Similar serotonin‐2A receptor binding in rats with different coping styles or levels of aggression

Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin‐2A receptor (5‐HT_2AR) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild‐type Groningen (WTG) and Roman high‐ and low avoidance (RHA, RLA). 5‐HT_2AR binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([³H]MDL‐100907) and agonist ([³H]Cimbi‐36) in binding assays. No differences in 5‐HT_2AR binding were observed in male animals with different coping styles. [³H]MDL‐100907 displayed a higher specific‐to‐nonspecific binding ratio than [³H]Cimbi‐36. Our findings suggest that in these particular rat strains, 5‐HT_2AR binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5‐HT_2AR is co‐varying with levels of aggression or active avoidance in WTG, RHA and RLA. Synapse, 69:226–232, 2015 . © 2015 Wiley Periodicals, Inc.     

Direct comparison of [18F]MH.MZ and [18F]altanserin for 5‐HT2A receptor imaging with PET

Imaging the cerebral serotonin 2A (5‐HT_2A) receptors with positron emission tomography (PET) has been carried out in humans with [¹¹C]MDL 100907 and [¹⁸F]altanserin. Recently, the MDL 100907 analogue [¹⁸F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine‐18. Here, we present a direct comparison of [¹⁸F]altanserin and [¹⁸F]MH.MZ. 5‐HT_2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [³H]MDL 100907, [¹⁸F]MH.MZ, and [¹⁸F]altanserin. [¹⁸F]MH.MZ and [¹⁸F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue‐compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [¹⁸F]MH.MZ and [¹⁸F]altanserin. Significant 5‐HT_2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [¹⁸F]MH.MZ and [¹⁸F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5‐HT_2A receptors in the pig brain. In the HPLC analysis of pig plasma, [¹⁸F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [¹⁸F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [¹⁸F]MH.MZ in high‐binding regions in vivo, we suggest that [¹⁸F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [¹⁸F]altanserin is a suitable tracer for high‐binding regions. Synapse, 2013. © 2013 Wiley Periodicals, Inc.     

Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination

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Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias

Levodopa‐induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l ‐Dopa) limiting the quality of life of Parkinson’s disease (PD) patients. We evaluated changes of the serotonin 5‐HT_2A receptors in control monkeys, in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys and in l ‐Dopa‐treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI‐1041, a selective NR1A/2B subunit antagonist of glutamate N‐methyl‐d ‐aspartic acid (NMDA) receptor, or Cabergoline, a long‐acting dopamine D₂ receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l ‐Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high‐performance liquid chromatography. [³H]Ketanserin‐specific binding to 5‐HT_2A receptors was measured by autoradiography. l ‐Dopa treatment that induced dyskinesias increased 5‐HT_2A receptor‐specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [³H]Ketanserin‐specific binding was increased in the dorsomedial caudate nucleus in l ‐Dopa‐treated MPTP monkeys compared with saline‐treated MPTP monkeys. Nondyskinetic monkeys treated with CI‐1041 or Cabergoline showed low 5‐HT_2A‐specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5‐HT_2A receptor binding was observed in any brain regions examined in saline‐treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5‐HT_2A receptors as a potential treatment for LID.     

Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5‐HT_2AR) agonist psilocybin. However, no studies have investigated whether 5‐HT_2AR availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5‐HT_2AR binding in neocortex imaged with [¹⁸F]altanserin or [¹¹C]Cimbi‐36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory‐Revised. No significant associations between neocortical 5‐HT_2AR binding and trait Openness were found for [¹⁸F]altanserin (p = 0.5) or [¹¹C]Cimbi‐36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5‐HT_2AR availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5‐HT_2AR with compounds such as psilocybin may contribute to long‐term changes in trait Openness, there is no evidence in favor of an association between 5‐HT_2AR and trait Openness.     

