these binding sites after rTMS was detected in the ventromedial hypothalamus, the basolateral amygdala and layers 5–6 of the parietal cortex. These findings imply that a single rTMS exposure can result in persistent effects on NMDA and 5-HT 1A binding sites even 24 h after stimulation and therefore may be of relevance with respect to the therapeutic action of rTMS reported from clinical studies.

Studies on the neuroprotective effect of pentobarbitone on MDMA-induced neurodegeneration.

Administration of a dose of 15 mg/kg of the recreationally used drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") to Dark Agouti rats resulted in an acute hyperthermic response which was followed 7 days later by a marked (approximately 45%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [3H]-paroxetine binding in cortex. These losses reflect the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. Administration of pentobarbitone (40 mg/kg) concurrently with MDMA produced a significant attenuation of the neurotoxic damage, but also acute hypothermia. When the temperature of the MDMA plus pentobarbitone-treated group was kept elevated to that of the MDMA-treated group by the use of a homeothermic blanket, the neuroprotective effect of pentobarbitone was lost. These data demonstrate that pentobarbitone appears to possess no intrinsic neuroprotective activity and the previously reported activity is due to a hypothermic action of the drug.

Chronic amitriptyline administration increases serotonin transporter binding sites in the hippocampus of aged rats

The effects of ageing and of chronic antidepressant treatment upon 5-HT transporter sites ([ 3H]paroxetine binding) in the rat hippocampus was examined. [ 3H]paroxetine binding to transporter sites was decreased with ageing in the hippocampus of control rats (38% decrease in dentate gyrus and CA4). Amitriptyline (10 mg/kg, i.p.) had no significant effect on [ 3H]paroxetine binding in 10 months old rats, but increased binding sites in 24 months rats in all hippocampal subregions (greatest increase of 109% in CA1 compared to saline controls). These data indicate an age-related decrease in hippocampal serotonin transporter sites and upregulation of these sites following 10 weeks of amitriptyline. The observed increase in transporter sites following amitriptyline may contribute to the general lower effectiveness of tricyclic antidepressants with ageing.

Serotonergic and Noradrenergic Markers of Post-Traumatic Stress Disorder with and without Major Depression

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline (NE) may play roles in the pathophysiology of post-traumatic stress disorder (PTSD). This study examines (1) the availability of plasma total tryptophan, the precursor of 5-HT, and tyrosine, the precursor of NE; and (2) the platelet 5-HT transporter and α2-adrenoceptor (α2-AR) binding sites in patients with PTSD and healthy volunteers. High-performance liquid chromatography (HPLC) was employed to measure plasma tryptophan and tyrosine as well as amino acids known to compete with the same cerebral transport system; that is, valine, leucine, phenylalanine, and isoleucine. The maximum number of binding sites (Bmax) and their affinity (Kd) for binding to [3H]-paroxetine and [3H]-rauwolscine, a selective α2-AR antagonist, were determined. [3H]-paroxetine and [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD than in healthy volunteers. [3H]-rauwolscine binding Kd values were significantly higher in patients with PTSD and concurrent major depression (MD) than in PTSD patients without MD and healthy volunteers. Plasma tyrosine concentrations and the ratio of tyrosine/valine + leucine + isoleucine + phenylalanine + tryptophan were significantly higher in PTSD patients with MD than in those without MD and healthy volunteers. The results show that PTSD is accompanied by lower affinity of paroxetine binding sites and that PTSD with concurrent MD is accompanied by lower affinity of α2-ARs and increased plasma tyrosine availability to the brain. The results suggest that (1) serotonergic mechanisms, such as defects in the 5-HT transporter system, may play a role in the pathophysiology of PTSD; and (2) that catecholaminergic mechanisms, such as increased precursor availability and lowered affinity of α2-ARs, may play a role in the pathophysiology of PTSD with concurrent MD.

Platelet [ 3H]paroxetine and [ 3H]lysergic acid diethylamide binding in seasonal affective disorder and the effect of bright light therapy

Background: Seasonal affective disorder (SAD) has been regarded as a melatonin disorder, but the pathophysiological mechanisms of SAD are to a large extent unclarified. Serotonergic mechanisms have also been studied, but they have shown inconsistent results. Methods: We have compared [ 3H]paroxetine and [ 3H]lysergic acid diethylamide (LSD) binding in platelets from 23 SAD patients and 23 controls. Then SAD patients had 4 weeks of light therapy. On the last treatment day new blood samples were drawn. Symptoms before and after light treatment were measured by SIGH-SAD. Results: B max for paroxetine binding before light treatment was higher in SAD patients compared to controls and also higher in responders than in nonresponders. B max decreased significantly during light treatment. We also found a negative correlation between the two B max values before but not after light treatment. There was a negative correlation between B max for paroxetine binding before treatment and clinical status after treatment. Patients with reduced B max for LSD binding after treatment had a better clinical treatment response. Conclusions: The present study indicates that serotonin receptor parameters might be suitable in the prediction of clinical response to light treatment.

Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets

The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain. A 5-HTT-linked promoter region (5-HTTLPR) insertion/deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele. In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The l variant was associated with more rapid initial platelet 5-HT uptake (Vmax), the index of platelet 5-HTT function most clearly heritable, while the s allele was dominant. The 5-HTTLPR genotype had no effect on platelet [3H]paroxetine binding (Bmax), affinity for [3H]5-HT or [3H]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research.

N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats.

The present study examined the effect of N-tert-butyl-alpha-phenylnitrone (PBN) on 3,4-methylenedioxmathamphetamine (MDMA)-induced depletion of serotonin in the CNS. Rats were treated with two concurrent injections of MDMA (20 mg/kg, s.c.), PBN (50-400 mg/kg dissolved in ethanol, 50 mg/ml of 25% ethanol, i.p.), saline or 25% ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later. Rectal temperature was measured prior to and hourly following the drug injection for 5 h. Monoamine levels in the tissue were measured by HPLC. Density of the 5-HT transporters was assayed by [3H]paroxetine binding. Rectal temperature of rats increased after MDMA, decreased after PBN, ethanol, PBN plus ethanol, and MDMA plus ethanol, and was not significantly altered after MDMA plus PBN. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, striatum, and brain stem of rats decreased significantly after MDMA or MDMA plus ethanol, but not after MDMA plus PBN, PBN plus ethanol (PBN dissolved in ethanol), or ethanol as compared to the saline controls. Levels of 5-HT and 5-HIAA in the brain tissues of rats treated with MDMA plus PBN were elevated as compared to those treated with MDMA plus saline. Similar results were observed in the density of 5-HT transporters in the frontal cortex and hippocampus. These results indicate that scavenging of free radicals of MDMA metabolites or reactive oxygen species by PBN and with lowering of body temperature protected against MDMA-induced depletion of serotonin transmitter.

Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids

Estrogen increases serotonin transporter (SERT) mRNA and binding sites in female rat brain. In order to determine whether changes in SERT are gender- and steroid-specific we have now carried out studies on adult male Wistar rats which were either intact or castrated (under halothane anesthesia) and injected with arachis oil, estradiol benzoate (EB), testosterone propionate (TP) or the non-aromatizable androgen, 5α-dihydrotestosterone (5α-DHT). The number of SERT mRNA-expressing cells in the dorsal raphe (DR) nucleus was decreased by castration and increased by treatment (for ∼32 h) with EB or TP, but not 5α-DHT. Sex steroids had no effect on the number of SERT mRNA-expressing cells in the median raphe nucleus. The density of SERT sites, assessed by autoradiography of [ 3 H ]paroxetine binding, was significantly reduced in arcuate nucleus and median raphe after castration, and increased in arcuate, basolateral amygdala and ventromedial hypothalamic nucleus by treatment with EB or TP, but not 5α-DHT. Estradiol, but not testosterone or 5α-DHT reduced the density of SERT sites in midbrain central grey. These data show that testosterone as well as estrogen affects SERT expression in male brain, and that the action of testosterone probably depends upon its enzymatic conversion, by aromatase, to estradiol. Our findings may have implications for sex steroid control of mood and behavior, and the action of neurotoxic derivatives of amphetamine, such as 3,4-methylenedioxymethamphetamine, in the human.

Persistently increased density of serotonin transporters in the frontal cortex of rats treated with fluoxetine during early juvenile life.

This experimental animal study was performed in order to assess possible long-term effects of the administration of the selective serotonin reuptake inhibitor fluoxetine (Prozac) during early periods of juvenile life on the developing central serotonergic and noradrenergic systems. Fluoxetine was administered via the drinking water (5 mg/kg/day) for a period of two weeks to very young (day 25) and somewhat older (day 50) rats. The effect of this treatment on the density of serotonin and noradrenaline transporters was measured by ligand-binding assays in various brain regions. The Bmax-values of [3H]-nisoxetine binding were not affected by either treatment schedule, but a significant increase of the Bmax-values of [3H]-paroxetine binding was found in the brains of early fluoxetine-treated rats. This increase was restricted to the frontal cortex and persisted long after the termination of the treatment into adulthood (day 90). The most likely explanation of this observation is a stimulatory effect of the fluoxetine treatment on the outgrowth of serotonergic projections in the frontal cortex of very young rats. This is the first empirical demonstration of long-lasting effects of the administration of a selective serotonin reuptake inhibitor during juvenile life on the maturation of the central serotonergic system.

