Serotonin Depletion-Induced Maladaptive Aggression Requires the Presence of Androgens

The sex hormone testosterone and the neurotransmitter serotonin exert opposite effects on several aspects of behavior including territorial aggression. It is however not settled if testosterone exerts its pro-aggressive effects by reducing serotonin transmission and/or if the anti-aggressive effect of serotonin requires the presence of the androgen. Using the resident intruder test, we now show that administration of the serotonin synthesis inhibitor parachlorophenylalanine (300 mg/kg x 3 days) increases the total time of attack as well as the percentage amount of social behavior spent on attack but not that spent on threat - i.e. that it induces a pattern of unrestricted, maladaptive aggression - in gonadectomized C57Bl/6 male mice receiving testosterone replacement; in contrast, it failed to reinstate aggression in those not given testosterone. Whereas these results suggest the pro-aggressive effect of testosterone to be independent of serotonin, and not caused by an inhibition of serotonergic activity, the pCPA-induced induction of maladaptive aggression appears to require the presence of the hormone. In line with these findings, pCPA enhanced the total time of attack as well the relative time spent on attacks but not threats also in wild-type gonadally intact male C57Bl/6 mice, but failed to reinstate aggression in mice rendered hypo-aggressive by early knock-out of androgen receptors in the brain (AR(NesDel) mice). We conclude that androgenic deficiency does not dampen aggression by unleashing an anti-aggressive serotonergic influence; instead serotonin seems to modulate aggressive behavior by exerting a parallel-coupled inhibitory role on androgen-driven aggression, which is irrelevant in the absence of the hormone, and the arresting of which leads to enhanced maladaptive aggression

Substantial Decrease in Comorbidity 5 Years After Gastric Bypass : A Population-based Study From the Scandinavian Obesity Surgery Registry

OBJECTIVE:: To evaluate effect on comorbid disease and weight loss 5 years after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity in a large nationwide cohort. BACKGROUND:: The number patients having surgical procedures to treat obesity and obesity-related disease are increasing. Yet, population-based, long-term outcome studies are few. METHODS:: Data on 26,119 individuals [75.8% women, 41.0 years, and body mass index (BMI) 42.8?kg/m] undergoing primary RYGB between May 1, 2007 and June 30, 2012, were collected from 2 Swedish quality registries: Scandinavian Obesity Surgery Registry and the Prescribed Drug Registry. Weight, remission of type 2 diabetes mellitus, hypertension, dyslipidemia, depression, and sleep apnea, and changes in corresponding laboratory data were studied. Five-year follow-up was 100% (9774 eligible individuals) for comorbid diseases. RESULTS:: BMI decreased from 42.8?±?5.5 to 31.2?±?5.5?kg/m at 5 years, corresponding to 27.7% reduction in total body weight. Prevalence of type 2 diabetes mellitus (15.5%–5.9%), hypertension (29.7%–19.5%), dyslipidemia (14.0%–6.8%), and sleep apnea (9.6%–2.6%) was reduced. Greater weight loss was a positive prognostic factor, whereas increasing age or BMI at baseline was a negative prognostic factor for remission. The use of antidepressants increased (24.1%–27.5%). Laboratory status was improved, for example, fasting glucose and glycated hemoglobin decreased from 6.1 to 5.4?mmol/mol and 41.8% to 37.7%, respectively. CONCLUSIONS:: In this nationwide study, gastric bypass resulted in large improvements in obesity-related comorbid disease and sustained weight loss over a 5-year period. The increased use of antidepressants warrants further investigation

