<p>Finding an indicator that can point to a high risk group for suicide has long been a desirable aid for the prevention of completed suicides. The studies reviewed in this essay presume that a biological aspect can point out the high risk individual. The focus of the studies lies on the serotonin 5-hydroxytryptamine (5-HT) monoamine neurotransmitter and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) which is the principal metabolite of 5-HT in depression. The studies on 5-HT metabolites have led to the belief that these may play a key role in the neurochemistry of suicidal behaviour. It is suggested that the core behavioural effect of low CSF 5-HIAA concentration might result in an increase in impulsive and violent behaviour to self and others. The predictability is based on the fact that patients with low CSF 5-HIAA are more prone to reattempt and complete suicide by violent means. A number of well-designed studies concerning suicidal individuals and control subjects have however not shown any difference in concentration of CSF 5-HIAA in suicide attempters compared to non-suicide attempters which could be explained by methodological flaws. Low CSF 5-HIAA does seem to characterize the high risk individual, but it is not yet determined what role it plays in actual suicidality.</p>

The aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats lesioned as neonates with the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At 3 days after birth Wistar rats were pretreated with desipramine (20 mg/kg ip) before bilateral icv administration of 5,7-DHT (37.5 μg base on each side) or saline-ascorbic (0.1%) vehicle (control). At 10 week levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were determined in frontal cortex, striatum, and hippocampus by an HPLC/ED technique. In the hypothalamus, frontal cortex, hippocampus and medulla oblongata, the level of histamine was analyzed by an immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped activity) were performed, and effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists S(+)chlorpheniramine (H1), cimetidine (H2), and thioperamide (H3) were determined. We confirmed that 5,7-DHT profoundly reduced contents of 5-HT and 5-HIAA in the brain in adulthood. Histamine content was also reduced in all examined brain regions. Moreover, in 5,7-DHT-lesioned rats the locomotor and oral activity responses to thioperamide were altered, and apomorphineinduced stereotype was intensified. From the above, we conclude that an intact central serotoninergic system modulates histamine H3 receptor antagonist effects on the dopaminergic neurons in rats.

As a first attempt at exploring an association between histaminergic and serotoninergic neuronal phenotypes in glucose regulation, the influence of the histamine H 3 receptor antagonist thioperamide on glucose uptake by brain was determined in rats in which the serotoninergic innervations of brain was largely destroyed perinatally. Male Wistar rats were initially treated on the 3rd day after birth with the serotoninergic neurotoxin 5,7- dihydroxytryptamine (5,7-DHT) (75 μg icv) or saline vehicle (10 μl icv). At 8 weeks lesioned and control rats were terminated in order to validate the effectiveness of 5,7-DHT: reduction in 5-HT and 5-HIAA by 83-91% and 69-83% in striatum, frontal cortex, and hippocampus (HPLC/ED method). Other groups of rats were pretreated with thioperamide (5.0 mg/kg ip) or saline vehicle 60 min prior to 6-[ 3 H]-D-glucose (500 μCi/kg ip). Fifteen-min later rats were decapitated and brains were excised and dissected to remove frontal cortex, striatum, hippocampus, thalamus/hypothalamus, pons, and cerebellum. Liquid scintillation spectroscopy was used to determine that [ 3 H]glucose uptake, which was enhanced in 5,7-DHT lesioned rats in cortex (by 88%), hippocampus, thalamus/hypothalamus, pons and cerebellum (each by 47-56%), and in striatum (by 35%). In contrast, thioperamide prevented the enhancement in [ 3 H]glucose uptake in all brain regions of 5,7-DHT neonatally lesioned rats; and [ 3 H]glucose levels were significantly different in all brain regions (except thalamus/hypothalamus) in thioperamide-versus saline-treated rats. These findings indicate a functional association between histaminergic and serotoninergic systems in brain in relation to glucose regulation.

Studies suggest that adoptees are at risk for a number of psychopathological behaviors. To understand the etiology of this risk, 150 socially housed rhesus macaques were studied, including 107 infants reared with their biological mothers and 43 infants reared with unrelated adoptive mothers. Mother-infant behaviors were recorded across the first 6 months of life. Analyses were performed using a hierarchical linear mixed model. All reported results were tested at p<0.05. Adopted infants were observed on average to approach and leave their mothers more frequently, explore the environment and locomote longer, exhibit more anxiety-like behavior, spend less time being held to their mother's breast, and were rejected by their mothers more when compared to nonadopted infants, indicating they are more likely responsible for maintaining the relationship. They also direct and receive more noncontact aggression on average to other social group members, and showed evidence of higher anxiety exhibiting high levels of anxiety-like self-directed behavior when compared to nonadopted infants. Also, results indicate that adopted infants have significantly lower levels of the CSF serotonin metabolites 5-hydroxyindoleacetic acid when compared to nonadopted infants.

