Central Monoaminergic Activity Research Articles

Sex Differences in Forebrain Monoaminergic Response to Song Performance

In many species, successful reproduction is dependent on the ability to adjust social behavior in response to an ever-changing social environment. Because a sexual signal's value and meaning can differ between females and males, responses to those signals should also differ. One way individuals can modulate social behavior is through experience-dependent modulation of the sensory systems that process social signals. Central monoamines (norepinephrine, dopamine, serotonin) modulate neural sensitivity to social stimuli and are key regulators of experience-dependent neuroplasticity in vertebrate sensory systems. However, few studies have examined how exposure to different sexual signals influences monoaminergic activity in female compared to male sensory systems. We used Lincoln's sparrows (Melospiza lincolnii) to examine sex differences in how variation in the trill performance of song influences central monoaminergic activity in the auditory telencephalon. Trill performance measures the rate at which a song syllable is produced relative to the syllable's frequency bandwidth and is thought to reflect the difficulty with which songs are produced. High-performance trills are more threatening to males but more attractive to females. We found that the effects of trill performance on monoaminergic activity were sex-dependent. Relative to the response to low-performance songs, exposure to high-performance songs decreased noradrenergic activity in the caudomedial nidopallium, and tended to decrease serotoninergic activity in the caudomedial mesopallium and caudomedial nidopallium of the auditory telencephalon in females, but in males, the monoamine measurements were indistinguishable between song treatments. These results suggest that the mechanisms underlying sensory processing of male sexual signals differ between the sexes.

Stress in Neonatal Rats with Different Maternal Care Backgrounds: Monoaminergic and Hormonal Responses.

The first 2 weeks of life in rats are known as the stress hyporesponsive period because stress responses in pups are diminished as compared to adult animals. However, it is considered a critical period in development in which infant rats are susceptible to environmental events, such as stressful stimuli and quality of maternal care received. These early life events have long-lasting effects, shaping a variety of outcomes, such as stress responsivity. This study investigated the effects of maternal care and sex differences on the response to an aversive stimulus in rat pups from high (HL) and low licking (LL) mothers. Plasma corticosterone, oxytocin, and central monoaminergic activity in 13-day-old rats submitted to cold stress were analyzed. Stress increased plasma corticosterone and marginally decreased hypothalamic dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio. HL pups showed higher levels of plasma oxytocin than LL pups. The maternal effect was also detected in the hippocampus, in which 5-hydroxyindole-3-acetic acid/serotonin (5-HIAA/5-HT) ratio was increased in HL pups, independently of the sex and stress. Investigating the early life events is useful not only into understand the neurobiological and hormonal mechanisms underlying maternal and stressful influences on infant development into a healthy or psychopathological adult phenotype, but also to unveil the immediate outcomes on infancy.

Stress in neonatal rats with different maternal care backgrounds: monoaminergic and hormonal responses.

The first 2weeks of life in rats are known as the stress hyporesponsive period because stress responses in pups are diminished as compared to adult animals. However, it is considered a critical period in development in which infant rats are susceptible to environmental events, such as stressful stimuli and quality of maternal care received. These early life events have long-lasting effects, shaping a variety of outcomes, such as stress responsivity. This study investigated the effects of maternal care and sex differences on the response to an aversive stimulus in rat pups from high (HL) and low licking (LL) mothers. Plasma corticosterone, oxytocin (OT), and central monoaminergic activity in 13-day-old rats submitted to cold stress were analyzed. Stress increased plasma corticosterone and marginally decreased hypothalamic dihydroxyphenylacetic acid/dopamine ratio. HL pups showed higher levels of plasma OT than LL pups. The maternal effect was also detected in the hippocampus, in which 5-hydroxyindole-3-acetic acid/serotonin ratio was increased in HL pups, independently of the sex and stress. Investigating the early life events is useful not only into understand the neurobiological and hormonal mechanisms underlying maternal and stressful influences on infant development into a healthy or psychopathological adult phenotype, but also to unveil the immediate outcomes on infancy.

Melanoma tumors alter proinflammatory cytokine production and monoamine brain function, and induce depressive-like behavior in male mice

Depression is a commonly observed disorder among cancer patients; however, the mechanisms underlying the relationship between these disorders are not well known. We used an animal model to study the effects of tumor development on depressive-like behavior manifestation, proinflammatory cytokine expression, and central monoaminergic activity. Male OF1 mice were inoculated with B16F10 melanoma tumor cells and subjected to a 21-day behavioral evaluation comprising the novel palatable food (NPF) test and tail suspension test (TST). The mRNA expression levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, and tumor necrosis factor-alpha (TNF-α), were measured in the hypothalamus and hippocampus and the levels of IL-6 and TNF-α were measured in the blood plasma. We similarly determined the monoamine turnover in various brain areas. The tumors resulted in increasing the immobility in TST and the expression level of IL-6 in the hippocampus. These increases corresponded with a decrease in dopaminergic activity in the striatum and a decrease in serotonin turnover in the prefrontal cortex. Similarly, a high level of tumor development produced increases in the brain expression levels of IL-6 and TNF-α and plasma levels of IL-6. Our findings suggest that these alterations in inflammatory cytokines and monoaminergic system function might be responsible for the manifestation of depressive-like behaviors in tumor-bearing mice.

