Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF^2L/2LCk-cre). A severe impairment specific for the serotonin 2A receptor (5-HT_2AR) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT_2ARs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered by BDNF depletion. 5-HT_2A ([³H]-MDL100907) and 5-HT_1A ([³H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT_2A receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT_1A receptor binding was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT_2A and 5-HT_1A mRNA expression but normal 5-HT_2C content in these brain regions in BDNF^2L/2LCk-cre mice. We investigated whether the reduction in frontal 5-HT_2AR binding was reflected in reduced functional output in two 5-HT_2A-receptor mediated behavioral tests, the head-twitch response (HTR) and the ear-scratch response (ESR). BDNF^2L/2LCk-cre mutants treated with the 5-HT_2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished ESR but no differences in HTR compared to wildtypes. These findings illustrate the context-dependent effects of deficient BDNF signaling on the 5-HT receptor system and 5-HT_2A-receptor functional output.     

Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus

Selective serotonin reuptake inhibitors (SSRIs), such as Prozac^®, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT_1A) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT_1A receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT_1A receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT_1A receptor signaling, but, in rats, these effects occur within 2 days; thus, estrogens or selective estrogen receptor modulators may serve as useful short-term tools to accelerate desensitization of 5-HT_1A receptors in response to SSRIs if candidate estrogen receptor targets in the hypothalamus are identified. We found high levels of GPR30, which has been identified recently as a pertussis-toxin (PTX) sensitive G-protein-coupled estrogen receptor, in the hypothalamic paraventricular nucleus (PVN) of rats. Double-label immunohistochemistry revealed that GPR30 co-localizes with 5-HT_1A receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-β-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT_1A receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT_1A receptor signaling in the PVN as measured by an attenuated oxytocin (by 29%) and ACTH (by 31%) response to DPAT. This study indicates that a putative extra-nuclear estrogen receptor, GPR30, may play a role in estradiol-mediated attenuation of 5-HT_1A receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.     

Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT_2A) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms.We assessed cerebral 5-HT_2A receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT_2A receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [¹⁸F]altanserin PET in a bolus–infusion approach. A significant global reduction of 20–30% in 5-HT_2A binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT_2A binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT_2A receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.     

Imaging phenotypes of major depressive disorder: genetic correlates

Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of, a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala–anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT_1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT_1A gene (HTR1A: −1019 C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the 5-HT transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene–gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data.     

Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women

Serotonin modulates the activity of the hypothalamic–pituitary–adrenal (HPA) axis particularly via the serotonin-1A receptor (5-HT_1A). Therefore, the rationale of this positron emission tomography (PET) study was to investigate the influence of the 5-HT_1A receptor distribution in the human brain on plasma levels of dehydroepiandrosterone sulfate (DHEAS) and cortisol in vivo. Eighteen healthy female were measured with PET and the selective 5-HT_1A receptor radioligand [carbonyl-¹¹C]WAY-100635. Nine a priori defined brain regions (hypothalamus, orbitofrontal cortex, amygdala, hippocampus, anterior and posterior cingulate cortices, dorsal raphe nucleus, retrosplenial cortex, and insula) and the cerebellum (reference region) were delineated on coregistered MR images. DHEAS and cortisol plasma levels were collected by blood sampling in the morning of the PET day. Linear regression analysis of DHEAS plasma level as dependent variable and hypothalamic 5-HT_1A receptor binding potential (BP) as independent variable showed a highly significant association (r = .691, p = .002). The hypothalamic 5-HT_1A BP predicted 47.7% of the variability in DHEAS plasma levels. Regressions were borderline significant (p < .01, Bonferroni corrected threshold <.0056) between 5-HT_1A BP in the anterior cingulate and orbitofrontal cortices and free cortisol levels. No significant associations between DHEAS or cortisol and the 5-HT_1A receptor BP in other investigated brain regions were found. In conclusion, the serotonergic system may influence the DHEAS plasma level by modulating CRH and ACTH release via hypothalamic 5-HT_1A receptors as reported for cortisol before. As disturbances of the HPA axis as well as changes of the 5-HT_1A receptor distribution have been reported in affective disorders, future studies should focus on these interactions.     