On the anxiogenic influence of serotonin

Despite over half a century of research on the role of serotonin in modulating anxiety, no consensus exists as to if serotonin should be regarded as acting mainly anxiety-dampening or anxiety-enhancing. This question is the focus of this thesis, with special emphasis on the role of serotonin in upholding differences in anxiety between and within sexes, and on the issue why some but not others report enhanced anxiety when exposed to selective serotonin reuptake inhibitors (SSRIs). In paper I, we investigate the impact of serotonin elevation and depletion on inter-individual differences in anxiety-like behaviour of male Wistar rats as measured using an animal model of anxiety, the elevated plus maze (EPM). We also investigate biochemical correlates of temperament, mainly through gene expression analyses using real-time quantitative PCR (rt-qPCR). Briefly, these experiments indicate that more "anxious" rats display a gene expression profile suggesting a higher capacity for serotonin production, and are more prone to display enhanced such behaviour when acutely exposed to an SSRI and also that differences in baseline temperament are abolished by serotonin depletion. In paper II, we investigate the possible role of three serotonin receptor subtypes in mediating the anxiogenic effect of acute SSRI administration (as studied in paper I) and find evidence for SSRI-induced acute anxiogenesis being dependent on 5- HT6 signalling. In paper III, we show that the oft-reported difference in anxiety-like behaviour between the sexes is serotonin-dependent. Further underlining the importance of sex steroid vs. serotonin interactions for EPM behaviour, the results in paper IV suggest that castration of male rats abolishes inter-individual differences in EPM behaviour and that the anxiogenic effect of this treatment in non-anxious rats is reversed by serotonin depletion. In paper V, we employ rt-qPCR to explore the effects of short-term administration of a serotonin synthesis inhibitor and an SSRI, respectively, on the expression of serotonin-related genes in six brain areas, the aim being to shed light on to what extent a measurable change in gene expression is a common adaptive response to changes in extracellular serotonin levels. While many genes were unaffected, some were markedly influenced. In paper VI, we perform a post hoc analysis of patient level-data from a large number of placebo-controlled depression trials, the aim being to investigate the prevalence of enhanced anxiety following initiation of treatment (as commonly seen in patients with panic disorder). We note such reactions to be rare in this patient 4  population, and also find no support for a suicide-provoking effect of these substances, but, in contrast, reduced rating of suicidal ideation in SSRI-treated subjects already after one week of treatment. In summary, our studies suggest that i) SSRI-induced enhanced anxiety, in both animals and humans, is confined to subjects with high baseline anxiety, ii) that enhanced anxiety in animals is associated with indices of enhanced serotonergic activity, and iii) that inter-individual differences in anxiety are abolished by serotonin depletion. The importance of interactions between sex steroids and serotonin in this context gained support by the observation that sex differences in EPM behaviour were abolished by serotonin depletion, and that castration-induced anxiety in non-anxious males (unlike the effects on aggression and sexual behaviour of such treatment) could be reversed by serotonin depletion

