Brain Serotonin System Research Articles

Effects of LPS and serotonergic drugs on hygienic behavior in mice

Hygienic self-grooming is a behavioral adaptation for removing litter particles and pathogenic agents from animal fur and skin. We studied contribution of brain serotonin system into mechanisms regulating hygienic behavior in intact mice and mice with LPS(lipopolysaccharide)-induced sickness. A spot of fluorescent dye was applied on the back of a mouse, and the decrease in its fluorescence served as an index of fur cleaning efficiency estimated using original classifier algorithm. Agonist of 5-HT1A receptor (8-OH-DPAT) or 5-HT2A/2C receptor (DOI) attenuated fur cleaning at a dose of 1mg/kg but not of 0.2mg/kg. MAO-A inhibitor clorgyline decreased hygienic self-grooming at a dose of 10 but not of 5mg/kg. SSRI paroxetine had no effect while fluoxetine diminished hygienic behavior at the higher dose used (20mg/kg). Inhibitory effect of LPS treatment (50μg/kg) on fur cleaning was not altered by administration of p-MPPI (5-HT1A receptor antagonist, 1mg/kg) or DOI (1mg/kg) while 8-OH-DPAT (1mg/kg) produced additive effect. The results suggest the involvement of 5-HT1A and 5-HT2A/2C brain serotonin receptors and MAO-A in the inhibition of hygienic behavior in mice. However, LPS-induced depression of fur cleaning appeared to be mediated via different mechanisms and enhanced by 5-HT1A receptor activation.

Estradiol modulation of cortical, striatal and raphe nucleus 5-HT 1A and 5-HT 2A receptors of female hemiparkinsonian monkeys after long-term ovariectomy

Depression is common in Parkinson’s disease and an imbalance in serotonin neurotransmission could be implicated. Estradiol is reported to modulate brain serotonin systems of rodents and monkeys, but this has not been explored in primate models of Parkinson’s disease. Thus, the present study investigated the effect of estradiol on 5-HT 1A and 5-HT 2A serotonin receptors in the cortex, striatum and raphe nucleus of long-term ovariectomized hemiparkinsonian monkeys. Seven monkeys were ovariectomized and received a month later a unilateral lesion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Four years after lesion and ovariectomy, three received a month of treatment with 17β-estradiol and four the vehicle. Autoradiography of [ 3H]8-OH-DPAT specific binding to 5-HT 1A receptors showed a decrease in the frontal cortex of monkeys treated with 17β-estradiol in both hemispheres of the brain. [ 3H]ketanserin specific binding to 5-HT 2A receptors was increased in the frontal cortex and the striatum of monkeys treated with 17β-estradiol in both the lesioned and intact sides of the brain. Autoradiography of [ 35S]GTPγS specific binding stimulated with R-(+)-8-OH-DPAT showed a decrease in the percentage of stimulation in the frontal cortex of monkeys treated with 17β-estradiol in both hemispheres of the brain and in the dorsal raphe nucleus. Treatment with 17β-estradiol was initiated a long time after ovariectomy in monkeys to model post menopausal hormonal conditions and showed that serotonin receptors were still responsive in the brain regions investigated. These results support a role for 17β-estradiol on serotonin activity in Parkinson’s disease and could be useful for treatment of depression associated with this disease.

Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats

The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT6 receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted drugs. The aim of the present study was to investigate whether the selective pharmacological blockade or activation of 5-HT6 receptors altered the maintenance of cocaine self-administration, reinstatement of cocaine-seeking behavior following an extinction of cocaine self-administration or cocaine-evoked conditioned place preference in rats. We also evaluated the effects of 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl)-2-benzothiophene-sulfonamide (SB 271046, a 5-HT6 receptor antagonist) or N-1-(6-chloroimidazo-[2, 1-b]-[1, 3]thiazole-5-sulfonyl)tryptamine (WAY 181187, a potent 5-HT6 receptor agonist) on locomotor activity in rats. Our results indicate that SB 271046 (1–10mg/kg) altered cocaine-maintained self-administration as well as cocaine-evoked reinstatement of cocaine seeking and expression of cocaine place preference in rats. We also demonstrate that pharmacological stimulation of 5-HT6 receptors by WAY 181187 (3–30mg/kg) attenuated the expression of cocaine conditioned place preference but not cocaine self-administration and reinstatement of cocaine seeking. WAY 181187 at the highest dose used (30mg/kg) reduced basal locomotor activity. Despite current results, the precise function and therapeutic relevance of 5-HT6 receptors need further clarification.