Differential effects of serotonin (5‐HT)2 receptor‐targeting ligands on locomotor responses to nicotine‐repeated treatment

We verified the hypothesis that serotonin (5‐HT)₂ receptors control the locomotor effects of nicotine (0.4 mg kg⁻¹) in rats by using the 5‐HT_2A receptor antagonist M100907, the preferential 5‐HT_2A receptor agonist DOI, the 5‐HT_2C receptor antagonist SB 242084, and the 5‐HT_2C receptor agonists Ro 60‐0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5‐HT₂ receptor ligands, M100907 (2 mg kg⁻¹) or DOI (1 mg kg⁻¹) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg⁻¹), Ro 60‐0175 (1 mg kg⁻¹), and WAY 163909 (1.5 mg kg⁻¹) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1–5, 10) with nicotine, none of 5‐HT₂ receptor ligands administered during the second withdrawal period (Days: 11–14) to nicotine‐treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5‐HT_2A receptors (but not 5‐HT_2C receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5‐HT_2A receptors enhances the development of nicotine sensitization and activation of 5‐HT_2C receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5‐HT₂ receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. Synapse 64:511–519, 2010. © 2010 Wiley‐Liss, Inc.     

Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

Prefrontal serotonin 2A receptors (5‐HT_2ARs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5‐HT_2AR at clinical relevant doses, and activation of 5‐HT_2A receptors by lysergic acid diethylamide (LSD) and LSD‐like drugs induces a schizophrenia‐like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well‐established model for schizophrenia‐like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5‐HT_2ARs. As a measure of 5‐HT_2AR functionality, we used the 5‐HT_2AR agonist 2,5‐dimethoxy‐4‐iodoamphetamine (DOI)‐induced head‐twitch response (HTR) and mRNA expression of the immediate‐early genes (IEGs) activity‐related cytoskeletal associated‐protein (Arc), c‐fos, and early growth response protein 2 (egr‐2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5‐day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5‐HT_2AR binding. Also, binding of the 5‐HT_1AR and the 5‐HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5‐HT_2AR could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc.     

5‐HT2A receptor blockade and 5‐HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate‐putamen

Both the 5‐HT_2A receptor (R) antagonist M100907 and the 5‐HT_2CR agonist MK212 attenuate cocaine‐induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose‐effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5‐HT_2A/5‐HT_2CR interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1‐h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine‐induced Fos expression in the dorsolateral caudate‐putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5‐HT_2ARs and 5‐HT_2CRs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5‐HT₂R subtypes on behavior. Further research investigating combined 5‐HT_2AR antagonism and 5‐HT_2CR agonism as a treatment for cocaine dependence is warranted. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

GABAA receptors mediate the attenuating effects of a 5‐HT3 receptor antagonist on methamphetamine‐induced behavioral sensitization in mice

We previously showed that 5‐HT₃ receptors are involved in the development and expression of methamphetamine (MAP)‐induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems areinvolved in the attenuating effects of the 5‐HT₃ receptor antagonist MDL72222 on MAP‐induced locomotor sensitization. Quantitative autoradiography of D1 ([³H]SCH23390), D2 ([³H]raclopride) receptor, and GABA_A receptor benzodiazepine ([³H]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D₁ and D₂ binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP‐induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D₁ and D₂ receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP‐treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [³H]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA_A benzodiazepine binding sites are involved in the attenuating effects of a 5‐HT₃ receptor antagonist on MAP‐induced locomotor sensitization. Synapse 64:274–279, 2010. © 2009 Wiley‐Liss, Inc.     

Hippocampal serotonin‐1A receptor function in a mouse model of anxiety induced by long‐term voluntary wheel running

We have recently demonstrated that, in C57/Bl6 mice, long‐term voluntary wheel running is anxiogenic, and focal hippocampal irradiation prevents the increase in anxiety‐like behaviors and neurobiological changes in the hippocampus induced by wheel running. Evidence supports a role of hippocampal 5‐HT_1A receptors in anxiety. Therefore, we investigated hippocampal binding and function of 5‐HT_1A receptors in this mouse model of anxiety. Four weeks of voluntary wheel running resulted in hippocampal subregion‐specific changes in 5‐HT_1A receptor binding sites and function, as measured by autoradiography of [³H] 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin binding and agonist‐stimulated binding of [³⁵S]GTPγS to G proteins, respectively. In the dorsal CA1 region, 5‐HT_1A receptor binding and function were not altered by wheel running or irradiation. In the dorsal dentate gyrus and CA2/3 region, 5‐HT_1A receptor function was decreased by not only running but also irradiation. In the ventral pyramidal layer, wheel running resulted in a decrease of 5‐HT_1A receptor function, which was prevented by irradiation. Neither irradiation nor wheel running affected 5‐HT_1A receptors in medial prefrontal cortex or in the dorsal or median raphe nuclei. Our data indicate that downregulation of 5‐HT_1A receptor function in ventral pyramidal layer may play a role in anxiety‐like behavior induced by wheel running. Synapse 67:648–655, 2013. © 2013 Wiley Periodicals, Inc.     