Vattenkraftens påverkan på akvatiska ekosystem : en litteratursammanställning

Arbetet med EU:s ramdirektiv för vatten har visat att fysisk påverkan är det vanligaste vattenmiljöproblemet (European Environment Agency 2012). Inom detta område är vattenkraften en av de största påverkanskällorna. Mot bakgrund av detta har Vattenmyndigheterna tillsammans med Havs- och vattenmyndigheten genomfört ett gemensamt projekt i syfte att ta fram information och vägledning för hur vattenkraften och dess miljöpåverkan skall hanteras i arbetet med vattenförvaltningen. Inom ramen för detta projekt har föreliggande litteratursammanställning genomförts. Syftet är att utöka kunskapsunderlaget inom området vattenkraftens påverkan på den akvatiska miljön. Detta för att utveckla arbetet med karaktärisering och statusklassning av vattenförekomster samt förbättra bedömningsunderlaget inför de statushöjande åtgärder som skall genomföras. Den viktigaste fysiska förändringen som en följd av vattenkraftutbyggnad är tillkomsten av dammar. De innebär att barriäreffekter uppstår, det vill säga att förutsättningar för uppströms förflyttning samt nedströms transport av sediment och dött och levande organiskt material i systemet, begränsas eller hindras. Även i övrigt förändras den fysiska miljön, bland annat genom de morfologiska förändringar som blir resultatet av rensning, kanalisering och torrläggning. Andra följdverkningar av vattenkraftutbyggnad är förändringar i erosion, vattentemperatur, isförhållanden och vattenkvalitet.  Vattenkraft har också en omfattande inverkan på hydrologin i vattensystemet. Regleringen av nivåer och flöden i dammar och kraftverk innebär förändringar i det totala flödesmönstret (säsongsvariationen), men även kortsiktiga fluktuationer i vattenföring samt förändringar när det gäller extremt höga och låga flöden. Energiproduktionens årscykel innebär vanligen omvänd vattenföring i de reglerade älvarna där huvuddelen av årets flöde passerar under vinterhalvåret, medan vårfloden reduceras eller uteblir och flödena under sommar och höst är lägre än under oreglerade förhållanden. Korttidsreglering innebär att flödet kan ändras flera gånger på kort tid, inom dygnet eller till och med inom en timme. Nolltappning innebär att flödet genom och förbi kraftverket helt kan stängas av vilket torrlägger vattendraget eller skapar perioder med sjöliknande förhållanden nedströms. I reglerade sjöar är fluktuationerna större och vattennivåerna, sett över en årscykel, generellt sett väsentligt annorlunda jämfört med under oreglerade förhållanden.  De hydrologiska och morfologiska förändringarna omsätts i påverkan på de akvatiska ekosystemen. Förutom de direkta effekterna av dammar (barriärer) omvandlas vattensystemen från att vara mångformiga till mer homogena miljöer. Strömsatta partier med heterogena habitat däms över eller torrläggs vilket gör att strömvattenkrävande arter försvinner eller reduceras i antal. Primär- och sekundärproduktion samt omsättning av organiskt material påverkas negativt vilket innebär att systemets biologiska produktionspotential sänks. Bottenfauna- och fisksamhällen förändras. Riktning och omfattning beror av lokala förhållanden, regleringsintensitet m.m. Över huvud taget är förändringarna av floran och faunan omfattande när det gäller artsammansättning, tätheter av organismer och produktionsförutsättningar. Därmed förändras också den biologiska mångfalden.  De slutgiltiga effekterna på ekosystemet varierar stort mellan olika vattenkraftanläggningar. Det beror på skillnader i anläggningarnas tekniska utformning, de geologiska och hydrologiska förutsättningarna i avrinningsområdet, klimat, regleringspåverkan uppströms och nedströms, den akvatiska faunans och florans artsammansättning, effekter av annan mänsklig aktivitet m.m. Vissa effekter uppstår alltid oavsett om det är ett strömkraftverk eller ett reglerkraftverk, medan andra är mer kopplade till regleringen. Även interaktionen mellan vatten- och landmiljön påverkas. Översvämning/störning av landmiljön, deposition av sediment och organiskt material samt utbytet mellan yt- och grundvatten är exempel på processer som har långtgående inverkan på ekosystemens struktur och funktion i strandnära landmiljöer. Dessa processer förändras eller uteblir i samband med reglering/kraftutbyggnad.  Förutom de lokala effekterna av vattenkraftanläggningar, uppstår förändringar i vattensystemet som helhet. Dessa förändringar är i många fall kumulativa. Vattenkemin förändras på sätt som gör att effekterna kan spåras ute i Östersjön, bland annat som en följd av minskad uttransport av kisel. Transporten av material reduceras eller förändras i hela systemet, temperaturregimen blir annorlunda som en följd av höga vinterflöden, överdämning ändrar närsaltbalansen nedströms samt ökar emissionen av växthusgaser. Vattenkraften i vattenförvaltninge

Data from: Serotonin depletion-induced maladaptive aggression requires the presence of androgens