On the role of the selective silencer Freud-1 in the regulation of the brain 5-HT1A receptor gene expression

Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

Receptor-genes cross-talk: effect of chronic 5-HT 1A 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.

Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction

Addiction and stress are linked at multiple levels. Drug abuse is often initiated as a maladaptive mechanism for coping with stress. It is maintained in part by negative reinforcement to prevent the aversive consequences of stress associated with abstinence. Finally, stress is a major factor leading to relapse in subjects in which drug seeking behavior has extinguished. These associations imply overlapping or converging neural circuits and substrates that underlie the processes of addiction and the expression of the stress response. Here we discuss the major brain serotonin (5-HT) system, the dorsal raphe nucleus (DRN)-5-HT system as a point of convergence that links these processes and how the stress-related neuropeptide, corticotropin-releasing factor (CRF) directs this by a bimodal regulation of DRN neuronal activity. The review begins by describing a structural basis for CRF regulation of the DRN-5-HT system. This is followed by a review of the effects of CRF and stress on DRN function based on electrophysiological and microdialysis studies. The concept that multiple CRF receptor subtypes in the DRN facilitate distinct coping behaviors is reviewed with recent evidence for a unique cellular mechanism by which stress history can determine the type of coping behavior. Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT–dopamine interactions in addiction.

Anxiety - bridging the heart/mind divide

Although the complimentary roles of heart and brain in anxiety have been recognised for centuries, the precise contribution of each and more importantly perhaps their interplay has proved difficult to describe. Recent data from human brain imaging and cardiovascular physiology studies are beginning to delineate the mechanistic pathways of anxiety disorders in general and panic in particular. Evidence for a dysfunction of brain gamma-amino butyric acid-A and serotonin (5HT) systems in both panic and cardiovascular regulation is reviewed along with new evidence for altered sympathetic nervous system activity in the heart and periphery. Testable hypotheses and research ideas are suggested.

5-HT and NA Reuptake Inhibitors and Appetite Regulation: The Role of the Central 5-HT Network

Brain serotonin (5-hydroxytryptamine; 5-HT) systems have been implicated in the leptin-independent neural regulation of appetite, as indicated by the anorectic effects of drugs that directly or indirectly stimulate postsynaptic 5-HT receptors. The identification of 5-HT subtype receptor functions in the regulation of feeding behavior and energy balance using genetic models has shed new light on the poorly understood area of leptin-independent appetite regulation. With the voluntary withdrawal of d-fenfluramine, which inhibits serotonin (5-HT) uptake and induces 5-HT release, due to primary pulmonary hypertension, research attention has been focused on the downstream pathways of central 5-HT subtype receptors, especially 5-HT2C receptors (5-HT2CRs), in the regulation of satiety. Central 5-HT systems which operate via 5- HT2CRs have a complex neural network, with certain neurons in the hypothalamus harboring appetite regulatory neuropeptides such as proopiomelanocortin (POMC) and corticosterone releasing hormone (CRH). The 5-HT drugs, which enhance 5-HT release via 5-HT2CR in the hypothalamus, induce the activation of hypothalamus-pituitary adrenal (HPA) axis as well as satiety. On the other hand, the selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and noradrenalin reuptake inhibitors (SNRIs) induce satiety without stimulating the HPA axis. 5-HT2CR and 5-HT1BR substantially contribute to the anorexic effects of fenfluramine, whereas inactivation of 5-HT2CR enhances the effects of SSRIs so as to increase extracellular 5-HT in the brain and induce the appetite suppressing effects via 5-HT1BR. Moreover, SNRIs induce satiety independently of 5-HT2CRs and 5-HT1BRs. alpha-1 Adrenoceptors likely contribute to the appetite suppressing effects of SNRIs. Thus, the complex 5-HT network systems orchestrate leptin-independent central appetite regulation.

