TREKing toward new antidepressants.
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Animals↗
Biomedical subjects
Rene Hen
Publications and source records attributed to Rene Hen.
Neural circuits and behaviour: developmental and evolutionary perspectives.
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Animals↗
State-dependent alterations in hippocampal oscillations in serotonin 1A receptor-deficient mice.
Mice lacking the serotonin 1A receptor (5-HT(1A)R) show increased levels of anxiety-related behavior across multiple tests and background strains. Tissue-specific rescue experiments, lesion studies, and neurophysiological findings all point toward the hippocampus as a potential mediator of the phenotype. Serotonin, acting through 5-HT(1A)Rs, can suppress hippocampal theta-frequency oscillations, suggesting that theta oscillations might be increased in the knock-outs. To test this hypothesis, local field potential recordings were obtained from the hippocampus of awake, behaving knock-outs and wild-type littermates. The magnitude of theta oscillations was increased in the knock-outs, specifically in the anxiety-provoking elevated plus maze and not in a familiar environment or during rapid eye movement sleep. Theta power correlated with the fraction of time spent in the open arms, an anxiety-related behavioral variable. These results suggest a possible role for the hippocampus, and theta oscillations in particular, in the expression of anxiety in 5-HT(1A)R-deficient mice.
Animals↗
Young and excitable: the function of new neurons in the adult mammalian brain.
Adult neurogenesis occurs in most species and is regulated by a wide variety of environmental and pharmacological challenges. The functional integration of neurons generated in the adult was first demonstrated in songbirds more than two decades ago. In the adult mammalian brain, neurons are continuously generated in two structures, the olfactory bulb and the hippocampus. Current evidence suggests that adult-born immature neurons have distinct electrophysiological properties from old neurons, and proposed roles in a variety of functions including olfaction, learning and mood regulation.
Aging↗
Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test.
Animal models exhibiting sensitivity to chronic, but not acute, antidepressant treatment are greatly needed for studying the neural mechanisms of the antidepressant response. Although several models of acute antidepressant effects provide excellent tools for antidepressant discovery, they do not permit investigation into their therapeutic effects, which require several weeks of treatment to emerge. The inhibition of feeding produced by novelty, termed 'hyponeophagia', provides an anxiety-related measure that is sensitive to the effects of chronic, but not acute or subchronic, antidepressant treatment. This review evaluates the value of hyponeophagia-based tests as tools for investigating the neurobiology of the therapeutic response to antidepressant treatment. Criteria for the development and validation of animal models used to study neurobiological mechanisms of the antidepressant response are presented. Methodological considerations affecting the reliability, specificity, and ease of use of hyponeophagia-based models are also discussed. Lastly, we present a newly revised hyponeophagia paradigm, called the novelty-induced hypophagia (NIH) test, which attempts to maximize the predictive validity and practicality of the test. The NIH paradigm provides a promising new model for investigations into the neurobiology underlying the antidepressant response.
Analysis of Variance↗
The developmental origins of anxiety.
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Animals↗
Effects of chronic fluoxetine in animal models of anxiety and depression.
The onset of the therapeutic response to antidepressant treatment exhibits a characteristic delay. Animal models sensitive to chronic, but not acute, antidepressant treatment are greatly needed for studying antidepressant mechanisms. We initially assessed four inbred mouse strains for their behavioral response to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is used for the treatment of mood and anxiety disorders. Only the highly anxious BALB/c strain exhibited sensitivity to fluoxetine in the forced swim test. Additionally, fluoxetine reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains. We then evaluated the effects of subchronic (approximately 4 days) and chronic (approximately 24 days) fluoxetine treatment (0, 10, 18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety measures were obtained using the open field and novelty-induced hypophagia tests. Antidepressant effects were evaluated using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related measures were reduced by 18 mg/kg/day. In the forced swim test, 10 and 18 mg/kg/day increased swimming and reduced immobility. Here we present several novel effects of chronic, but not subchronic, antidepressant treatment.
Analysis of Variance↗
Genetic approaches to the study of anxiety.
Anxiety and its disorders have long been known to be familial. Recently, genetic approaches have been used to clarify the role of heredity in the development of anxiety and to probe its neurobiological underpinnings. Twin studies have shown that a significant proportion of the liability to develop any given anxiety disorder is due to genetic factors. Ongoing efforts to map anxiety-related loci in both animals and humans are underway with limited success to date. Animal models have played a large role in furthering our understanding of the genetic basis of anxiety, demonstrating that the genetic factors underlying anxiety are complex and varied. Recent advances in molecular genetic techniques have allowed increasing specificity in the manipulation of gene expression within the central nervous system of the mouse. With this increasing specificity has come the ability to ask and answer precise questions about the mechanisms of anxiety and its treatment.
