Decrease In Serotonergic Activity Research Articles

The role of blocking serotonin 2C receptor by fluoxetine in the treatment of bulimia

Fluoxetine serves as a primary drug for the pharmacological treatment of binge eating. Its activity usually consists in blocking 2C serotonin receptors. This may be considered to be controversial since agonists of this receptor are effective in pharmacological treatment of bulimia. Bulimia episodes occur as a result of a decrease in serotonergic activity in the central nervous system. The mechanism is clinically confirmed. Drugs which increase the activity of the serotonin system in suppressing binge eating proved effective. The anorexigenic effect of drugs which increase the activity of the serotonin system results from the stimulation of serotonin receptors and not from their blocking. Appetite regulation and binge eating are associated with the activity of the dopaminergic and serotonergic systems. Experimental studies conducted so far prove that the increase in dopaminergic activity in the structures of the reward system is caused by stimulation, and not blocking, of serotonin 2C receptors. The anorexigenic effect of proserotonin drugs may also result from the stimulation of type 3 serotonin receptors and possibly 2C on neurons located in the nucleus of solitary tract. The psychopharmacological investigation conducted in this paper revealed the role of 5-HT2C receptors in the pathogenesis of bulimia nervosa and the mechanism of action of fluoxetine in the treatment of binge eating. Based on existing knowledge, the fact that fluoxetine blocks these receptors does not appear to play a significant role in appetite suppression. Due to few experimental works, the problem requires further research.

Serotonin precursor (5-hydroxytryptophan) causes substantial changes in the fighting behavior of male crickets, Gryllus bimaculatus

This study demonstrates that injection of the serotonin precursor 5-HTP causes substantial changes in the behavioral state, fighting behavior and ability to establish winner-loser relationships in male crickets (Gryllus bimaculatus). The characteristic features of 5-HTP-treated crickets include an elevated posture, enhanced general activity, longer duration of fighting, enhanced rival singing and a decreased ability to produce a clear fight loser. In addition, 5-HTP-treated males showed a slightly delayed latency to spread their mandibles, a decreased number of attacks and an equal potential to win in comparison to controls (physiological solution-treated males). The obtained results imply a significant role for serotonin in the regulation of social status-related behaviors in G. bimaculatus. Specifically, these data indicate that a decrease in serotonergic activity may be functionally important for the control of loser behavior and that some behavioral features of dominant male crickets are likely to be connected with the activation of the serotonergic system.

Brain‐encysting trematodes and altered monoamine activity in naturally infected killifishFundulus parvipinnis

This paper presents novel evidence to address mechanisms by which trematode parasites effect behavioural changes in naturally infected fish hosts. California killifish Fundulus parvipinnis infected with the brain-encysting trematode Euhaplorchis californiensis display conspicuous swimming behaviours that render them 30 times more likely to be eaten by birds, the parasite's final host. Prevalence of E. californiensis reaches nearly 100% in most F. parvipinnis populations, with parasite biomass constituting almost 2% of F. parvipinnis biomass in some locations. Despite having thousands of cysts on their brains, infected fish grow and mature at rates comparable to those of uninfected populations. The lack of general pathology combined with the specificity of the altered behaviours suggests that the behavioural changes are due to parasite manipulation. The monoamine neurotransmitters serotonin and dopamine, which control locomotion and social behaviour in fishes and other vertebrates, were examined to explore the underlying mechanisms of this behaviour modification. Whereas previous studies were similarly conducted with experimentally infected fish, in this study, brain dopaminergic and serotonergic activity were analysed in naturally infected fish to assess how E. californiensis may alter F. parvipinnis monoamines in a naturally occurring system. A parasite density-associated decrease in serotonergic activity occurred in the hippocampus of naturally infected fish, as well as a decrease in dopaminergic activity in the raphe nuclei, suggesting that E. californiensis inhibits serotonin and dopamine signaling in naturally infected F. parvipinnis. The neurochemical profile of infected fish is consistent with the hypothesis that E. californiensis affects brain monoaminergic systems in order to induce impulse-driven, active, and aggressive behaviour in its hosts.

