On the role of 5‐HT1A receptor gene in behavioral effect of brain‐derived neurotrophic factor

Experiments were made on a congenic AKR.CBA‐D13Mit76C (76C) mouse strain created by transferring a chromosome 13 fragment containing the 5‐HT_1A receptor gene from a CBA strain to an AKR background. It was shown that 76C mice differed from AKR mice by decreased 5‐HT_1A receptor and tryptophan hydroxylase‐2 (tph‐2) genes expression in the midbrain. Functional activity of 5‐HT_2A receptors and 5‐HT_2A receptor mRNA levels in the midbrain and hippocampus of 76C mice were decreased compared with AKR mice. Central brain‐derived neurotrophic factor (BDNF) administration (300 ng i.c.v.) reduced 5‐HT_1A and 5‐HT_2A receptor mRNA levels in the frontal cortex and tph‐2 mRNA level in the midbrain of AKR mice. However, BDNF failed to produce any effect on the expression of 5‐HT_1A, 5‐HT_2A, and tph‐2 genes in 76C mice but decreased functional activity of 5‐HT_2A receptors in 76C mice and increased it in AKR mice. BDNF restored social deficiency in 76C mice but produced asocial behavior (aggressive attacks towards young mice) in AKR mice. The data indicate that a small genetic variation altered the response to BDNF and show an important role of 5‐HT_1A receptor gene in the 5‐HT system response to BDNF treatment and in behavioral effects of BDNF. © 2014 Wiley Periodicals, Inc.     

Serotonin (5‐HT) regulates neurite outgrowth through 5‐HT1A and 5‐HT7 receptors in cultured hippocampal neurons

Serotonin (5‐HT) production and expression of 5‐HT receptors (5‐HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5‐HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5‐HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G‐protein‐coupled 5‐HT_1AR and 5‐HT₇R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5‐HT promotes neurite outgrowth through 5‐HT_1AR and 5‐HT₇R. The involvement of 5‐HT_1AR and 5‐HT₇R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5‐HT and specific antagonists for 5‐HT_1AR and 5‐HT₇R (WAY‐100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5‐HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT₇R was blocked, the addition of 5‐HT increased the number of primary neurites, suggesting that 5HT₇R could inhibit neuritogenesis. In contrast, 5‐HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY‐100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5‐HT_1AR and 5‐HT₇R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. © 2014 Wiley Periodicals, Inc.     

Alterations in 5‐HT2A receptor binding in various brain regions among 6‐hydroxydopamine‐induced Parkinsonian rats

The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5‐hydroxytryptamine (5‐HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6‐hydroxydopamine (6‐OHDA). 5‐HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [³H]ketanserin‐binding autoradiography. In the 6‐OHDA‐induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [³H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [³H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5‐HT_2A receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5‐HT_2A receptors in treating neurodegenerative disorders and implicates 5‐HT_2A receptors as a novel therapeutic target in the treatment of PD. Synapse 64:224–230, 2010. © 2009 Wiley‐Liss, Inc.     

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5‐HT2A and 5‐HT2C serotonergic receptors in post‐ictal antinociception

The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5‐hydroxytryptamine (5‐HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post‐ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure‐induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic‐clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA‐mediated Cl^‐ influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl₂/0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post‐ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5‐HT_2A/2C receptors, decreased tonic‐clonic seizure‐induced antinociception. Both dmPAG and vlPAG treatment with either the 5‐HT_2A receptor selective antagonist R‐96544 (10 nM/0.2 µL), or the 5‐HT_2C receptors selective antagonist RS‐102221 (0.15 µg/0.2 µL) also decrease post‐ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5‐HT_2A and 5‐HT_2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post‐ictal antinociception. Synapse, 68:16–30, 2014 . © 2013 Wiley Periodicals, Inc.     

Optimising PET approaches to measuring 5‐HT release in human brain

A major goal in neuroscience is the measurement of neurotransmitters in living human brain. To date this has only been done reliably with dopamine using certain PET and SPECT radiotracers. The use of this technique has greatly advanced our understanding of dopamine and the dopaminergic system in normal and abnormal brain function. Transferring this technology to other neurotransmitter systems has proved less fruitful. The serotonergic system (5‐HT) is one such system. 5‐HT has been implicated in a wide range of brain functions and their disorders. The ability to measure 5‐HT using this technique would be invaluable. In this article, we explore the key pharmacological features of current radiotracers for 5‐HT receptors that might be sensitive to endogenous 5‐HT. We also estimate the likely brain concentrations of the current available tranche of agents that might be used to enhance synaptic 5‐HT concentration, so taking into account the potential for these to interact with the receptors directly and produce a spurious displacement signal. Synapse 69:505–511, 2015 . © 2015 Wiley Periodicals, Inc.     