Brain serotonin transporter in human methamphetamine users

Research on methamphetamine (MA) toxicity primarily focuses on the possibility that some of the behavioural problems in human MA users might be caused by damage to brain dopamine neurones. However, animal data also indicate that MA can damage brain serotonin neurones, and it has been suggested that cognitive problems and aggression in MA users might be explained by serotonergic damage. As information on the brain serotonin system in human MA users is fragmentary, our objective was to determine whether protein levels of serotonin transporter (SERT), a key marker of serotonin neurones, are decreased in brain of chronic MA users. SERT immunoreactivity was measured using an immunoblotting procedure in autopsied brain of 16 chronic MA users testing positive for the drug in blood and brain and matched controls. SERT levels were non-significantly decreased (-14% to -33%) in caudate, putamen and thalamus (normal in hippocampus), and, unlike the robust striatal dopamine reduction, there was marked overlap between control and MA user ranges. Concentrations of SERT were significantly decreased (-23% to -39%) in orbitofrontal and occipital cortices (normal in frontopolar and temporal cortices). Our data suggest that MA might modestly damage brain serotonin neurones and/or inhibit SERT protein expression, with cerebral cortex being more affected than sub-cortical regions. The SERT reduction in orbitofrontal cortex complements other data suggesting involvement of this area in MA-related behaviour. Decreased brain SERT could also be related to the clinical finding that treatment with a selective serotonin re-uptake inhibitor might increase relapse to MA.

Role of Serotonin in Obsessive–Compulsive Disorder

Obsessive–compulsive disorder (OCD) is a psychiatric disorder consisting of obsessions and compulsions. Over the past two decades, it has been suggested that OCD might be related to the functioning of brain serotonin systems, mainly because of the antiobsessional efficacy of selective serotonin-reuptake inhibitors (SSRIs). Although the efficacy of SSRIs suggests a role of the serotonergic system in OCD, the exact function of serotonin is still unclear. Is the serotonergic system implicated in the pathophysiology of OCD, or is it implicated in the treatment effect in OCD? Do SSRIs compensate for a fundamental abnormality of the serotonergic system, or do SSRIs modulate an intact serotonergic system to compensate for another neurotransmitter mechanism? This review summarizes evidence supporting a role for the serotonin transporter and serotonin receptor subtypes in the pathophysiology and treatment of OCD.

Auditory evoked potentials as indicator of brain serotonin system and as predictor of pharmacotherapeutic response in psychiatric patients

Auditory evoked potentials as indicator of brain serotonin system and as predictor of pharmacotherapeutic response in psychiatric patients

From gene to aggressive behavior: The role of brain serotonin

This article addresses a question at the juncture of neurophysiology and neurogenetics--the role of the brain neurotransmitter serotonin in the genetic control of behavior. Published data are presented, along with results obtained from studies performed at the Behavioral Neurogenomics Laboratory. The role of protein elements of the brain serotonin system (key enzymes in serotonin metabolism and serotonin 5-HT(1A) receptors), which are subject to the direct influence of genes, in the genetic predisposition to aggressive behavior is discussed. Experimental results obtained in Norwegian rats selected over more than 50 generations for the absence of aggressivity and for high aggressivity to humans are presented, along with data from experiments on mouse lines and mice with genetic knockout of MAO A. These data provide evidence that 1) brain serotonin makes a significant contribution to the mechanisms underlying genetically determined individual differences in aggressivity, and 2) the genes encoding the main enzymes of serotonin metabolism in the brain (tryptophan hydroxylase-1 and MAO A) and the 5-HT(1A) receptor are members of a set of genes modulating aggressive behavior.

The immobility produced by intermittent swim stress is not mediated by serotonin

Exposure to uncontrollable stressors such as intermittent swim stress (ISS) produces a behavioral syndrome that resembles behavioral depression including immobility in a Forced Swim Test (FST) and escape learning deficits. The results of previous studies suggest that stress causes a temporary sensitization of the brain serotonin (5-HT) system that is necessary and sufficient for producing behavioral depression. If this hypothesis is true in the ISS paradigm, then enhancing or inhibiting 5-HT transmission during stress should exacerbate or block the development of behavioral depression, respectively. The selective 5-HT uptake inhibitor fluoxetine (FLX) was administered prior to ISS or confinement; 24 h later the FST was used to detect behavioral immobility. ISS, but not FLX, significantly increased immobility in the FST. The purported 5-HT uptake enhancer tianeptine (TPT) was administered in place of FLX. Again ISS increased immobility in the FST, but TPT had no effect. These results suggested that 5-HT is not a critical mediator of ISS induced behavioral depression. However, some authors have raised concern that TPT does not act directly on 5-HT. Therefore, the 5-HT synthesis inhibitor, para-chlorophenylaline (PCPA) was administered to deplete central 5-HT before stress. PCPA did not alter immobility in the FST. Finally, a sub-chronic regimen of FLX given after ISS, but before the FST, was without effect on reversing the ISS-induced immobility. Taken together, these experiments indicate that ISS produces a significant behavioral depression manifested as increased immobility but offer no support of the hypothesis that 5-HT is a critical mediator of these effects.