Sleep, Serotonin, and Suicide

The author hypothesizes that sleep loss associated with a decrease in serotonergic activity plays a significant role in attempted suicide. Recent research has emphasized the role of the economic recession on the occurrence of suicide, but with no attention paid to possible biological aspects. In this brief review, the association between sleep, the serotonergic system, and suicide is initially introduced. Then, with consideration of recent research, a hypothesis regarding the oc- currence of suicide is proposed. Finally, based on that hypothesis, three factors possibly germane to reducing suicides (sufficient sleep duration, activation of the serotonergic system, and activation of the prefrontal cortex) are discussed.

P02-302 Kynurenine involvement in pathogenesis of hyperkinetic children syndrome

Objectives:The aim of the study was to evaluate the response of different monoaminergic systems to psychostimulant treatment in children with mild form of hyperkinetic syndrome (HKS).Methods:The levels of N-methylnicotinamide (end product of kynurenine pathway of tryptophan metabolism), 5-hydroxyindoleacetic (product of serotonin pathway of tryptophan metabolism), homovanillic and vanillylmandelic acids were measured in daily (3 days) urine samples of children (30 patients, 7-11 years old) with mild HKS with normal intellect or borderline mental insufficience. Biochemical measurements were performed before and 3 weeks after sydnocarb medication (5-15 mg sydnocarb daily). (Sydnocarb is a psychostimulant introduced into the clinical practice in the Soviet Union in the 70th of XX century).Results:After 3 weeks of sydnocarb therapy there were found the improvement of children's clinical status in both groups. It was followed by a significant decrease in the excretion of homovanillic (by 45 %), vanillylmandelic (by 35 %) and 5-hydroxyindoleacetic (by 50 %) acids but by a significant increase in N-methylnicotinamide excretion (by 30%).Conclusions:Psychostimulant medication has revealed the involvement of kynurenine and serotonin in HKS pathogenetic mechanisms. There were found a reciprocal relationship between serotonergic and kynurenine systems. It is proposed the kynurenine hypothesis of pathogenesis of HKS. It is characterized by the decreased activity of kynurenine system in HKS children. Clinical improvement of HKS children under psychostimulant medication is connected with activation of kynurenine system along with the decrease of serotonergic activity.

Impact de la personnalité sur l’intensité du syndrome de sevrage alcoolique : une étude préliminaire avec le modèle de Cloninger