Regional brain serotonin receptor changes in portacaval shunted rats

The pathogenesis of hepatic encephalopathy is unknown, but metabolic perturbations, including hyperammonaemia and increased brain turnover of serotonin (5-HT), have been identified. Possible alterations of 5-HT receptors in the brain have been rudimentarily studied. We therefore investigated the 5-HT_{1 A}, 5-HT_{1 B} and 5-HT_{2 A} receptor density in 18–22 different regions in the brain of portacaval shunted rats by means of radioligand binding with autoradiographical evaluation. The results revealed a decreased 5-HT_{1 A} receptor binding in seven serotonergic projection areas of the brain, and an increase in the nucleus accumbens, hypothalamus and subiculum. No changes in the raphe nuclei were observed. An increased 5-HT_{1 B} receptor binding was seen in five brain regions: basal ganglia, olfactorial regions, hippocampus, mid brain and thalamus. However, decreased binding was seen in three regions of cortical areas and hippocampus. The 5-HT_{2 A} receptor binding site density was essentially unaltered. These findings suggest that perturbations in the central serotonergic neurotransmission may play a functional role in chronic hepatic encephalopathy.     

The Effects of Hypothyroidism on 5-HT1A and 5-HT2A Receptors and the Serotonin Transporter Protein in the Rat Brain

The effects of hypothyroidism on 5-HT_1A and 5-HT_2A receptors and the serotonin transporter protein were studied in thyroidectomized male Wistar rats in two experimental groups: 1) animals kept on an iodine-free diet (hypothyroid rats) and 2) animals kept on thyroxine (15 g/kg) for 21 days (giving normal thyroid hormone levels, euthyroid animals). Sham-operated rats served as controls. Binding of [³H]8-OH-DPAT with 5-HT_1A receptors and [³H]citalopram with the transporter protein in the hippocampus and midbrain showed no changes in hypothyroid rats as compared with controls. Conversely, there were significant decreases in [³H]ketanserin binding to 5-HT_2A receptors in the frontal cortex in hypothyroid rats as compared with controls; this decrease was reversed by thyroxine treatment. Thus, losses of cortical 5-HT_2A receptors appears to be the main consequence of hypothyroidism at the level of the serotonin system of the brain.     

Mirtazapine abolishes hyperthermia in an animal model of serotonin syndrome

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. Hyperthermia is the most serious symptom of this syndrome. Hyperthermia in 5-HT syndrome is reportedly the result of activation of 5-HT_2A receptors. Mirtazapine is a novel antidepressant and a potent 5-HT₂ receptor antagonistic. Although mirtazapine has been reported to cause 5-HT syndrome, the pharmacological profile of mirtazapine suggests that it improves hyperthermia in 5-HT syndrome. In the present study, we evaluated whether mirtazapine attenuates hyperthermia in a rat model of 5-HT syndrome. This model was induced by administration of tranylcypromine, a nonselective monoamine oxidase inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor. Upon injection of these two drugs, the rectal temperature of the rats increased to over 40 °C. Pre- and post-administration of mirtazapine abolishes hyperthermia in this model of 5-HT syndrome. Post-administration of ritanserin, a 5-HT_2A receptor antagonist, completely inhibited hyperthermia and pre-administration of WAY100635, a 5-HT_1A receptor antagonist, significantly attenuated the ability of mirtazapine to abolish hyperthermia. The results of the present study suggest that mirtazapine inhibits hyperthermia in an animal model of 5-HT syndrome by blocking the activation of 5-HT_2A receptors, and that it partly inhibits hyperthermia by activating the 5-HT_1A receptors. The present study indicates that mirtazapine is unlikely to cause 5-HT syndrome and may be a useful drug for treating this condition.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT1A and 5-HT2A receptors functional activity and expression of key genes of the brain serotonin system

Among serotonin (5-HT) receptors, the 5-HT₃ receptor is the only ligand-gated ion-channel. Little is known about the interaction between the 5-HT₃ receptor and other 5-HT receptors and influence of 5-HT₃ chronic activation on other 5-HT receptors and the expression of key genes of 5-HT system. Chronic activation of 5-HT₃ receptor with intracerebroventricularly administrated selective agonist 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) (14 days, 40 nmol, i.c.v.) produced significant desensitization of 5-HT₃ and 5-HT_1A receptors. The hypothermic responses produced by acute administration of selective agonist of 5-HT₃ receptor (m-CPBG, 40 nmol, i.c.v.) or selective agonist of 5-HT_1A receptor (8-hydroxy-2-(di-n-propylamino)tetralin) (8-OH-DPAT, 1 mg/kg, i.p.) was significantly lower in m-CPBG treated mice compared with the mice of control groups. Chronic m-CPBG administration failed to induce any significant change in the 5-HT_2A receptor functional activity and in the expression of the gene encoding 5-HT_2A receptor. Chronic activation of 5-HT₃ receptor produced no considerable effect on the expression on 5-HT₃, 5-HT_1A, and 5-HT transporter (5-HTT) and tryptophan hydroxylase-2 (TPH-2) genes – the key genes of brain 5-HT system, in the midbrain, frontal cortex and hippocampus. In conclusion, chronic activation of ionotropic 5-HT₃ receptor produced significant desensitization of 5-HT₃ and postsynaptic 5-HT_1A receptors but caused no considerable changes in the expression of key genes of the brain 5-HT system.     

Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A

Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT_1A, 5-HT_2A, and 5-HT_2C) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). Samples were obtained from postmortem brain tissue (Brodmann area 10) from 20 persons with a history of MDD and 20 matched controls as determined by a retrospective diagnostic evaluation obtained from family members. Levels of 5-HT_1A, 5-HT_2A, and 5-HT_2C receptor were quantitated via Western blot analyses. Basal and stimulated PKA and PKC activity were also determined. The depressed samples showed significantly increased 5-HT_2A receptor abundance relative to controls, but no differences in 5-HT_1A or 5-HT_2C receptors. Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT_2A receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT_2A receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT_2A receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT_2A receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.     

Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease: a combined [C]DASB and [F]altanserin-PET study

In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT_2A) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT_2A receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [¹⁸F]altanserin and [¹¹C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([¹¹C]DASB). Overall [¹⁸F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [¹¹C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [¹¹C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT_2A receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.     

Receptor-genes cross-talk: effect of chronic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior

Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT_1A receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT_1A receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT_1A receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT_1A receptors. The decrease in 5-HT_1A gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT_2A receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT_1A and 5-HT_2A receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT_1A-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT_1A receptors on 5-HT_1A, 5-HT_2A and TPH-2 gene expression demonstrated the role of 5-HT_1A receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.     

Regulation of cortical and striatal 5-HT1A receptors in the MPTP-lesioned macaque

Serotonergic 1A (5-HT_1A) receptor agonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in Parkinson's disease (PD), though the mechanism(s) and site(s) of action remain unclear. We employed [³H]-WAY 100,635 autoradiographic receptor binding to measure 5-HT_1A receptor levels in 4 groups of macaques: normal (vehicle-vehicle); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, without exposure to L-DOPA, i.e., untreated parkinsonian (MPTP-vehicle); MPTP-lesioned, receiving a single administration of L-DOPA to alleviate parkinsonism (MPTP-L-DOPA-acute); and MPTP-lesioned, chronically treated with L-DOPA, parkinsonism alleviated but exhibiting dyskinesia (MPTP-L-DOPA-chronic). We demonstrate that 5-HT_1A receptor binding decreases (by 10%-20%, p < 0.05) in the external layers, but increases (by 80%-100%, p < 0.05) in the middle layers, of the premotor and motor cortex of all MPTP-lesioned macaques. In the striosomes of the caudate nucleus, 5-HT_1A receptor binding increases in MPTP-vehicle macaques (by 50%, p < 0.05), compared with normal macaques. While 5-HT_1A receptor binding is low in the matrix of the caudate nucleus in normal macaques, it increases (by 200%, p < 0.05) in MPTP-L-DOPA-chronic macaques. These data suggest that 5-HT_1A receptors are involved in the pathophysiology of both parkinsonism and complications of L-DOPA therapy.     

Pharmacological,neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist

A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT_1A receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT_1A receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K_i value of 0.8 nM. Its binding affinity is in the same range as that observed for the (±)8-OH-DPAT, a reference 5HT_1A agonist compound. Notably, JB-788 only bound weakly to 5-HT_1B or 5-HT_2A receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, α₂, β₁ and β₂ adrenergic receptors, or dopaminergic D₁ receptors. JB-788 was found to display substantial binding affinity for dopaminergic D₂ receptors and, to a lesser extend to α₁ adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT_1A, thus acting as a potent 5-HT_1A receptor agonist (E_max. 75%, EC₅₀ 3.5 nM). JB-788 did not exhibit any D₂ receptor agonism but progressively inhibited the effects of quinpirole, a D₂ receptor agonist, in the cAMP accumulation test with a K_i value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.     