Loudness dependence of the auditory evoked N1/P2 component as an indicator of serotonergic dysfunction in patients with schizophrenia — A replication study

Serotonergic dysfunction appears to be involved in the pathogenesis of schizophrenia. The loudness dependence of auditory evoked potentials (LDAEP) has been suggested to be a valid indicator of the brain serotonin system's activity in humans. Patients with schizophrenia showed weaker LDAEP, indicating high serotonergic activity, in comparison to healthy controls. Thus, we were able again to demonstrate electrophysiological evidence for an upregulated serotonergic system in schizophrenia.

CB1 knockout mice display impaired functionality of 5‐HT1A and 5‐HT2A/C receptors

Interaction between brain endocannabinoid (EC) and serotonin (5-HT) systems was investigated by examining 5-HT-dependent behavioral and biochemical responses in CB(1) receptor knockout mice. CB(1) knockout animals exhibited a significant reduction in the induction of head twitches and paw tremor by the 5-HT(2A/C) receptor selective agonist (+/-) DOI, as well as a reduced hypothermic response following administration of the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT. Additionally, exposure to the tail suspension test induced enhanced despair responses in CB(1) knockout mice. However, the tricyclic antidepressant imipramine and the 5-HT selective reuptake inhibitor fluoxetine induced similar decreases in the time of immobility in the tail suspension test in CB(1) receptor knockout and wild-type mice. No differences were found between both genotypes with regard to 5-HT(2A) receptor and 5-HT(1A) receptors levels, measured by autoradiography in different brain areas. However, a significant decrease in the ability of both, the 5-HT(1A) receptor agonist (+/-)-8-OH-DPAT and the 5-HT(2A/C) receptor agonist (-)DOI, to stimulate [(35)S]GTPgammaS binding was detected in the hippocampal CA(1) area and fronto-parietal cortex of CB(1) receptor knockout mice, respectively. This study provides evidence that CB(1) receptors are involved in the regulation of serotonergic responses mediated by 5-HT(2A/C) and 5-HT(1A) receptors, and suggests that a reduced coupling of 5-HT(1A) and 5-HT(2A) receptors to G proteins might be involved in these effects.

Brain regional α-[11C]methyl-L-tryptophan trapping, used as an index of 5-HT synthesis, in healthy adults: absence of an age effect

Previous functional neuroimaging studies suggest that selective aspects of the brain serotonin (5-HT) system change during the aging process. Here, we assessed the effects of aging on the brain regional alpha-[(11)C]methyl-L: -tryptophan (alpha-[(11)C]MTrp) trapping rate constant (K*; microl.g(-1).min(-1)), which, with certain assumptions, could be taken as a proxy of 5-HT synthesis. Thirty-six healthy right-handed subjects had positron emission tomography (PET) scans following injection with alpha-[(11)C]MTrp [18 males aged 46.6 +/- 22.2 years (range 20-80 years) and 18 females aged 33.0 +/- 15.5 years (range 20-80 years)]. The trapping rate constant, K*, was calculated with the graphical method for irreversible ligands using the sinus-venous input function. A priori selected volumes of interest (VOIs) were defined using an automatic algorithm. VOI analysis showed no correlation between age and brain regional K* values. As reported by others, significant age-related reductions of gray matter were observed in the thalamus and frontal and cingulate cortices; even with partial volume correction there was still no significant relationship between K* and age. Further exploratory SPM voxelwise correlation between age and alpha-[(11)C]MTrp trapping, using p = 0.05 (uncorrected), as well as voxel-based morphometry, was in agreement with the VOI analysis. The dissociation between age-related changes in brain anatomy and this index of serotonin synthesis suggests independent mechanisms underlying the normal aging process.

