Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm

OBJECTIVE: Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT(2) receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT(2) receptor density increases during 5-HT depletion). METHOD: Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT(2) binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT(2) binding potential was measured with [(18)F]setoperone positron emission tomography. RESULTS: In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT(2) binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT(2) binding potential, compared to healthy subjects, particularly in Brodmann's area 9. CONCLUSIONS: Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated with major depression.     

Mapping of 5-HT2A receptors and their mRNA in monkey brain: [3H]MDL100,907 autoradiography and in situ hybridization studies

The anatomic distribution of serotonin 5-HT2A receptors visualized with [3H]MDL100,907 and of their mRNA detected by in situ hybridization were studied in monkey brain. Both autoradiographic patterns of signal showed heterogeneous distributions and were in general in good agreement in the majority of brain regions. In most neocortical areas, [3H]MDL100,907 presented a four-banded pattern with layers I and III-IV more intensely labeled and layers II and V-VI showing weaker labeling. 5-HT2A receptor mRNA was detected in layers III and IV, and in some cases also in layers II and V. In intra- and extra-calcarine areas of striate cortex a five-banded pattern was distinguished, with layers III and IVc-V showing the highest densities of [3H]MDL100,907 labeling. These two areas showed the highest neocortical hybridization signal. An unexpected finding was the presence of low densities of [3H]MDL100,907 labeling and 5-HT2A receptor mRNA in choroid plexus. Comparison of the distribution of [3H]MDL100,907 and [3H]ketanserin binding sites in monkey brain regions with high nonspecific [3H]ketanserin binding (caudate, putamen, substantia nigra, inferior olive) revealed specific binding of [3H]MDL100,907 with very low nonspecific binding. Some differences were noted between the distribution of [3H]MDL100,907-labeled 5-HT2A receptors in monkey brain and the previously reported distribution of these receptors in human brain: absence of striosome labeling in monkey striatum and different patterns of neocortical labeling. The present results provide the first detailed comparison of 5-HT2A receptor and mRNA distribution in primate brain. The observed species differences in 5-HT2A receptor distribution should be considered when extrapolating results among different species.     

Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment

BACKGROUND: Pharmacological and postmortem investigations suggest that patients with major depressive disorder have alterations in function or density of brain serotonin1A (5-HT1A) receptors. The aim of the present study was to use positron emission tomography with the selective 5-HT1A receptor antagonist [11C]WAY-100635 to measure 5-HT1A receptor binding in depressed patients before and during treatment with selective serotonin reuptake inhibitors. METHODS: Positron emission tomographic scans with [11C]WAY-100635 were performed on 25 patients with major depressive disorder. These included 15 unmedicated depressed patients. Ten of these unmedicated patients were scanned again during selective serotonin reuptake inhibitor treatment. A further 10 patients with major depressive disorder were scanned on one occasion only while taking selective serotonin reuptake inhibitors. Comparisons were made with [11C]WAY-100635 positron emission tomographic scans in 18 healthy volunteer subjects. Region of interest analysis and statistical parametric mapping were performed on binding potential images generated using a reference tissue model. RESULTS: Binding potential values were reduced across many of the regions examined, including frontal, temporal, and limbic cortex in both unmedicated and medicated depressed patients compared with healthy volunteers. Binding potential values in medicated patients were similar to those in unmedicated patients. CONCLUSIONS: Major depressive disorder is associated with a widespread reduction in 5-HT1A receptor binding. This reduced 5-HT1A receptor binding was not changed by selective serotonin reuptake inhibitor treatment.     

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.     

Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11)C]MDL 100,907.