Altered [ 3H]imipramine and 5-HT2 but not [ 3H]paroxetine binding sites in platelets from depressed patients

Background: Serotonergic system alterations were studied in 51 depressed patients classified according to DSM-III-R criteria for major depression with melancholia compared to 31 healthy controls. Method: [ 3H]Imipramine and [ 3H]paroxetine binding sites and the 5HT2 receptor were simultaneously determined in blood platelet membranes. Results: A significantly lower maximum binding in [ 3H]imipramine binding was observed in depressed patients compared to controls (1134±74 vs. 1712±106 fmol/mg protein, P<0.0001) without changes in the equilibrium dissociation constant (1.10±0.05 vs. 1.25±0.09 nM). [ 3H]Paroxetine binding did not differ between the two groups ( B max, 1441±55 vs. 1280±81 fmol/mg protein; K d, 0.060±0.002 vs. 0.062±0.002 nM). The K d value of 5HT2 binding was lower in depressed patients than controls (0.95±0.04 vs. 1.15±0.09 nM, P<0.039) without changes in maximum binding (140±11 vs. 127±14 fmol/mg protein). Conclusions: Taken together, these results suggest that [ 3H]imipramine and 5HT2 receptors may be good biological markers for serotonergic dysfunction in depressive disorders.

Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain.

The effects of chronic administration of interferon (IFN; recombinant human IFN-alphaA/D) on serotonergic binding sites in rat brain were investigated. IFN was injected daily for 2 weeks at a dose of 100000 I.U./kg, (i.p.) in male Wistar rats. IFN did not alter either [3H]ketanserin binding to 5-HT2A receptors or [3H]paroxetine binding to 5-HT transporters. Scatchard analysis of [3H]8-hydroxy-dipropylaminotetraline (8-OH-DPAT) binding to 5-HT1A receptors demonstrated the presence of high- and low-affinity binding sites in both treatment and control groups. IFN significantly increased both Kd and Bmax measures of [3H]8-OH-DPAT binding at low-affinity binding sites, but not at the high-affinity sites. These results suggest that IFN affects the low-affinity 5-HT1A receptors sites and may be involved in the development of IFN-induced psychiatric disturbances.

Reduced brain serotonin transporter availability in major depression as measured by [ 123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography

Background: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [ 123I]β-CIT SPECT and platelet [ 3H]paroxetine binding. Methods: Drug-free depressed and healthy subjects were injected with 211 ± 22 MBq [ 123I]β-CIT and imaged 24 ± 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V 3″ = (brainstem-occipital)/occipital), a measure proportional to the binding potential (B max/K d), was used for all comparisons. Results: Results showed a statistically significant reduction in brainstem V 3″ values in depressed as compared to healthy subjects (3.1 ± .9 vs. 3.8 ± .8, p = .02). Platelet [ 3H]paroxetine binding was not altered (B max = 2389 ± 484 vs. 2415 ± 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [ 123I]β-CIT binding ( r = −0.14, p = .48). Conclusions: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.

Relationship between [125I]RTI-55-labeled cocaine binding sites and the serotonin transporter in rat placenta.

We investigated the characteristics of cocainelike binding sites in rat placenta using [125I]RTI-55. [3H]paroxetine binding and immunocytochemical staining for serotonin [5-hydroxytryptamine (5-HT)] and for the 5-HT transporter were also used to obtain evidence for rat placental 5-HT uptake. [125I]RTI-55 saturation analyses with membranes from normal gestational day 20 placentas yielded curvilinear Scatchard plots that were resolved into high- and low-affinity components (mean dissociation constants of 0.29 and 7.9 nM, respectively). Drug competition studies with various monoamine uptake inhibitors gave rise to complex multiphasic displacement curves, although the results obtained with the selective 5-HT uptake inhibitor citalopram suggest that the 5-HT transporter is an important component of placental high-affinity [125I]RTI-55 binding. The presence of a rat placental 5-HT uptake system was additionally supported by the [3H]paroxetine binding experiments and by the presence throughout the placenta of immunoreactivity for 5-HT and the 5-HT transporter. Immunostaining with both antibodies was most intense in the junctional zone, whereas the density of [125I]RTI-55 binding sites was greater in the placental labyrinth. This discrepancy may be due to the fact that [125I]RTI-55 appears to be labeling additional cellular components besides the 5-HT transporter. The presence of cocaine- and antidepressant-sensitive 5-HT transporters in the placenta has important implications for the possible effects of these compounds on pregnancy and fetal development.

Serotonergic hyperinnervation of the frontal cortex in an animal model of depression, the bulbectomized rat.