123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Numerous findings indicate alterations in brain serotonin systems in obsessive-compulsive disorder (OCD). We investigated the in vivo availability of thalamus-hypothalamus serotonin transporters (SERT) in patients with DSM-IV OCD who displayed prominent behavioral checking compulsions (OC-checkers). Four hours after injection of [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT), single photon emission computed tomography (SPECT) scans were performed in 24 medication-free non-depressed OC-checkers and 24 age- and gender-matched healthy controls. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [(123)I]-beta-CIT brain binding was used (V''(3)=(thalamus and hypothalamus-cerebellum)/cerebellum). Drug-free non-depressed OC-checkers showed an 18% reduced brain serotonin transporter availability in the thalamus and hypothalamus, as compared with healthy control subjects (1.38+/-0.19 vs 1.69+/-0.21; p<0.001). There was a strong negative correlation between severity of OC symptomatology (Y-BOCS scores) and SERT availability (r=-0.80; p<0.001). Moreover, we found a significant positive correlation between illness duration and serotonin transporter availability (r=0.43; p<0.05). This first report of significantly reduced [(123)I]-beta-CIT binding in the thalamus-hypothalamus region in OC-checkers suggests reduced brain serotonin transporter availability, which is more pronounced with increased severity of OC symptomatology and short duration of illness. The results provide direct evidence for an involvement of the serotonergic system in the pathophysiology of OCD.

Review: Serotonin by stress interaction: a susceptibility factor for the development of depression?

A genetic predisposition to depression may be a potential risk factor in the development of depression. Although the neurobiological equivalent of the predisposition remains unclear, it seems as though the brain serotonin (5-HT) system plays an important mediating role. Therefore, individuals with a family history of depression (FH+) may be more likely to develop depression due to an innate vulnerability related to altered serotonergic neurotransmission in the brain. A major problem, however, is that the role of brain 5-HT in depression is complex and this serotonin-related innate vulnerability, by itself, is not sufficient enough to cause a depressive episode. In the search for additional factors, stress has received particular attention. Stressful life events influence and precede the onset of depression. Furthermore, depression is associated with stress hormone dysregulation and bidirectional interactions are thought to occur between stress-related changes in the neuroendocrine stress system and the 5-HT system. In the current review, we argue that healthy individuals with a positive family history of depression are more prone to develop depression due to a genetic 5-HT susceptibility, which deteriorates stress coping mechanisms and increases stress vulnerability.

A negative feedback system between brain serotonin systems and plasma active ghrelin levels in mice

Brain serotonin (5-hydroxytryptamine; 5-HT) systems contribute to regulate eating behavior and energy homeostasis. 5-HT2C receptors and 5-HT1B receptors have been shown to mediate anorexic effects of 5-HT drugs such as d-fenfluramine, which stimulates 5-HT release and inhibits 5-HT reuptake, and m-chlorophenylpiperazine (mCPP), a 5-HT2C receptor agonist. Here, we report that 24-h fasting increased the expression of hypothalamic 5-HT2C receptor and 5-HT1B receptor genes in association with increases in plasma active ghrelin levels compared with fed state in mice. Treatment with mCPP or fenfluramine significantly inhibited the increases in plasma active ghrelin levels. mCPP or fenfluramine significantly increased the expression of hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript genes while having no significant effects on the expression of hypothalamic neuropeptide Y, agouti- related protein, and ghrelin genes. These results suggest that there is a negative feedback system between brain 5-HT systems and plasma active ghrelin levels in energy homeostasis in mice.

Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

The biological effects of the melanin-concentrating hormone (MCH) are mediated by the melanin concentrating hormone receptor 1 (MCHR1) in mice. This receptor is enriched in brain areas that are involved in the modulation of mood and affect, suggesting that MCH-dependent signaling may influence neurobiological mechanisms underlying fear and anxiety processes. To test this, we have generated mice lacking functional MCHR1 and characterized phenotypic traits using a number of behavioral tests. Mice carrying a null mutation of the MCHR1 gene display anxiolytic-like behavior across a battery different behavioral paradigms commonly used to assess fear and anxiety responses in rodents: open field, elevated plus maze, social interaction, and stress-induced hyperthermia. The brain serotonin (5-HT) system is central to the control of mood- and anxiety-related processes. To examine the impact of MCHR1 receptor deletion on 5-HT neurotransmission, we used in vivo microdialysis in freely moving knockout and wild-type mice. Baseline dialysate 5-HT levels were significantly lower in MCHR1 knockout mice as compared with wild-type controls (9.53+/-0.24 fmol for wild types vs 6.91+/-0.36 fmol for knockouts) in the prefrontal cortex (PFC), one of the main target structures of the serotonergic system and one that is highly associated with the control of emotional processes. Moreover, forced swim increased 5-HT efflux in the PFC of wild-type but not MCHR1 knockout mice. In summary, we show that MCHR1 can modulate stress- and anxiety-like behaviors and suggest that this may be due to changes in serotonergic transmission in forebrain regions.