Antidepressant medication exposure and 5‐HT1A autoreceptor binding in major depressive disorder

Objective: We have previously reported higher brain serotonin 1A (5‐HT_1A) autoreceptor binding in antidepressant‐naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5‐HT_1A receptor binding after medication discontinuation. Methods: Positron emission tomography (PET) imaging with the 5‐HT_1A receptor radioligand [¹¹C]WAY‐100635 was performed in 66 individuals with current DSM‐IV MDD to examine relationships between 5‐HT_1A binding and time since most recent antidepressant treatment. All subjects were medication‐free for at least 2 weeks prior to scanning. Thirty‐two additional MDD comparison subjects were antidepressant naïve. Results: No differences in [¹¹C]WAY‐100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [¹¹C]WAY‐100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. Conclusion: These results indicate that any antidepressant‐associated downregulation of 5‐HT_1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness‐related binding levels.     

Is desire for social relationships mediated by the serotonergic system in the prefrontal cortex? An [18F]setoperone PET study

Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT_2A receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [¹⁸F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT_2A receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT_2A receptor non-displaceable binding potential (BP_nd) in these regions. Scores of RD were negatively correlated with 5HT_2A BP_nd in the ACC (BA 32, r?=?–.528, p?=?.012) and OFC (BA 11, r?=?–.489, p?=?.021; BA 47, r?=?–.501, p?=?.017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships.     

Effect of a hallucinogenic serotonin 5‐HT2A receptor agonist on visually guided,hippocampal‐dependent spatial cognition in C57BL/6J mice

By acting on serotonin 5‐HT_2A receptors (5‐HT_2ARs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual‐evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal‐dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB‐2 is a selective agonist of 5‐HT_2ARs. Mice received TCB‐2 (1.0 mg kg⁻¹, i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivo single‐unit recording, respectively. TCB‐2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal‐directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5‐HT_2AR antagonist MDL 11,939. Interestingly, TCB‐2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context‐specific episodic memory. Systemic TCB‐2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB‐2 impaired the long‐term stability of place fields for the novel environment initially encoded under the influence of TCB‐2, which could be prevented by 5‐HT_2AR antagonist MDL 11,939. Our data indicate that hallucinogenic 5‐HT_2AR agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal‐directed spatial behavior. Moreover, activation of 5‐HT_2ARs does not impair the coding and retrieval of spatial information, but impairs the long‐term stability of new formed place fields of CA1 neurons. © 2017 Wiley Periodicals, Inc.     

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Though transduction mechanisms recruited by heterologously expressed 5‐HT_2A receptors have been extensively studied, their interaction with specific subtypes of G‐protein remains to be directly evaluated in cerebral tissue. Herein, as shown by an immunocapture/scintillation proximity analysis, 5‐HT, the prototypical 5‐HT_2A agonist, DOI, and Ro60,0175 all enhanced [³⁵S]GTPγS binding to Gαq/11 in rat cortex with pEC₅₀ values of 6.22, 7.24 and 6.35, respectively. No activation of Go or Gs/olf was seen at equivalent concentrations of DOI. Stimulation of Gαq/11 by 5‐HT (30 μM) and DOI (30 μM) was abolished by the selective 5‐HT_2A vs. 5‐HT_2C/5‐HT_2B antagonists, ketanserin (pK_B values of 9.11 and 8.88, respectively) and MDL100,907 (9.82 and 9.68). By contrast, 5‐HT‐induced [³⁵S]GTPγS binding to Gαq/11 was only weakly inhibited by the preferential 5‐HT_2C receptor antagonists, RS102,221 (6.94) and SB242,084 (7.39), and the preferential 5‐HT_2B receptor antagonist, LY266,097 (6.66). The antipsychotic, clozapine, which had marked affinity for 5‐HT_2A receptors, blocked the recruitment of Gαq/11 by 5‐HT and DOI with pK_B values of 8.54 and 8.14, respectively. Its actions were mimicked by the “atypical” antidepressant and 5‐HT_2A receptor antagonist, mirtazapine, which likewise blocked 5‐HT and DOI‐induced Gαq/11 protein activation with pK_B values of 7.90 and 7.76, respectively. In conclusion, by use of an immunocapture/scintillation proximity strategy, this study shows that native 5‐HT_2A receptors in rat frontal cortex specifically recruit Gαq/11 and that this action is blocked by clozapine and mirtazapine. Quantification of 5‐HT_2A receptor‐mediated Gαq/11 activation in frontal cortex should prove instructive in characterizing the actions of diverse classes of psychotropic agent. Synapse 63:95–105, 2009. © 2008 Wiley‐Liss, Inc.     