The personality of alcohol dependant patients as a factor influencing the intensity of the alcohol withdrawal syndrome has been seldom examined. Cloninger's biosocial model of personality describes four temperaments (novelty seeking, harm avoidance, reward dependence, persistence) which, except for persistence, are admittedly linked to specific central neurotransmitters, and three characters. Novelty seeking is linked with low levels of mesencephalic dopamine, harm avoidance with high levels of serotonin in the septo-hippocampic system and reward dependence with low levels of noradrenaline in the ascending pathways from the locus coeruleus to the limbic system. The same neurotransmitters pathways are known to be involved in alcohol withdrawal, with a decrease of dopaminergic activity in the mesolimbic system, a decrease of serotonergic activity in the nucleus accumbens and an increase of the noradrenergic system. In view of the similarities between the neurobiological systems involved in Cloninger's model and in the neurobiological changes occurring during the withdrawal period, one would expect to observe severe withdrawal symptoms more frequently for patients with high novelty seeking, low harm avoidance and low reward dependence. To test this hypothesis, alcohol dependent patients according to DSM IV classification criteria who have drunk in the last twenty four hours were included in the study and received a standardized withdrawal treatment. The withdrawal syndrome intensity was examined with repeated measures of CIWA-Ar, the scores of which were correlated with TCI-R. Twenty eight patients, between 30 et 65 years old and drinking 22,2 +/- 12 standard drinks per day were included. Antidepressant drugs, benzodiazepines and neuroleptics treatment introduced before hospitalisation were stopped or decreased as much as possible. A correlation matrix was carried out between all the variables which could influence withdrawal intensity (age at the hospitalisation, age at the begining of the dependance, ratio between the time of the dependance and the patients' age, the number of alcohol withdrawals carried out and the number of standard drinks per day), and showed a positive correlation between the number of standard drinks per day and withdrawal intensity at day 3 (r=0.7, p<0.000), at day 4 (r=0.52, p<0.005), at day 7 (r=0.41, p<0.036) and at day 8 (r=0.44, p<0.02); as between the ratio between the time of the dependance and the patients' age and withdrawal intensity at day 2 (r=0.43, p<0.03) and at day 5 (r=0.5, p<0.01). Therefore, partial correlations were calculated between the dimensions of personality and withdrawal intensity. The study showed a positive correlation between withdrawal intensity and harm avoidance from day 5 onwards (r=0.6 and P<0.003 at day 5, r=0.59 and P<0.004 at day 6, r=0.56 and P<0.006 at day 7, r=0.66 and P<0.001 at day 8), a negative correlation between withdrawal intensity and reward dependence at day 7 and 8 (r=- 0.45 and P<0.037 at day 7, r=- 0.49 and P<0.02 at day 8) and a negative correlation between withdrawal intensity and persistence from day 6 onwards (r=- 0.5 and P<0.017 at day 6, r=- 0.5 and P<0.019 at day 7, r=- 0.51 and P<0.014 at day 8). No correlation was found between withdrawal intensity and novelty seeking. The same relevant results were found again with the 22 patients without anti-depressant drugs' population. Personality dimensions seem to influence alcohol withdrawal intensity once the severe symptomatology is over, while high doses of anti withdrawal treatment in the first days of abstinence may decrease the influence of personality on withdrawal symptoms. The positive correlation between harm avoidance and withdrawal intensity seems to invalidate our neurobiological hypotheses, but can be explained by clinical observations and corroborate studies assessing the influence of personality in benzodiazepine withdrawal intensity and in pain perception. This result encourages the introduction of support therapy during withdrawal and a cognitive-behavioural therapy before withdrawal in order to decrease patients' sensitivity to anxiety. The negative correlation between reward dependence and withdrawal intensity confirms the neurobiological hypotheses, but the weak correlation demands to be cautious in the interpretation of the results. The negative correlation between persistence and withdrawal intensity was expected. The characteristics associated with persistence seem to act as protective factors during alcohol withdrawal, whereas those associated with harm avoidance appear to increase the symptoms of alcohol withdrawal. In contrast, the neurobiological hypotheses are only partially confirmed.

P.6.a.007 Risks and pattern of alcohol withdrawal delirium

P.6.a.007 Risks and pattern of alcohol withdrawal delirium

Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats

The forced swim test (FST) has been considered as a pharmacologically valid test of the depressive syndrome in rodents. However, few studies have focused on neurochemical and behavioral responses during FST in both male and female rats. Thus, we investigated certain behavioral and neuroendocrine responses as well as the serotonergic activity after the application of FST in both sexes. Our data show that the duration of immobility was increased in both male and female rats during the 2nd session of the FST. Sex differences are observed in some behavioral responses, such as head swinging that is mostly present in male rats. In female rats FST induced a decrease in serotonergic activity in hippocampus and hypothalamus while in male rats it induced an increase in serotonergic activity in hypothalamus. Corticosterone serum levels were elevated in both sexes. However, hippocampal GR mRNA levels tended to be increased in males and females respectively. Moreover, hypothalamic serotonin (5-HT) 1A mRNA levels were decreased in female rats while in male rats hippocampal 5-HT 1A mRNA levels were increased. These data have shown that FST induces “depressive like symptoms” in both sexes and provide evidence that sex differences characterize certain behavioral aspects in the FST. Notably, hippocampal and hypothalamic serotonergic activity has been differentially modified in male rats compared with female rats and these neurochemical findings could be relevant to the differentiated expression of 5-HT 1A receptor. Hypothalamic–pituitary–adrenal axis activity was also affected by FST application in a sex specific manner. The present results support that FST induced behavioral, neurochemical and neurobiological alterations, which are sex dependent.