Animals↗
The serotonergic system and anxiety.
The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.
Animals↗
Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.
Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.
Animals↗
Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system.
BACKGROUND: Dopamine transporter (DAT) knockdown (KD) mice, with approximately 90% loss of expression of the DAT, allow for the examination of the behavioral consequences of a chronically dysregulated dopamine system. The DAT KD mice have hyperdopaminergic tone, are hyperactive, and show impaired response inhibition in a number of paradigms. We hypothesized that the DAT KD mice would also display deficits in prepulse inhibition (PPI) and would be perseverative in their locomotor behavior. METHODS: Basal levels of PPI and patterns of locomotor behavior were measured in two cohorts of DAT KD mice. In addition, measurements of locomotor behavior were recorded after pretreatment with 100 mg/kg valproate in both DAT KD and wildtype mice. RESULTS: The DAT KD mice were hyperactive and displayed perseverative motor behavior but had normal levels of PPI. The clinically effective antimania drug valproate significantly attenuated the hyperactivity and perseverative locomotor behavior in the DAT KD mice and had no effect in control mice. CONCLUSIONS: The DAT KD mice appear to provide a model of some aspects of manic behavior. With limited models of bipolar disorder, the DAT KD mice might provide a vehicle to screen for new psychiatric therapies to treat mania and its related symptoms.
Animals↗
Maternal effects in infant and adult phenotypes of 5HT1A and 5HT1B receptor knockout mice.
The influence of the pre- and postweaning maternal environment on the offspring's phenotype was examined in 5-HT1A and 5-HT1B receptor knockout mice (KO1A and KO1B, respectively). We have previously shown that, when born to and raised by homozygous dams of the same genotype, adult KO1A are more anxious than wild-type (WT) mice, and adult KO1B are hyperactive and slightly less anxious than WT mice. We extend our studies here to the behavioral results of the offspring's own genotype, when the dam's genotype is constant, and the effects of the dam's genotype when the offspring's genotype is constant. In Experiments 1 and 2, KO1A-/- pups produced less ultrasonic vocalizations (USV) than controls in an isolation test on postnatal Day 7 when born to and reared by KO1A dams, either -/- or +/-. Heterozygous F1 pups reared by KO1A-/- dams produced more USV and were less anxious in the plus-maze at 2 to 3 months of age than F1 pups born to and reared by WT dams (Experiment 3). F1 pups reared by KO1B-/- dams produced less USV and were more anxious in the plus-maze than F1 pups reared by WT dams (Experiment 4). The results support a role for maternal effects that may comprise direct effects such as the dam's behavior and nutritional care of the pup, and possibly more complex indirect effects through the establishment of idiosyncratic dam-pup dyadic interactions. We recommend that breeding techniques that rely on same genotype (mutant-mutant or WT-WT) breeding pairs not be used to generate offspring when the focus of research is the study of gene function, but rather when familial effects need to be studied.
Animals↗
Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.
Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of alpha-synuclein. Rarely, PD may be caused by missense mutations in alpha-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that alpha-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in alpha-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal alpha-synuclein function may be important to DA neuron viability.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice.