The positron emission tomography (PET) ligand [(11)C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT(2A)) receptor in human brain. The aim of this work was to contribute to the verification of the tracer kinetic modelling in human studies. Five healthy volunteers were scanned twice after intravenous bolus injection of approximately 370 MBq [(11)C]MDL 100,907 using dynamic PET. One scan was performed under baseline condition, the other scan commenced 90 mins after a single oral dose of 30 mg of the antidepressant mirtazapine, which binds to the 5-HT(2A) receptor. There did not appear to be radiolabelled metabolites of [(11)C]MDL 100,907 in human plasma, which are likely to cross the blood-brain barrier. Total volumes of distribution VD in 11 different brain regions were estimated using a reversible, two tissue, four rate constants compartment model with a variable fractional blood volume term and the metabolite-corrected plasma input function. There were no significant changes of the VD in the cerebellum between the baseline and the blocked scans confirming the cerebellum as a region devoid of displaceable binding. Regional estimates of binding potential were then obtained indirectly using the cerebellar VD and occupancies calculated. The mean occupancy with this clinically effective dose of mirtazapine was 60% without significant regional differences. This study confirmed the use of an arterial input kinetic model for the quantification of 5-HT(2A) receptor binding with [(11)C]MDL 100,907 and the use of the cerebellum as a reference region for the free and nonspecific binding.     

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635

Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.     

Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS: Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS: The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS: These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.     

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.     

Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat

The present study evaluated, via a combined electrophysiological and dialysis approach, the potential influence of serotonin (5-HT)(2C) as compared to 5-HT(2A) and 5-HT(2B) receptors on dopaminergic, adrenergic, and serotonergic transmission in frontal cortex (FCX). Whereas the selective 5-HT(2A) antagonist MDL100,907 failed to modify extracellular levels of dopamine (DA), noradrenaline (NA) or 5-HT simultaneously quantified in single dialysate samples of freely-moving rats, the 5-HT(2B)/5-HT(2C) antagonist SB206,553 dose-dependently increased levels of DA and NA without affecting those of 5-HT. This action was attributable to 5-HT(2C) receptor blockade inasmuch as the selective 5-HT(2C) antagonist SB242,084 likewise increased FCX levels of DA and NA, whereas the selective 5-HT(2B) antagonist SB204,741 was ineffective. Further, the preferential 5-HT(2C) receptor agonist Ro60-0175 dose-dependently depressed FCX levels of DA. The suppressive influence of 5-HT(2C) receptors on DA release was also expressed on mesolimbic and nigrostriatal dopaminergic pathways, in that levels of DA in nucleus accumbens and striatum were likewise reduced by Ro60-0175 and elevated, though less markedly, by SB206,553. In line with the above findings, Ro60-0175 dose-dependently decreased the firing rate of ventrotegmental dopaminergic and locus coeruleus (LC) adrenergic perikarya, whereas their activity was dose-dependently enhanced by SB206,553. Furthermore, SB206,553 transformed the firing pattern of ventrotegmental dopaminergic neurons into a burst mode. In contrast to SB206,553, MDL100,907 had little affect on the firing rate of dopaminergic or adrenergic neurons. In conclusion, as compared to 5-HT(2A) and 5-HT(2B) receptors, 5-HT(2C) receptors exert a tonic, suppressive influence on the activity of mesocortical - as well as mesolimbic and nigrostriatal - dopaminergic pathways, likely via indirect actions expressed at the level of their cell bodies. Frontocortical adrenergic, but not serotonergic, transmission is also tonically suppressed by 5-HT(2C) receptors.     

5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex.

BACKGROUND: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT(1A) receptors. 5-HT(1A) receptor agonism may be an important feature in ziprasidone's clinical actions because 5-HT(1A) agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D(2) antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT(1A) agonist activity of ziprasidone by measuring the contribution of 5-HT(1A) receptor activation to the ziprasidone-induced cortical dopamine release in rats. METHODS: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT(1A) receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT(1A) antagonist, WAY-100635. For comparison, the D(2)/5-HT(2A) antagonists clozapine and olanzapine, the D(2) antagonist haloperidol, the 5-HT(2A) antagonist MDL 100,907 and the 5-HT(1A) agonist 8-OHDPAT were included. RESULTS: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (> or =3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT(1A) agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D(2) antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT(2A) antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. CONCLUSIONS: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT(1A) receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT(1A) receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.     

Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes

BACKGROUND: Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin2 BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin. METHODS: Regional 5-HTT BP was measured in 20 nonsmoking medication-free (> or =3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [11C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale. RESULTS: No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F(1,26), 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]). CONCLUSIONS: Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.     