Sex differences in serotonergic activity in dorsal and median raphe nucleus

There is evidence on the existence of sex differences in the serotonergic system of the raphe. This study examines sex-based differences in serotonergic activity in the dorsal (DRN) and median (MRN) raphe nucleus; two structures that have consistently been implicated in the brain circuitry associated with fear and anxiety reactions. We also analyzed the effects of the elevated plus-maze (EPM) test, which allows the measuring of behavioral reactions to stress on rats produced by fear to height and open spaces on such sex differences. The present study was carried out on 70- to 80-day-old rats exposed or not to the EPM test. Immediately after the test, or 10–12 days later, groups of animals were sacrificed to measure serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) concentration in the DRN and MRN, to calculate the serotonergic activity ([5-HIAA]/[5-HT]). Serotonergic activity in the female's DRN was consistently higher than in male's DRN. Such differences were not observed in the MRN. While exposed to the EPM test, female rats display more aversive responses than males, only during the day of diestrus 1. After the EPM test, serotonergic activity decreased in the female's DRN and in the male's MRN, both immediately and 10–12 days later. The sex-based differences in fear/anxiety reported in this study could be linked to the observed decrease in serotonergic activity in the DRN of female rats after the EPM test.

Monoaminergic changes associated with socially induced sex reversal in the saddleback wrasse

The process of sex reversal in fishes is socially mediated and requires a total reorganization of the hypothalamo–pituitary–gonadal axis. When the ratio of males to females in a population of saddleback wrasse ( Thalassoma dupperrey) is too low, the largest female becomes male over the course of 6 to 8 weeks. This event requires the conversion of external social cues into internal chemical cues. In an attempt to investigate the role monoamines might play in this process, two females were housed together in floating enclosures in order to induce sex reversal in the larger. Brains were sampled at various time points throughout the process of sex reversal. Monoamines were measured in the amygdala, preoptic area, ventral hypothalamus, locus coeruleus and raphe nucleus. Changes were demonstrated in monoamine metabolism for all brain regions examined. The most important changes in monoamine-system activation were seen during the first week of sex reversal. It is during this time that transitional animals undergo behavioral sex reversal. There is an increase in serotonergic activity in the amygdala which is likely related to territorial acquisition. The absence of male aggression results in a less stressful environment for the female and a reduction in serotonergic activity in the preoptic area allowing for an increase in noradrenergic activity potentially triggering the reorganization of the reproductive axis. In the ventral hypothalamus, there is a decrease in noradrenergic and increase in dopaminergic activity associated with this change from female to male. The locus coeruleus shows an increase in noradrenergic activity later in the process of sex reversal which is probably a response to more circulating androgens. In the raphe nucleus, there is a decrease in serotonergic activity at the time of behavioral sex reversal. This decrease in serotonergic activity is linked to the behavioral component of sex reversal. This study suggests that monoamines play a very important role in both behavioral and gonadal sex reversal in the saddleback wrasse, the former under the control of serotonin in the raphe and the latter mediated via serotonergic effects on norepinephrine in the preoptic area.

Chronic morphine increases GABA tone on serotonergic neurons of the dorsal raphe nucleus: association with an up-regulation of the cyclic AMP pathway