Depression and other mood disorders, as well as cognitive and motor dysfunction have been linked with changes in monoamine levels in the brain. Environmental acetylcholinesterase (AChE) inhibitors, such as organophosphate insecticides (OPs), have also been shown to induce these problems. This study investigated whether insecticide-induced AChE inhibition, induced by chlorpyrifos (CPS), may contribute to the types of forebrain monoaminergic alterations associated with psychiatric, cognitive and motor dysfunction. Increased synaptic ACh, resulting from CPS-induced AChE inhibition, may alter the synthesis or release of monoamines through prolonged action of ACh on monoaminergic neurons that contain ACh receptors. Adult, male Sprague-Dawley rats were subjected to a single subcutaneous dose of CPS or corn oil vehicle. Brains were rapidly removed and the frontal cortex, hippocampus and striatum were bilaterally dissected on ice. These three regions from one side were assayed for AChE activity, while those from the opposite side were processed for high performance liquid chromatography with electrochemical detection (HPLC-ED) analysis of monoamine neurotransmitters and their metabolites. In the initial, exploratory experiment, inhibition of AChE activity was 66.8% in the frontal cortex, 43.8% in the hippocampus and 46.9% in the striatum, 7 days after a 60mg/kg dose of CPS. No significant differences in concentration of monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the hippocampus or striatum. However, in the frontal cortex of the CPS-treated rats there was a significant increase in median dihydroxyphenylacetic acid (DOPAC) concentration (P=0.019) and a very strong statistical trend toward increased dopamine (DA) concentration (P=0.0506). The second experiment examined the time course of AChE inhibition produced by a higher dose (200mg/kg) of CPS and how monoamine levels changed in conjunction with this pattern of AChE inhibition. Percent inhibition of AChE activity in CPS-treated animals, at 4, 14 and 21 days post-exposure was 77.0%, 86.6% and 81.9% in the frontal cortex, 86.1%, 85.9% and 83.2% in the hippocampus and 90.1%, 89.8% and 85.5% in the striatum. No significant differences in monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the hippocampus or striatum. A statistical trend toward a decrease in serotonin (5-HT) was seen in the frontal cortex at 14 days (P=0.0753) following CPS exposure. A very consistent, yet non-significant pattern of an increase in monoamines at 4 days post-CPS was observed in all instances, except for 5-hydroxyindoleacetic acid (5-HIAA) in the striatum. Therefore, the final experiment employed a more powerful design to focus on monoamine levels during, or shortly after, the change in AChE activity that rapidly follows exposure to 200mg/kg CPS. This experiment also employed a behavioral analysis on the day of sacrifice to assess the presence or absence of clinical signs of toxicity associated with this dose. Of the 30 CPS-treated rats, only 1 animal displayed a single behavioral sign of cholinergic poisoning. Percent inhibition of AChE activity at 2 and 4 days after treatment was 81.4% and 79.4% in the frontal cortex, 53.4% and 83.5% in the hippocampus, and 80.5% and 87.8% in the striatum. No significant changes in monoamine neurochemicals were observed between vehicle control and CPS-treated groups in either the frontal cortex or hippocampus. However, a significant increase in DOPAC (P=0.0285) in the striatum, 2 days after CPS treatment, was observed. In addition, a strong statistical trend toward decreased striatal 5-HT (P=0.0645) was reported 4 days after CPS treatment. The only significant correlation between AChE activity and monoamine concentration was observed for 5-HIAA in the striatum of CPS-treated, 2 day survivors (P=0.0445). However, it was of low magnitude (r=0.525, r2=0.276). CPS has a limited capacity to produce changes in monoamine neurotransmitters and/or their metabolites in the frontal cortex and striatum of the mammalian brain. These changes are primarily seen in the dopaminergic system. Alterations of monoamines do not appear to be strongly associated with incident levels of AChE inhibition. The biological implication of the limited OP induced changes in central monoamines remains significant, as changes in monoamines in the CNS nervous system have been linked to psychiatric, cognitive and motor dysfunction. / Master of Science

Finding an indicator that can point to a high risk group for suicide has long been a desirable aid for the prevention of completed suicides. The studies reviewed in this essay presume that a biological aspect can point out the high risk individual. The focus of the studies lies on the serotonin 5-hydroxytryptamine (5-HT) monoamine neurotransmitter and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) which is the principal metabolite of 5-HT in depression. The studies on 5-HT metabolites have led to the belief that these may play a key role in the neurochemistry of suicidal behaviour. It is suggested that the core behavioural effect of low CSF 5-HIAA concentration might result in an increase in impulsive and violent behaviour to self and others. The predictability is based on the fact that patients with low CSF 5-HIAA are more prone to reattempt and complete suicide by violent means. A number of well-designed studies concerning suicidal individuals and control subjects have however not shown any difference in concentration of CSF 5-HIAA in suicide attempters compared to non-suicide attempters which could be explained by methodological flaws. Low CSF 5-HIAA does seem to characterize the high risk individual, but it is not yet determined what role it plays in actual suicidality.