For the last two decades, the involvement of 5-HT(1A) receptors in the regulation of vigilance states has been studied extensively thanks to pharmacological tools, but clear-cut conclusion has not been reached yet. By studying mutant mice that do not express this receptor type (5-HT(1A)-/-) and their wild-type 129/Sv counterparts, we herein demonstrate that 5-HT(1A) receptors play key roles in the control of spontaneous sleep-wakefulness cycles, as well as in homeostatic regulation and stress-induced adaptive changes of paradoxical sleep. Both strains of mice exhibited a diurnal sleep-wakefulness rhythm, but 5-HT(1A)-/- animals expressed higher amounts of paradoxical sleep than wild-type mice during both the light and the dark phases. In wild-type mice, pharmacological blockade of 5-HT(1A) receptors by WAY 100635 (0.5 mg/kg, i.p.) promoted paradoxical sleep, whereas the 5-HT(1A) agonist 8-OH-DPAT (0.25-1 mg/kg, s.c.) had an opposite effect. In contrast, none of the 5-HT(1A) receptor ligands affected sleep significantly in 5-HT(1A)-/- mice. However, 5-HT(1B) receptor stimulation by CP 94253 (1-3 mg/kg, i.p.) induced a reduction in paradoxical sleep in both strains, this effect being more pronounced in 5-HT(1A)-/- mutants. Finally, in contrast to wild-type mice, 5-HT(1A)-/- mutants did not exhibit any rebound of paradoxical sleep after either a 9 hr instrumental paradoxical sleep deprivation or a 90 min immobilization stress. Altogether, these data indicate that, in the mouse, 5-HT(1A) receptors participate in the spontaneous and homeostatic regulation, as well as in stress-induced adaptive changes of paradoxical sleep.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Participation of 5-HT(1B) receptors in the inhibitory actions of serotonin on masculine sexual behaviour of mice: pharmacological analysis in 5-HT(1B) receptor knockout mice.
1 The role of the 5-Hydroxytryptamine(1B) (5-HT(1B)) receptor subtype in masculine sexual behaviour in mice was analysed in both 5-HT(1B) receptor knockout (KO(1B)) and wild-type (WT) animals. 2 Comparison of male copulatory behaviour of WT and KO(1B) strains revealed that KO(1B) mice become interested earlier in sexual behaviour, but require more stimulation to achieve ejaculation than its corresponding WT strain. 3 The pharmacological manipulation of male sexual activity in the WT strain showed that the serotonin precursor 5-Hydroxytryptophan (5-HTP), the 5-HT(1B) agonist (1-(m-trifluoromethylphenyl) piperazine (TFMPP) and the 5-Hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT) all inhibited male copulatory behaviour in mice. 4 In KO(1B) mice, TFMPP lacked an effect, 5-HTP exerted a mild inhibitory effect while 8-OH-DPAT provoked only a tendency towards a reduction in the percentage of animals that achieved ejaculation. In general, KO(1B) mice were less sensitive to the inhibitory actions of 5-HTP and 8-OH-DPAT than the WT strain. 5 Based on these results, we can suggest that serotonin plays a general inhibitory role in the sexual behaviour of male mice and that both 5-HT(1B) and 5-HT(1A) receptor subtypes participate in the inhibitory actions of this neurotransmitter. 6 The absence of the 5-HT(1B) receptor subtype affected both components of mouse masculine sexual behaviour, motivation and execution, further confirming the involvement of this receptor subtype in the control of this behaviour. In addition, the diminished sensitivity to serotonergic stimulation exhibited by KO(1B) mice suggests the occurrence of compensatory changes as a consequence of the absence of the 5-HT(1B) receptor subtype.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Reconsideration of 5-hydroxytryptamine (5-HT)(7) receptor distribution using [(3)H]5-carboxamidotryptamine and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline: analysis in brain of 5-HT(1A) knockout and 5-HT(1A/1B) double-knockout mice.
The characterization and anatomical distribution of 5-hydroxytryptamine (5-HT)(7) receptor binding sites in brain tissue has been hampered by the lack of a specific radioligand. In the present autoradiographic study, we took advantage of 5-HT(1A) knockout and 5-HT(1A/1B) double-knockout mice to revisit the pharmacological characterization and anatomical localization of 5-HT(7) binding sites in mouse brain using [(3)H]5-carboxamidotryptamine (5-CT) and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT). The distribution pattern of [(3)H]5-CT binding sites (2 nM) in the brain of mice lacking the 5-HT(1A/1B) receptor was scarce and confined to the septum, globus pallidus, thalamus, hypothalamus, amygdala, cortex, and substantia nigra. The low densities of [(3)H]5-CT binding sites detected in septum, thalamus, hypothalamus, amygdala, and cortex were displaced by 10 microM of the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl)pyrrolidine-1-sulfonyl) phenol (SB-269970). The SB-269970-insensitive [(3)H]5-CT binding sites detected in globus pallidus and substantia nigra of 5-HT(1A/1B) knockout mice were displaced by N-[3-(2-dimethylamino)ethoxy-4-methoxy-phenyl]-2'-methyl-4'- (5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide hydrochloride (SB-216641) (1 microM), demonstrating the 5-HT(1D) nature of these binding sites. In contrast to the low densities of [(3)H]5-CT binding sites, high-to-moderate densities of [(3)H]8-OH-DPAT binding sites (10 nM) were found throughout the brain of 5-HT(1A) and 5-HT(1A/1B) knockout mice (olfactory system, septum, thalamus, hypothalamus, amygdala, CA3 field of the hippocampus, cortical mantle, and central gray). These [(3)H]8-OH-DPAT binding sites were displaced by 10 microM SB-269970, risperidone, and methiothepin but not by pindolol, N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide (WAY- 100135), or citalopram. We conclude that despite its high affinity for the 5-HT(7) receptor in tissue homogenates, [(3)H]5-CT is not a good tracer for measuring 5-HT(7) receptor binding sites autoradiographically. Also, the lower affinity ligand [(3)H]8-OH-DPAT is a much better tracer for autoradiographic studies at the 5-HT(7) receptor binding sites.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
5-HT(2A) receptors: location and functional analysis in intestines of wild-type and 5-HT(2A) knockout mice.