Major adaptations after chronic exposure to morphine include an up-regulation of the adenosine 3′,5′-monophosphate pathway. Acute opioids, via μ-opioid receptors, disinhibit midbrain serotonergic neurons by suppressing inhibitory GABAergic transmission in the dorsal raphe nucleus and adjacent periaqueductal gray. This study examined whether chronic morphine induces a compensatory increase in GABA inputs to 5-hydroxytryptamine neurons and whether this was associated with an up-regulation of the adenosine 3′,5′-monophosphate pathway. The firing rate of serotonergic neurons was reduced in brain slices from morphine-dependent rats, an effect reversed by the GABA A antagonist bicuculline. The reduction in firing rate was accompanied by an increased frequency of spontaneous GABAergic inhibitory postsynaptic currents, indicating increased GABA tone in the slice. The increase in GABA tone in brain slices from dependent rats was associated with increased induction of inhibitory postsynaptic currents by the adenylyl cyclase activator forskolin, suggesting an up-regulation of the adenosine 3′,5′-monophosphate pathway. Indeed, chronic morphine increased levels of adenylyl cyclase VIII (but not of adenylyl cyclase I, III or V) immunoreactivity in the dorsal raphe nucleus area. Two adenosine 3′,5′-monophosphate-mediated mechanisms for the increase in GABA tone were discerned. The first, which predominated when impulse-flow was blocked by tetrodotoxin, involves protein kinase A since it was sensitive to protein kinase A inhibitors. The second, seen when impulse-flow was intact (i.e. absence of tetrodotoxin), was insensitive to protein kinase A inhibitors but was suppressed by ZD7288, a blocker of hyperpolarizing-activated I h channels which are directly activated by adenosine 3′,5′-monophosphate. We conclude that chronic morphine induces an up-regulation of the adenosine 3′,5′-monophosphate pathway in GABAergic inputs to serotonergic cells, resulting in an increase in spontaneous and impulse-flow dependent GABA release. These changes would lead to an increase in GABA tone and subsequently to the reported decrease in serotonergic activity during opiate withdrawal.

Biphasic effects of pu-chung-i-chi-tang on sedation and excitation.

The biphasic effects of Pu-Chung-I-Chi-Tang (PCT) on sedation and excitation in acute treatment or after one-week consecutive treatment were studied. The results indicated that PCT produces sedation in acute treatment and excitation after one-week consecutive treatment. The sedative mechanism of PCT in acute treatment might be due to an increase in serotonergic activity and a decrease in dopaminergic activity. However, the excitatory mechanism of PCT after one-week consecutive treatment might involve the increase in dopaminergic activity and the decrease in serotonergic activity.

Changes in CSF neurotransmitters in infantile spasms

Cerebrospinal fluid (CSF) from 7 patients with infantile spasms (mean age: 6.7 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of neurotransmitter metabolites was analyzed using high-performance liquid chromatography and compared to the metabolite concentration in the CSF from 7 age-matched controls (mean age: 6.1 months). Pretreatment levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, 3-methoxy-4-hydroxyphenyl glycol (MHPG), and kynurenine were significantly lower in infantile spasm patients compared to controls. Following treatment, marked increases in 5-HIAA and decreases in kynurenine levels were observed in the CSF of the 5 infants whose seizures were eliminated or reduced by ACTH. In the 2 nonresponders 5-HIAA levels decreased. The level of MHPG was reduced slightly in 5 infants, including the 2 nonresponders, and was increased in 2 responders. CSF homovanillic acid levels increased in 4 infantile spasm infants and decreased in 3 following ACTH. These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms. The possibility that elimination of seizures by ACTH may be related to decreased production of certain kynurenine metabolites, particularly quinolinic acid, is discussed.

Studies on CSF tryptophan metabolism in infantile spasms

Cerebrospinal fluid from 8 patients with infantile spasms (mean age: 6.1 months) was collected before treatment. The concentration of cerebrospinal fluid tryptophan metabolites was analyzed using high-performance liquid chromatography and compared to metabolite concentrations in cerebrospinal fluid from 20 age-matched controls (mean age: 5.8 months). The levels of cerebrospinal fluid serotonin, 5-hydroxyindoleacetic acid, and kynurenine were significantly lower in infantile spasm patients compared to controls ( P < .05). In contrast, the levels of cerebrospinal fluid 3-hydroxykynurenine were significantly higher in infantile spasm patients than in controls ( P < .05). There were no significant differences in the levels of cerebrospinal fluid tryptophan and 5-hydroxytryptophan. Although the study population was small, these findings suggest that the presence of seizures in infantile spasms is associated with a decrease in serotonergic metabolites which, in turn, may indicate a decrease in serotonergic activity, altered clearance of these metabolites, or altered turnover in the direction of 3-hydroxykynurenine. The perturbance caused by increased 3-hydroxykynurenine and decreased kynurenine in the homeostatic balance between these 2 tryptophan metabolites could further contribute to the pathogenesis of infantile spasms.