Chronic fluoxetine treatment accelerates kindling epileptogenesis in mice independently of 5‐HT2A receptors

Patients with epilepsy often have mood disorders, and these are commonly treated with antidepressant drugs. Although these drugs are often successful in mitigating depressive symptoms, how they affect the epileptogenic processes has been little studied. Recent evidence has demonstrated that treatment with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs adversely promotes epileptogenesis, which may be of great concern considering the number of patients exposed to these drugs. This study investigated 5‐HT_2A receptor signaling as a potential mechanism driving the pro‐epileptogenic effects of the prototypical SSRI fluoxetine. Male homozygous 5‐HT_2A receptor knockout mice or wild‐type littermates (n = 9‐14/group) were treated with continuous fluoxetine (10 mg kg^?1d^?1, sc) or vehicle and subjected to electrical kindling of the amygdala. Compared to vehicle, fluoxetine treatment accelerated kindling epileptogenesis (P < .001), but there was no effect of genotype (P = .75), or any treatment x genotype interaction observed (P = .90). Of interest, fluoxetine treatment increased afterdischarge thresholds in both genotypes (P = .007). We conclude that treatment with fluoxetine promotes epileptogenesis in mice, but this effect is not mediated by 5‐HT_2A receptors. This suggests that antidepressants may accelerate the onset of acquired epilepsy in patients who have experienced epileptogenic cerebral insults.     

Effect of glial cell line‐derived neurotrophic factor on behavior and key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders

The effect of glial cell line‐derived neurotrophic factor (GDNF) on behavior and on the serotonin (5‐HT) system of a mouse strain predisposed to depressive‐like behavior, ASC/Icg (Antidepressant Sensitive Cataleptics), in comparison with the parental “nondepressive” CBA/Lac mice was studied. Within 7 days after acute administration, GDNF (800 ng, i.c.v.) decreased cataleptic immobility but increased depressive‐like behavioral traits in both investigated mouse strains and produced anxiolytic effects in ASC mice. The expression of the gene encoding the key enzyme for 5‐HT biosynthesis in the brain, tryptophan hydroxylase‐2 (Tph‐2), and 5‐HT_1A receptor gene in the midbrain as well as 5‐HT_2A receptor gene in the frontal cortex were increased in GDNF‐treated ASC mice. At the same time, GDNF decreased 5‐HT_1A and 5‐HT_2A receptor gene expression in the hippocampus of ASC mice. GDNF failed to change Tph2, 5‐HT_1A, or 5‐HT_2A receptor mRNA levels in CBA mice as well as 5‐HT transporter gene expression and 5‐HT_1A and 5‐HT_2A receptor functional activity in both investigated mouse strains. The results show 1) a GDNF‐induced increase in the expression of key genes of the brain 5‐HT system, Tph2, 5‐HT_1A, and 5‐HT_2A receptors, and 2) significant genotype‐dependent differences in the 5‐HT system response to GDNF treatment. The data suggest that genetically defined cross‐talk between neurotrophic factors and the brain 5‐HT system underlies the variability in behavioral response to GDNF. © 2013 Wiley Periodicals, Inc.     

Functional 5‐HT1a receptor polymorphism selectively modulates error‐specific subprocesses of performance monitoring

Our study investigates the dependence of response monitoring and error detection on genetic influences modulating the serotonergic system. This was done using the event‐related potentials (ERPs) after error (Ne/ERN) and correct trials (Nc/CRN). To induce a sufficient amount of errors, a standard flanker task was used. The subjects (N = 94) were genotyped for the functional 5‐HT1A C(−1019)G polymorphism. The results show that the 5‐HT1A C(−1019)G polymorphism specifically modulates error detection. Neurophysiological modulations on error detection were paralleled by a similar modulation of response slowing after an error, reflecting the behavioral adaptation. The 5‐HT1A −1019 CC genotype group showed a larger Ne and stronger posterror slowing than the CG and GG genotype groups. More general processes of performance monitoring, as reflected in the Nc/CRN, were not affected. The finding that error‐specific processes, but not general response monitoring processes, are modulated by the 5‐HT1A C(−1019)G polymorphism is underlined by a wavelet analysis. In summary, the results suggest a specific effect of the 5‐HT1A C(−1019)G polymorphism on error monitoring, as reflected in the Ne, and suggest a neurobiological dissociation between processes of error monitoring and general response monitoring at the level of the serotonin 1A receptor system. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Oestradiol Alters Central 5‐HT1A Receptor Binding Potential Differences Related to Psychosocial Stress but not Differences Related to 5‐HTTLPR Genotype in Female Rhesus Monkeys