La 3,4-metilendioximetanfetamina (MDMA), una sustancia popularmente conocida como éxtasis, es una droga ilícita consumida habitualmente por adolescentes y adultos jóvenes. Además, el policonsumo es una práctica habitual entre los usuarios de la MDMA, siendo la cocaína una de las drogas más frecuentemente asociadas a esta sustancia. El objetivo del presente trabajo fue evaluar los efectos a corto y largo plazo que se producen tras la administración de la MDMA (5, 10, o 20 mg/kg) sola o en combinación con cocaína (25 mg/kg) en ratones adolescentes. En el estudio sobre el efecto agudo, observamos que ambas drogas administradas individual o simultáneamente incrementan la actividad motora. La dosis alta de MDMA disminuye de los contactos sociales en la prueba de la interacción social afectando igualmente el test de retención de la evitación pasiva. Sin embargo, sólo la co-administración de MDMA en combinación con cocaína produjo un efecto ansiolítico caracterizado por un aumento del tiempo de permanencia en los brazos abiertos del laberinto elevado en cruz. Igualmente, el análisis neuroquímico reveló que los ratones que recibieron MDMA en combinación con cocaína mostraron un incremento en el turnover de DA en el estriado, pero una disminución del de serotonina en la corteza. Los estudios de los efectos a largo plazo, realizados tres semanas después de haber finalizado un tratamiento con MDMA sola o en combinación con cocaína (2 administraciones por día durante 3 días consecutivos), mostraron que los ratones expuestos a la MDMA, sola o más cocaína, incrementaron el tiempo dedicado a las conductas sociales, aunque los que también habían recibido cocaína presentaban además conductas de amenaza. Observamos un efecto neurotóxico en los ratones tratados únicamente con 20 mg/kg de MDMA que mostraron un decremento de la concentración de DA en el estriado, no observándose este deterioro en los tratados además con cocaína. Por otra parte, mediante el condicionamiento de la preferencia de lugar (CPL) confirmamos que la MDMA posee efectos reforzantes y que esta sustancia es capaz de reinstaurar la preferencia de lugar una vez que esta se ha extinguido. La expresión y la reinstauración del CPL inducido por la MDMA dependen de la pauta de condicionamiento que condiciona los efectos neurotóxicos producidos por esta droga. Para finalizar, el tratamiento con MDMA sola o en combinación con cocaína durante la adolescencia favorece los efectos reforzantes de la MDMA durante el periodo adulto. Además, la exposición previa a la cocaína aumenta el tiempo necesario para extinguir la preferencia de lugar inducida por la MDMA. / 3,4-methylene-dioxy-methamphetamine (MDMA), commonly known as ecstasy, is an illicit recreational drug consumed by teenagers and young adults. The poly-drug pattern is the most common among those observed in MDMA users, with cocaine being a frequently associated drug. The aim of the present study was to evaluate the short- and long-term effects of exposure to MDMA (5, 10, or 20 mg/kg), alone or plus cocaine (25 mg/kg), on adolescent mice. In the acute phase, both drugs produced hyperactivity whether administered alone or concurrently. The highest MDMA dose decreased social contacts and affected the passive avoidance task. However, an anxiolytic effect, studied by means of the elevated plus maze and expressed as an increase in the time spent on the open arms, was observed only in animals treated with both cocaine and MDMA. Neurochemical analyses revealed an increase in striatal DA turnover and a decrease in serotonin cortical turnover in mice treated with MDMA plus cocaine. The studies conducted to establish long-term effects, which were performed 3 weeks after a 3-day treatment of two daily injections of MDMA alone or plus cocaine (6 administrations) during the adolescent period, showed that mice treated with MDMA alone and plus cocaine spent more time engaged in social contact, although those also treated with cocaine exhibited threat behaviors. Furthermore, we observed a neurotoxic effect in mice exposed to 20 mg/kg of MDMA, evident in a decrease in DA levels in the striatum, but this effect was not detected in mice additionally treated with cocaine. On the other hand, using the conditioned place preference (CPP), we have confirmed the rewarding effects of MDMA. In addition, we also show that MDMA can produce reinstatement of place preference after the extinction of this response. The expression and reinstatement of MDMA-induced CPP depend on the conditioning protocol, which conditions the neurotoxic effects produced by this drug. Finally, exposure during adolescence to MDMA alone or plus cocaine facilitates the rewarding effects of MDMA in adulthood. Moreover, previous experience of cocaine increases the time required to extinguish the MDMA-induced CPP.