The distribution and function of the 5-hydroxytryptamine (5-HT(2A)) receptor were investigated in the intestines of wild-type (5-HT(2A) +/+) and knockout (5-HT(2A) -/-) mice. In 5-HT(2A) +/+ mice, rats, and guinea pigs, 5-HT(2A) receptor immunoreactivity was found on circular and longitudinal smooth muscle cells, neurons, enterocytes, and Paneth cells. Muscular 5-HT(2A) receptors were concentrated in caveolae; neuronal 5-HT(2A) receptors were found intracellularly and on the plasma membranes of nerve cell bodies and axons. Neuronal 5-HT(2A) immunoreactivity was detected as early as E14 in ganglia, intravillus nerves, and the deep muscle plexus. The 5-HT(2A) -/- colon did not express 5-HT(2A) receptors and did not contract in response to exogenous 5-HT. 5-HT(2A) -/- enterocytes were smaller, Paneth cells fewer, and muscle layers thinner (and showed degeneration) compared with those of 5-HT(2A) +/+ littermates. The 5-HT(2A) receptor may thus be required for the maintenance and/or development of enteric neuroeffectors and other enteric functions, although gastrointestinal and colonic transit times in 5-HT(2A) -/- and +/+ mice did not differ significantly.
Animals↗
Juvenile 5HT(1B) receptor knockout mice exhibit reduced pharmacological sensitivity to 5HT(1A) receptor activation.
Serotonin is an important modulator of anxiety and thus drugs that act on this system have frequently been shown to be either anxiogenic or anxiolytic. In addition serotonin has important trophic functions during early development and disruption of serotonin homeostasis is likely to have long-lasting repercussions in the adult. In the present study we examined the contribution of two serotonin receptor subtypes (5HT(1A) and 5HT(1B)) to the pathophysiology of anxiety during development. For this, we have studied homozygous knockout mice lacking the 5HT(1B) receptor and examined the effect of pharmacological manipulations of 5HT(1A) and 5HT(1B) receptors on locomotor activity and emission of ultrasonic vocalization (USV) in 7-8 days old mice. As shown before, drug naïve 5HT(1B) knockout pups showed reduced USV and were hyperactive, in comparison to wild type controls. The administration of RU24969 (a 5HT(1A/1B) agonist) showed a dose-dependent decrease in USV in the wild type and a biphasic effect in the mutants and resulted in dose-dependent increase in activity in the wild type and, to a lesser extent, in the knockouts. The selective 5HT(1A) agonist, 8OH-DPAT, dose-dependently blocked vocalization in both genotypes and also increased locomotion. To differentially activate 5HT(1B) receptors we first blocked 5HT(1A) receptors with WAY100315 and then treated with RU24969. At a high testing temperature, pretreatment with WAY100315 resulted in an anxiogenic effect in wild type pups but not in the knockouts. In agreement with our findings that 5HT(1B) knockout mice were in general less sensitive to 5HT(1A) activation, 5HT(1A) receptor binding was reduced in the knockouts in comparison to controls. Finally, treatment with diazepam dose-dependently decreased USVs in both group with the knockouts showing enhanced sensitivity to this drug. Our results show that important adaptations to a disturbance of serotonin homeostasis occur during the first week of life within the serotonergic system. The observed decreased in sensitivity of 5HT(1B) knockout mice to 5HT(1A) and increased to GABA(A) manipulations are discussed within the context of serotonergic plasticity during development and the implication for clinical treatment of anxiety in genetically predisposed individuals.
Animals↗