Social subordination in female macaques represents a well‐described model of chronic psychosocial stress. Additionally, a length polymorphism (5‐HTTLPR) in the regulatory region of the serotonin (5‐HT) transporter (5‐HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5‐HTTLPR polymorphism. The present study determined the effects of social status and the 5‐HTTLPR genotype on 5‐HT1A receptor binding potential (5‐HT1A BP_ND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β‐oestradiol (E₂) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p‐[¹⁸F]MPPF was performed to determine the levels of 5‐HT1A BP_ND under a non‐E₂ and a 3‐week E₂ treatment condition. The short variant (s‐variant) 5‐HTTLPR genotype produced a significant reduction in 5‐HT1A BP_ND in the mPFC regardless of social status, and subordinate s‐variant females showed a reduction in 5‐HT1A BP_ND within the ACC. Both these effects of 5‐HTTLPR were unaffected by E₂. Additionally, E₂ reduced 5‐HT1A BP_ND in the dorsal raphe of all females irrespective of psychosocial stress or 5‐HTTLPR genotype. Hippocampal 5‐HT1A BP_ND was attenuated in subordinate females regardless of 5‐HTTLPR genotype during the non‐E₂ condition, an effect that was normalised with E₂. Similarly, 5‐HT1A BP_ND in the hypothalamus was significantly lower in subordinate females regardless of 5‐HTTLPR genotype, an effect reversed with E₂. Taken together, the data indicate that the effect of E₂ on modulation of central 5HT1A BP_ND may only occur in brain regions that show no 5‐HTTLPR genotype‐linked control of 5‐HT1A binding.     

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     

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     

A selective,high affinity 5‐HT2B receptor antagonist inhibits visceral hypersensitivity in rats

Background RS‐127445 is a selective, high affinity 5‐HT_2Breceptor antagonist. We investigated whether 5‐HT_2Breceptor antagonists can reduce colonic visceral hypersensitivity caused by restraint stress or by proximal colonic inflammation. Methods Visceral hypersensitivity was induced in rats by either restraint stress or injection of 2, 4, 6‐trinitrobenzene sulfonic acid (TNBS) into the proximal colon. Restraint stress produced a significant increase in numbers of abdominal contractions evoked by colorectal distension (CRD), measured as a quantitative index of visceral nociception in rats. Seven days after TNBS injection, the pain threshold to CRD at the non‐inflamed distal colon, that was determined as the minimum pressure required to evoke abdominal cramp, was significantly decreased. The effect of RS‐127445 on visceral hypersensitivity was assessed in either naïve or TNBS‐treated rats. Key Results Oral administration of a selective, high affinity 5‐HT_2Breceptor antagonist, RS‐127445, significantly inhibited visceral hypersensitivity provoked by restraint stress (35 to 74% inhibition at 1 to 10 mg kg^?1). Oral RS‐127445 produced a significant suppression of TNBS‐induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg kg^?1), although it was without significant effect on the visceral nociceptive threshold of naïve rats. RS‐127445 (1 to 30 mg kg^?1, p.o.) also dose‐dependently reduced the restraint stress‐induced defecation in naïve and TNBS‐treated rats. Conclusions & Inferences These results suggest that 5‐HT_2Breceptors are involved in signaling from the colon in rats in which there is visceral hypersensitivity and that a selective 5‐HT_2Breceptor antagonist could have therapeutic potential for the treatment of gut disorders characterized by visceral hypersensitivity.     

Cloning and immunoreactivity of the 5‐HT1Mac and 5‐HT2Mac receptors in the central nervous system of the freshwater prawn Macrobrachium rosenbergii

Biogenic amines are implicated in several mental disorders, many of which involve social interactions. Simple model systems, such as crustaceans, are often more amenable than vertebrates for studying mechanisms underlying behaviors. Although various cellular responses of biogenic amines have been characterized in crustaceans, the mechanisms linking these molecules to behavior remain largely unknown. Observed effects of serotonin receptor agonists and antagonists in abdomen posture, escape responses, and fighting have led to the suggestion that biogenic amine receptors may play a role in modulating interactive behaviors. As a first step in understanding this potential role of such receptors, we have cloned and fully sequenced two serotonin receptors, 5‐HT_1Mac and 5‐HT_2Mac, from the CNS of the freshwater prawn Macrobrachium rosenbergii and have mapped their CNS immunohistochemical distribution. 5‐HT_1Mac was found primarily on the membranes of subsets of cells in all CNS ganglia, in fibers that traverse all CNS regions, and in the cytoplasm of a small number of cells in the brain and circum‐ and subesophageal ganglia (SEG), most of which also appear to contain dopamine. The pattern of 5‐HT_2Mac immunoreactivity was found to differ significantly; it was found mostly in the central neuropil area of all ganglia, in glomeruli of the brain's olfactory lobes, and in the cytoplasm of a small number of neurons in the SEG, thoracic, and some abdominal ganglia. The observed differences in terms of localization, distribution within cells, and intensity of immunoreactive staining throughout the prawn's CNS suggest that these receptors are likely to play different roles. J. Comp. Neurol. 513:399–416, 2009. © 2009 Wiley‐Liss, Inc.     

Serotonin transporter, 5‐HT1A receptor,and behavior in DBA/2J mice in comparison with four inbred mouse strains

Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5‐HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5‐HT transporter (5‐HTT) mRNA level, 5‐HT_1A receptor mRNA level, and 5‐HT_1A receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5‐HTT mRNA level in the midbrain and a reduced density of 5‐HT_1A receptors in the frontal cortex without significant changes in 5‐HT_1A receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light‐dark box and elevated plus‐maze tests, were found. The results suggested the involvement of decreased 5‐HTT gene expression and 5‐HT_1A receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive‐like behaviors. © 2009 Wiley‐Liss, Inc.