We studied the influence of olfactory bulbectomy in rats on three different parameters of serotonin (5-HT) presynapses, 5-HT transporter density, tryptophan hydroxylase apoenzyme concentration, and the levels of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) in various brain regions. Compared with sham-operated controls, the Bmax values of [3H]paroxetine binding, the apoenzyme concentration of tryptophan hydroxylase and the level of 5-HIAA, and, therefore, the 5-HIAA/5-HT ratio were significantly and selectively increased in the frontal cortex of bulbectomized rats, measured 12 weeks after surgery. The most likely explanation of the concomitant increase in levels of all three markers of 5-HT presynapses in the frontal cortex is an increased density of 5-HT innervation in this remote projection field of the raphe nuclei. It is suggested that the bulbectomy-associated axotomy of 5-HT fibers projecting to the bulb stimulates collateral sprouting and synaptogenesis, especially in the frontal cortex. The resulting 5-HT hyperinnervation must be expected to alter global neuronal activity in this region and to impair the balance of information flow between this and other brain regions, resulting in a multitude of secondary behavioral and neurochemical changes. The frontocortical abnormalities observed by brain imaging studies in the brains of depressed patients may also be explained by a selective 5-HT hyperinnervation of this brain region.

No Association between the Serotonin Transporter-Linked Promoter Region Polymorphism and Either Schizophrenia or Density of the Serotonin Transporter in Human Hippocampus

Allelic association case-control analysis of a deletion/insertion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has suggested associations with unipolar disorder, bipolar disorder, depression, and Alzheimer's disease. Moreover, the heterozygous long form of the 5-HTTLPR has been associated with increased levels of mRNA for the serotonin transporter (5-HTT) and increased serotonin uptake in lymphoblastic cell lines. This study attempts to determine whether there is an association between 5-HTTLPR genotype and schizophrenia or the binding of [3H]paroxetine to the human hippocampal 5-HTT. DNA from the cerebellum from 58 schizophrenic and 62 control subjects was used to genotype the 5-HTTLPR. In addition, the relationship between 5-HTTLPR genotype and the affinity and density of [3H]paroxetine binding to the hippocampal 5-HTT was assessed. There were no associations between 5-HTTLPR allotype or genotype and/or the parameters of [3H]paroxetine binding to the hippocampal 5-HTT. Our data suggest that 5-HTTLPR genotype neither confers an increased susceptibility for schizophrenia nor dictates the expression of the 5-HTT in the human hippocampus.

Expression and regulation of the human dopamine transporter in a neuronal cell line

Human cocaine users exhibit increased striatal [ 3 H ]WIN35428 binding to the dopamine transporter (DAT). However, the nature of the changes induced in the DAT are complex and may not result from a simple increase in number of DAT molecules. To better understand the regulation of DAT inhibitor binding sites and their relationship to the overall process of dopamine uptake, a neuronal model system expressing the human DAT has been developed. Initial experiments were attempted with native dopaminergic neurons so as to allow examination of DAT interactions with vesicular release and storage mechanisms. Dissociated fetal rat mesencephalic neurons, of various ages and mixtures with target cells, were grown to confluence. However, [ 3 H ]WIN35428 binding was of low affinity at all levels of maturity. Following this, a simpler model was assessed, using DAT cDNA transfected into neuroblastoma-derived Neuro2A cells. Initially, no specific and little non-specific [ 3 H ]WIN35428 or [ 3 H ]paroxetine binding was found in non-transfected cells. After transfection with the human DAT inserted in the pcDNA vector, both DAT binding and dopamine uptake were significantly and stably present. Treatment with (−)cocaine, 10 −6 M for 24 h, increased DAT binding and uptake, which did not occur in parallel COS-7 experiments. Other experiments with Neuro2A cells also found that dopamine uptake was down-regulated by treatment with a PKC activator. These results suggest that the transfected Neuro2A neurons should be useful for ongoing experiments examining the regulation of the DAT by assorted treatments.

The Role of Serotonin in Posttraumatic Stress Disorder: Neurobiology and Pharmacotherapy

AbstractMuch attention has been given to the role of catecholamine dysfunction in posttraumatic stress disorder (PTSD), and only recently have researchers begun to focus on serotonin (5-HT) in PTSD. Serotonin appears to be a factor in responses followin extreme stress, such as those that precede PTSD. In this review, the authors provide a brief overview of the concept of PTSD and specific issues of clinical concern. The role 5-HT in the neurobiology of PTSD is explored in a review of animal model studies and of clinical investigations of paroxetine binding, pharmacologic challenges, and neuroimaging. Data on the use of 5-HT in PTSD treatment are provided in a review of both open-label and controlled studies of serotonergically active drugs.