The sex hormone testosterone and the neurotransmitter serotonin exert opposite effects on several aspects of behavior including territorial aggression. It is however not settled if testosterone exerts its pro-aggressive effects by reducing serotonin transmission and/or if the anti-aggressive effect of serotonin requires the presence of the androgen. Using the resident intruder test, we now show that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (300 mg/kg x 3 days) increases the total time of attack as well as the percentage amount of social behavior spent on attack but not that spent on threat – i.e. that it induces a pattern of unrestricted, maladaptive aggression – in gonadectomized C57Bl/6 male mice receiving testosterone replacement; in contrast, it failed to reinstate aggression in those not given testosterone. Whereas these results suggest the pro-aggressive effect of testosterone to be independent of serotonin, and not caused by an inhibition of serotonergic activity, the pCPA-induced induction of maladaptive aggression appears to require the presence of the hormone. In line with these findings, pCPA enhanced the total time of attack as well the relative time spent on attacks but not threats also in wild-type gonadally intact male C57Bl/6 mice, but failed to reinstate aggression in mice rendered hypo-aggressive by early knock-out of androgen receptors in the brain (ARNesDel mice). We conclude that androgenic deficiency does not dampen aggression by unleashing an anti-aggressive serotonergic influence; instead serotonin seems to modulate aggressive behavior by exerting a parallel-coupled inhibitory role on androgen-driven aggression, which is irrelevant in the absence of the hormone, and the arresting of which leads to enhanced maladaptive aggression

Behavioral data

The .xlsx file contains raw data of behavioral parameters for individual mice as well as treatment and genotypes

Comparison between the resident intruder baseline test (Test 1) and post-treatment test (Test 2) in animals receiving saline or pCPA (300 mg/kg/day for three days) with respect to mean percentage of the total time of social interaction spent on threat, attack and social behavior, respectively.

<p>The tests lasted for 15 min. A. Testosterone-treated gonadectomized mice (saline: n = 9, pCPA: n = 9) (experiment I). B. Wild-type mice (saline: n = 10, pCPA: n = 9) (experiment II). * p < 0.05, ** p < 0.01, *** p < 0.001 against mice treated with (linear mixed model).</p

Mean duration of attacks (±SEM) in mice given saline or pCPA (300 mg/kg/day for three days).

<p>The test lasted for 15 min. A. Testosterone-treated gonadectomized mice (saline: n = 9, pCPA: n = 9) (experiment I). B. Wild-type mice (saline: n = 10, pCPA: n = 9) (experiment II). * p < 0.05, ** p < 0.01 compared to mice treated with saline (general linear model).</p

Ghrelin influences novelty seeking behavior in rodents and men.

Recent discoveries indicate an important role for ghrelin in drug and alcohol reward and an ability of ghrelin to regulate mesolimbic dopamine activity. The role of dopamine in novelty seeking, and the association between this trait and drug and alcohol abuse, led us to hypothesize that ghrelin may influence novelty seeking behavior. To test this possibility we applied several complementary rodent models of novelty seeking behavior, i.e. inescapable novelty-induced locomotor activity (NILA), novelty-induced place preference and novel object exploration, in rats subjected to acute ghrelin receptor (growth hormone secretagogue receptor; GHSR) stimulation or blockade. Furthermore we assessed the possible association between polymorphisms in the genes encoding ghrelin and GHSR and novelty seeking behavior in humans. The rodent studies indicate an important role for ghrelin in a wide range of novelty seeking behaviors. Ghrelin-injected rats exhibited a higher preference for a novel environment and increased novel object exploration. Conversely, those with GHSR blockade drastically reduced their preference for a novel environment and displayed decreased NILA. Importantly, the mesolimbic ventral tegmental area selective GHSR blockade was sufficient to reduce the NILA response indicating that the mesolimbic GHSRs might play an important role in the observed novelty responses. Moreover, in untreated animals, a striking positive correlation between NILA and sucrose reward behavior was detected. Two GHSR single nucleotide polymorphisms (SNPs), rs2948694 and rs495225, were significantly associated with the personality trait novelty seeking, as assessed using the Temperament and Character Inventory (TCI), in human subjects. This study provides the first evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also points to an association between food reward and novelty seeking in rodents