Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5-HT Receptor Knockout Mice

Jones, M. D.; Lucki, Irwin

doi:10.1038/sj.npp.1300664

Cited by 100 publications

(62 citation statements)

References 55 publications

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“…Insofar as the reduced immobility of female Ucn-2-deficient mice resulted primarily from an increase in swimming behavior, their antidepressant-like phenotype may be linked to altered serotonergic neurotransmission. Interestingly, female, but not male, 5-HT 1B -deficient mice also selectively show reduced immobility in the forced-swim and tail-suspension tests (Jones and Lucki, 2005), putatively through a mechanism involving disinhibition of 5-HT signaling. Furthermore, several other studies have demonstrated a differential sensitivity of females to genetic deletion or polymorphisms of modulators of serotonin function (Bouali et al, 2003;Cornelissen et al, 2005;Jones and Lucki, 2005).…”

Section: Discussionmentioning

confidence: 99%

Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Chen¹,

Zorrilla²,

Smith³

et al. 2006

J. Neurosci.

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Gender differences in hypothalamus-pituitary-adrenal (HPA) axis activation and the prevalence of mood disorders are well documented. Urocortin 2, a recently identified member of the corticotropin-releasing factor family, is expressed in discrete neuroendocrine and stress-related nuclei of the rodent CNS. To determine the physiological role of urocortin 2, mice null for urocortin 2 were generated and HPA axis activity, ingestive, and stress-related behaviors and alterations in expression levels of CRF-related ligands and receptors were examined. Here we report that female, but not male, mice lacking urocortin 2 exhibit a significant increase in the basal daily rhythms of ACTH and corticosterone and a significant decrease in fluid intake and depressive-like behavior. The differential phenotype of urocortin 2 deficiency in female and male mice may imply a role for urocortin 2 in these gender differences.

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Section: Discussionmentioning

confidence: 99%

Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Chen¹,

Zorrilla²,

Smith³

et al. 2006

J. Neurosci.

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“…In contrast, female mice lacking 5-HT1B receptors exhibit reduced depressive behaviour, whereas male mice are similar to wild-type controls. Again, antidepressant treatment decreases immobility in both male and female 5-HT1B knockout mice (Jones and Lucki, 2005). Finally, female but not male 5-HT3 knockouts show depressive behaviour with enhanced immobility and decreased swimming levels during a second FST session (Bhatnagar et al, 2004).…”

Section: Sex Differences In Animal Models Of Depressionmentioning

confidence: 99%

Sex differences in animal models of psychiatric disorders

Kokras

Dalla

2014

British J Pharmacology

359

187

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Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both male and female animals in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories. LINKED ARTICLESThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-20 Abbreviations 5-HTT, 5-HT transporter; 8-OH-DPAT, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; Akt1, V-akt murine thymoma viral oncogene homologue 1; BDNF, brain-derived neurotrophic factor; BTBR, BTBR T + tf/J; CMS, chronic mild stress; COMT, catechol-O-methyltransferase-deficient mice; CR, conditioned response; CRF, corticotrophinreleasing factor; CS, conditioned stimulus; D1 receptor, dopamine 1 receptor; D2 receptor, dopamine 2 receptor; DISC1, disrupted-in-schizophrenia 1; Ehmt1, euchromatin histone methyltransferase 1; FBGRKO, forebrain glucocorticoid type II receptor (NR3C1) knockout; FSL, flinders sensitive rat line; FST, forced swim test; GSK3, glycogen synthase kinase 3; HAB, high anxiety-related behaviour rats; ICSS, intracranial self-stimulation; LAB, low anxiety-related behaviour rats; LI, latent inhibition; Mthfr, methylenetetrahydrofolate reductase; OCD, obsessive-compulsive disorder; PPI, prepulse inhibition; PTSD, post-traumatic stress disorder; SSRI, selective 5-HT re-uptake inhibitors; US, unconditioned stimulus; WKY, Wistar Kyoto IntroductionThe total disease burden for neuropsychiatric disorders in the European Union has been recently ...

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“…3b, unpaired Student's t test, P ϭ 0.037, Cohen's d ϭ 0.88). Immobility in the tail suspension test (TST) is believed to reflect diminished capacity for stress-alleviating behaviors, and reduced SERT function achieved with acute SSRI treatment decreases immobility (22). Despite differences in basal TST immobility, sensitivity to citalopram (20 mg/kg) appeared identical between genotypes (shown as % reduction in immobility over saline, Fig.…”

Section: Impact Of Slc6a4 Variation In Recombinant Inbredmentioning

confidence: 99%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5-HT Receptor Knockout Mice

Cited by 100 publications

References 55 publications

Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Sex differences in animal models of psychiatric disorders

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

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