5-HT2C receptor involvement in female rat lordosis behavior

Adult, hormone-primed, ovariectomized rats (CDF-344) with bilateral implants within the ventromedial nucleus of the hypothalamus (VMN), were injected with 0.5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone. This priming produced rats with 2 different levels of sexual receptivity. Rats with a lordosis to mount ratio (L/M)>/=0.5 were used to examine the potential lordosis-inhibiting effects of the 5-HT2A receptor antagonist, R(+)-a-(2, 3-dimethoxyphenyl)-1-[2(4-fluoro-phenylethyl)]-4-piperidine-methanol (MDL 100,907), and the 5-HT2C receptor antagonist, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2, 3-f]indole (SB 206553). Rats with low sexual receptivity (L/M<0.5) were bilaterally infused with the 5-HT2A/2C receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), or DOI plus either MDL 100,907 or SB 206553 to determine if either drug would attenuate the lordosis-facilitating effects of DOI. The 5-HT2C receptor antagonist, but not the 5-HT2A receptor antagonist, effectively inhibited lordosis behavior. Similarly, SB 206553 was more effective than MDL 100,907 in reducing the DOI-induced increase in lordosis responding. However, both drugs limited the duration of lordosis responding initiated by DOI. These results are consistent with prior suggestions that 5-HT2A/2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that 5-HT2C, rather than 5-HT2A, receptors are primarily responsible for the effects of 5-HT2 receptor-active drugs on lordosis behavior.     

Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide.

BACKGROUND: In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT(2A)) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT(2A) receptor binding, lifetime aggression, and suicide. METHODS: The 5-HT(2A) receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [(3)H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [(3)H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. RESULTS: In suicide subjects, lifetime aggression scores correlated positively with [(3)H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [(3)H] ketanserin binding between the suicide subjects and nonsuicide subjects. CONCLUSIONS: The relationship between aggression and 5-HT(2A) receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT(2A) receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.     

Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](+/-)DOI and [3H]ketanserin

5-HT2A receptors have been visualized with [3H]MDL100,907 in selected human brain areas by autoradiography. These areas included caudate and putamen, nucleus dentatus of the cerebellum, substantia nigra, nucleus raphe dorsalis, locus coeruleus and inferior olive. In the striatum [3H]MDL100,907 labelling was compared with the pattern obtained with [125I](+/-)DOI and [3H]ketanserin. [3H]MDL100, 907 and [125I](+/-)DOI showed an identical patchy distribution which was hardly observed with [3H]ketanserin. In the remaining regions, [3H]MDL100,907 and [3H]ketanserin autoradiographical signals and percentage of specific binding were compared. Whereas the pattern of distribution was identical for both radioligands, [3H]MDL100,907 presented a much lower percentage of nonspecific binding compared with [3H]ketanserin. These results confirm the presence of 5-HT2A receptors in human striosomes and in those areas where [3H]ketanserin presented a high nonspecific binding, and they highlight the advantage of using [3H]MDL100,907 to visualize these receptors.     

Functional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons

Previous studies, using in vivo extracellular unitary recordings in anaesthetized rats, have shown that the selective 5-HT(1A) receptor antagonist WAY 100,635 suppressed the firing rate of locus coeruleus (LC) norepinephrine (NE) neurons and that this effect was abolished by lesioning 5-HT neurons. In the present experiments, the selective 5-HT(2A) receptor antagonist MDL 100,907, while having no effect on the spontaneous firing activity of LC neurons in controls, was able to restore NE neuronal discharges following the injection of WAY 100,635. The 5-HT(1A) receptor agonist 8-OH-DPAT enhanced the firing activity of NE neurons and this action was entirely dependent on intact 5-HT neurons, unlike the inhibitory effect of the 5-HT(2) receptor agonist DOI. Taken together, these data indicate that 5-HT(2A) but not 5-HT(1A) receptors controlling LC firing activity are postsynaptic to 5-HT neurons. Prolonged, but not subacute, administration of selective 5-HT reuptake inhibitors (SSRIs) produces a decrease in the spontaneous firing activity of LC NE neurons. MDL 100,907 partially reversed this suppressed firing activity of LC neurons in paroxetine-treated rats. Although the alpha(2)-adrenoceptor antagonist idazoxan also enhanced the firing activity of NE neurons in paroxetine-treated rats, this increase was similar to that obtained in controls. In conclusion, prolonged SSRI treatment enhances a tonic inhibitory influence by 5-HT on LC neurons through postsynaptic 5-HT(2A) receptors that are not located on NE neurons. A speculative neuronal circuitry accounting for these phenomena on LC NE activity is proposed.     

Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone.

BACKGROUND: The neuroreceptor changes involved in therapeutic efficacy of various antidepressants remain unclear. Preclinical studies have shown that long-term administration of various antidepressants causes down-regulation of brain serotonin 2 (5-HT2) receptors in rodents, but it is unknown if similar changes occur following antidepressant treatment in depressed patients. Our purpose, therefore, was to assess the effects of treatment with desipramine hydrochloride on brain 5-HT2 receptors in depressed patients using positron emission tomography (PET) and fluorine-18 (18F)-labeled setoperone. METHODS: Eleven patients who met DSM-IV criteria for major depression as determined by a structured clinical interview for DSM-III-R diagnosis and suitable for treatment with desipramine were recruited. Ten patients underwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine. RESULTS: Eight of the 10 patients responded to desipramine treatment as indicated by more than 50% decrease in Hamilton Depression Rating Scale scores. Depressed patients showed a significant decrease in 5-HT2 receptor binding as measured by setoperone binding in frontal, temporal, parietal, and occipital cortical regions following desipramine treatment. The decrease in 5-HT2 receptor binding was observed bilaterally and was particularly prominent in frontal cortex. CONCLUSIONS: Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain following desipramine treatment, but it is unknown if this change in 5-HT2 receptors is due to clinical improvement or an effect of desipramine that is unrelated to clinical status.     

Dysfunctional attitudes and cognitive schemas in bipolar manic and unipolar depressed outpatients: implications for cognitively based psychotherapeutics

Dysfunctional thought patterns are presumed to underlie cognitive biases in mood disorder patients. However, few studies have compared dysfunctional thought patterns in bipolar manic and unipolar depressed patients. Cognitive schemas and dysfunctional attitudes were evaluated using the cognitive checklist for mania and Dysfunctional Attitudes Scale (DAS) in 34 bipolar manic, 35 unipolar depressed, and 29 nonpsychiatric control subjects. Unipolar depressed subjects had significantly higher total DAS scores and subfactor scores as compared with nonpsychiatric controls, whereas bipolar patients had intermediate scores between both groups. Significant correlations emerged between cognitive checklist for mania total and subcomponent scores and the DAS (total, performance subfactor, and approval subfactor scales) for the bipolar, but not the unipolar or nonpsychiatric control groups. Core beliefs among bipolar patients appear negativistic during manic phases, potentially reflecting an overcompensation for depression. The findings support clinical approaches targeting depressive cognitions regardless of the presence of manic symptoms.     

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.     

Effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT(2)) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT(2A) antagonist M100,907, the 5-HT(2C) antagonist SB242,084 and the mixed 5-HT(2A/C) antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT(2) receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT(2C) but not 5-HT(2A) mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2(2C) receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT(2C) antagonism could be targeted as a key property in the development of new antipsychotic medications.     

Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers

OBJECTIVE: The authors investigated the relationship between anxiety--a facet of the Revised NEO Personality Inventory dimension of neuroticism--and serotonin 5-HT(1A) receptor binding potential. METHOD: Positron emission tomography with [(11)C]WAY-100635 was used to estimate regional 5-HT(1A) binding potential in 19 healthy volunteers who completed the Revised NEO Personality Inventory. Correlation coefficients were calculated to determine the degree of association between 5-HT(1A) binding potential and personality inventory measures. RESULTS: There was a significant negative correlation between 5-HT(1A) binding potential and anxiety in four regions: the dorsolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, and occipital cortex. CONCLUSIONS: The inverse relationship between 5-HT(1A) receptor binding potential and anxiety is consistent with 1) animal models that have shown higher anxiety in mice lacking 5-HT(1A) receptors and 2) clinical trial data that have demonstrated antianxiety properties of partial 5-HT(1A) agonists.