An approach for serotonin depletion in pigs: Effects on serotonin receptor binding

Depletion of central serotonin (5‐HT) levels and dysfunction in serotonergic transmission are implicated in a variety of human CNS disorders. The mechanisms behind these serotonergic deficits have been widely studied using rodent models, but only to a limited extent in larger animal models. The pig is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para‐chlorophenylalanine (pCPA). On day 5, tissue concentrations of 5‐HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused average decreases in 5‐HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5‐HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5‐HT₄ receptor binding in nucleus accumbens, but did not alter 5‐HT_1A and 5‐HT_2A receptor or serotonin transporter binding in any brain region. In conclusion, 4 days treatment with pCPA effectively reduces 5‐HT levels in the pig brain. Further, whereas several 5‐HT markers did not change after the pCPA treatment, 5‐HT₄ receptors were consistently upregulated, indicating a greater susceptibility of this receptor to altered 5‐HT levels. This porcine model of serotonin depletion will be useful in future studies of cerebral serotonergic dysfunction. Synapse 2011. © 2010 Wiley‐Liss, Inc.     

Acute and chronic effects of citalopram on 5‐HT1A receptor—Labeling by [18F]MPPF and—Coupling to receptors‐G proteins

Selective serotonin reuptake inhibitors take several weeks to produce their maximal therapeutic antidepressant effect. This delay has been attributed to the gradual desensitization of somatodendritic serotonin 5‐HT_1A autoreceptors. We evaluated adaptive changes of 5‐HT_1A receptors after acute and chronic citalopram challenges in rat. Small animal positron emission tomography trial and quantitative ex vivo autoradiography studies using [¹⁸F]MPPF were employed, as well as in vitro 8‐OH‐DPAT‐stimulated [³⁵S]‐GTPγS binding assay. Additionally, 5‐HT_1A receptor knock‐out mice were used to assess the specificity of [¹⁸F]MPPF. Acute treatment with citalopram did not alter [¹⁸F]MPPF binding in dorsal raphe nucleus (DR), frontal cortex, or hippocampus. The absence of [¹⁸F]MPPF binding in the brain of 5‐HT_1A knock‐out mice demonstrates the specificity of MPPF for 5‐HT_1A receptor brain imaging, but the high affinity of [¹⁸F]MPPF compared to 5‐HT suggests that it would only be displaced by dramatic increases in extracellular 5‐HT. Chronic citalopram did not modify 5‐HT_1A receptor density in any of the brain regions studied. In addition, this treatment did not modify 8‐OH‐DPAT‐stimulated [³⁵S]‐GTPγS binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [¹⁸F]MPPF appears to be an efficient radioligand to quantify specifically 5‐HT_1A receptor density in brain imaging. The delayed therapeutic efficacy of citalopram did not appear to be linked to either a downregulation of 5‐HT_1A receptors or to a 5‐HT_1A receptor‐G protein decoupling process in serotonergic neurons, but to increased functional sensitivity of postsynaptic 5‐HT_1A receptors. Synapse 63:106–116, 2009. ©2008 Wiley‐Liss, Inc.     