Involvement of brain serotonin 5-HT<Subscript>1A</Subscript> receptors in genetic predisposition to aggressive behavior

Experiments were performed on Norwegian rats selected over more than 59 generations for high and low levels of high-affective defensive aggressivity and on highly aggressive (offensive) Tg8 mice with irreversible monoamine oxidase A knockout. There were significant differences in the functional state and expression of 5-HT_1A receptors between highly aggressive and non-aggressive animals. Functional activity assessed in terms of hypothermia evoked by a 5-HT_1A agonist was significantly greater in non-aggressive rats and mice than in aggressive animals. The high level of functional activity in non-aggressive rats coincided with a greater level of expression of 5-HT_1A receptors in the midbrain. The level of 5-HT^1A receptor mRNA in aggressive mice was unchanged in the midbrain and hypothalamus and was increased in the frontal cortex and amygdaloid complex. These results led to the conclusion that 5-HT_1A receptors play a significant role in the mechanisms of genetic predisposition to aggressive behavior. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 56, No. 4, pp. 537–542, July–August, 2006.     

UHF-dielectrometry of the urine in prognosis of aggregation stability

The hypothermic effects of 5-HT_1A serotonin receptor agonist 8-OH-DPAT after intranasal, intraperitoneal, and subcutaneous administration were compared. In a dose of 1 mg/kg 8-OH-DPAT induced similar thermal reactions after administration by all three routes. In a dose of 0.5 mg/kg 8-OH-DPAT caused no appreciable changes in body temperature after intraperitoneal injection and decreased it after subcutaneous and intranasal administration. No genotypic differences in the effects of 5-HT_1A receptor agonist administered by different routes were detected in four inbred mouse strains. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 413-415, October, 2008     

Effect of antagonists and agonists of 5-HT1 and 5-HT2 serotonin receptors on the predator aggressiveness of wild norway rats

The effect of agonists of serotonin receptors on predator aggressiveness (the “mouse killing” test) is studied on Norway rats. Ipsapirone and eltoprazine are found to have no effect on predator aggressiveness. 1-[3-(Trifluoromethyl)phenyl]piperazine×HCl (TFMPP) considerably reduces aggressiveness. The serotonin precursor 5-hydroxyptryptophan also lowers it, while the antagonist of 5-HT_2A receptors ketanserin abolishes the inhibitory effect of 5-hydroxytryptophan. Presumably, the inhibitory effects of serotonin on predator aggressiveness are realized via the 5-HT_2A and 5-HT_2C brain serotonin receptors. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 5, pp. 687–689, June, 1996     

Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex

Although loss of cholinergic neurons in the basal forebrain is considered a key initial feature in Alzheimer's disease (AD), changes in other transmitter systems, including serotonin and 5-HT_2A receptors, are also associated with early AD. The aim of this study was to investigate whether elimination of the cholinergic neurons in the basal forebrain directly affects 5-HT_2A receptor levels. For this purpose intraventricular injection of the selective immunotoxin 192 IgG-Saporin was given to rats in doses of either 2.5 or 5 μg. The rats were sacrificed after 1, 2, 4 and 20 weeks. 5-HT_2A protein levels were determined by western techniques in frontal cortex and hippocampus. A significant 70% downregulation in frontal cortex and a 100% upregulation in hippocampus of 5-HT_2A receptor levels were observed 20 weeks after the cholinergic lesion when using the highest dose of 192 IgG-Saporin. Our results show that cholinergic deafferentation leads to decreased frontal cortex and increased hippocampal 5-HT_2A receptor levels. This is probably a consequence of the interaction between the serotonergic and the cholinergic system that may vary depending on the brain region.     

Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus

A recent [¹⁸F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT_1A receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [¹⁸F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [¹⁸F]MPPF (which is antagonist) displayed a transient increase in 5-HT_1A receptor density 7 days after Aβ injection, whereas [¹⁸F]F15599 (a radiolabelled 5-HT_1A agonist) binding was unchanged suggesting that the overexpressed 5-HT_1A receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT_1A receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT_1A receptors in AD.     

Serotonin receptor 5-HT5A in rat hippocampus decrease by leptin treatment

5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT_5A receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT_5A receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin + serotonin treated. The results showed that even though the 5-HT_5A gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT_5A serotonin receptor decreased significantly in the dentate gyrus.