Aggression is related to frontal serotonin‐1A receptor distribution as revealed by PET in healthy subjects

Objectives: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5‐HT_1A receptor, and sex hormones. Experimental Design: Thirty‐three healthy volunteers (16 women, aged 26.24 ± 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl‐¹¹C]WAY‐100635 to quantify 5‐HT_1A binding potentials (BP_NDs) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17ß‐estradiol and sex hormone‐binding globulin (SHBG) were measured. Relations between aggression scores, regional 5‐HT_1A BP_NDs, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. Principal Observations: Statistical analyses revealed higher 5‐HT_1A receptor BP_NDs in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5‐HT_1A BP_NDs in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). Conclusions: The present study provides first‐time evidence for a specific interrelation between the 5‐HT_1A receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down‐stream control due to higher amounts or activities of frontal 5‐HT_1A receptors in more aggressive subjects, which is presumably modulated by sex hormones. Hum Brain Mapp 30:2558–2570, 2009. © 2008 Wiley‐Liss, Inc.     

The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5‐HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5‐HT type 4 receptor (5‐HT₄R) facilitates memory and learning and further that the 5‐HT₄R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT₄R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [¹¹C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5‐HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP_ND, (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP_ND and delayed recall (p = 0.014). These findings provide evidence that the 5‐HT₄R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013. © 2012 Wiley Periodicals, Inc.     

Increased levels of 5‐HT1A receptor binding in ventral visual pathways in Parkinson's disease

Visual hallucinations are common in advanced Parkinson's disease (PD). The pathophysiology of visual hallucinations may involve enhanced serotonergic neurotransmission. The atypical antipsychotics clozapine and quetiapine, which have affinity for 5‐HT_2A and 5‐HT_1A receptors, are effective against visual hallucinations in PD. 5‐HT_2A receptors are increased in ventral visual pathways in PD patients with visual hallucinations, and we hypothesized that 5‐HT_1A receptors were also involved in visual hallucinations in PD. Autoradiographic binding using [³H]‐WAY‐100,635 and NAN‐190 was performed in brain sections from 6 PD patients with visual hallucinations, 6 PD patients without visual hallucinations, and 5 age‐matched controls. All PD subjects had been treated with L ‐dopa. Brain areas studied were the orbitofrontal, inferolateral temporal, and motor cortices, as well as the striatum, globus pallidus, substantia nigra, and thalamus. 5‐HT_1A‐binding levels were dramatically increased in the ventral visual pathways of all PD patients compared with controls (0 vs 11 and 0 vs 100 nmol/mg, respectively; both P < .05). There was no significant difference in 5‐HT_1A‐binding levels in PD patients with visual hallucinations compared with PD patients without visual hallucinations or with controls in any of the brain areas studied (P > .05). Gross abnormalities in 5‐HT_1A levels in ventral visual areas occurred in all PD patients exposed to L ‐dopa. However, as there was no difference in 5‐HT_1A‐binding levels between hallucinators and nonhallucinators, alterations in 5‐HT_1A receptor levels may not contribute specifically to visual hallucinations in PD. However, the discrete anatomical distribution of rises to the ventral visual areas suggests some role in predisposing to visual hallucinations. © 2012 Movement Disorder Society     

Nigrostriatal upregulation of 5‐HT2A receptors correlates with motor dysfunction in progressive supranuclear palsy

A dysfunction of multiple neurotransmitter systems is assumed as a neurochemical basis of the akinetic‐rigid syndrome of progressive supranuclear palsy (PSP). In vitro studies have produced conflicting results on the serotoninergic system in PSP. We, therefore, studied the binding potential of the serotonin 2A (5‐HT_2A) receptor ligand [ 18 F]altanserin in 8 patients with clinically probable PSP and 13 healthy controls using positron emission tomography. We found an up‐regulation of 5‐HT_2A receptors in the substantia nigra and, to a lower degree, in the striatum, while neocortical 5‐ HT_2A receptor densities showed no changes upon partial‐volume correction. Nigral and striatal receptor changes were significantly correlated with patients' scores of motor dysfunction (UPDRS III, PSP‐rating scale) pointing to a functional relevance of the described findings. © 2009 Movement Disorder Society