Corticotropin releasing factor influences aggression and monoamines: Modulation of attacks and retreats

Salmonids establish social hierarchies as a result of aggressive social interactions. The establishment of dominant or subordinate status is strongly linked to neuroendocrine responses mediated through the stress axis. In this study, we tested the effects of introcerebroventricular (icv) corticotropin releasing factor (CRF) on the behavioral outcome, plasma cortisol and monoamine function in trout subjected to a socially aggressive encounter. Rainbow trout were treated with an icv injection of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Fish were allowed to interact with a similarly sized conspecific for 15 min. Following the behavioral interaction, plasma cortisol and central monoamine concentrations were analyzed. Trout treated with CRF were victorious in approximately 66% of the aggressive encounters against aCSF-treated opponents. Trout injected with CRF exhibited a reduction in the total number of attacks and decreased latency to attack. When trout were divided into winners and losers, only victorious CRF-treated fish exhibited a reduced latency to attack and fewer retreats. Social stress increased cortisol levels in both winners and losers of aggressive interaction. This effect was enhanced with the additional stress incurred from icv injection of aCSF. However, icv CRF in addition to social stress decreased plasma cortisol in both winners and losers. While aggression stimulated significant changes in serotonergic and dopaminergic activity, the magnitude and direction were dependent on limbic brain region, CRF dose, and outcome of social aggression. With broad effects on aggressive behavior, anxiety, stress responsiveness, and central monoaminergic activity, CRF plays an important role in modulating the behavioral components of social interaction.

The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-γ, TNF-α and IL-6 cytokines following mitogen stimulation ( p < 0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan ( p < 0.005) and kynurenic acid ( p < 0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.

Psychosomatic concept of hyperthyroidism - Graves type: Behavioral and biochemical characteristics

In this study we test the hypothesis that specific behavioral and biochemical vulnerabilities characterize individuals with hyperthyroidism-Graves type, one of the classically cited "psychosomatic disorders". The sample included 24 subjects with Graves disease and 34 controls. All participants were evaluated for personality and temperament characteristics and for platelet MAO activity. A smaller group of panic disorder patients was tested with the same set of measures to ensure a validity of the study, especially regarding results on personality tests. Individuals with hyperthyroidism had lower platelet MAO activity and higher scores on histrionic (Hy), depressive (D) and hypochondriac (H) subscale on the MMPI-201 than normal controls. Their TPQ temperament scores were characterized by high Harm Avoidance, whereas other temperament traits were average. Platelet MAO activity was inversely correlated with the MMPI-201 psychopatic deviance scale (Pd) and positively correlated with the TPQ Reward Dependence scale. Our results provide support for the psychosomatic concept of Graves' disease. Personality features, temperament traits, and platelet MAO activity of hyperthyroid individuals are different from those in normal controls and correspond to those observed in anxiety disorders. We propose that the observed behavioral and biochemical similaritites between hyperthyroid and anxiety disorder patients represent an equicausality phenomenon, where the same underlying heritable factors, such as variable central monoaminergic activity coupled with temperament-related susceptibility to stress, facilitate phenotypic manifestation of a number of psychosomatic and psychialric disorders--including Graves disease. The observed correlations between personality traits and MAO activity provide support for the hypothesized functional relationship between the underlying central monoaminergic activity and temperament traits associated with anxiety, depression, and impulsivity.

Prediction of Clinical Response to Antidepressants in Patients with Depression: Neurophysiology in Clinical Practice

Brain monoaminergic neurotransmission is involved in the pathophysiology of various psychiatric disorders including depression. Reliable indicators of central monoaminergic activity might be helpful to specifically identify and differentiate dysfunctions in individual patients in order to selectively adjust medication and predict clinical response. In patients with depression, predictors of treatment response to serotonergic versus non-serotonergic (e.g., noradrenergic) antidepressants could be of considerable clinical relevance by avoiding unfavorable factors such as a prolonged duration of the disorder, risk of suicidality and therapy-resistance. Consequently, these tools might help to decrease direct and indirect costs of treatment. The loudness dependence of the N1/P2 component of auditory evoked potentials (LD) has been proposed as a noninvasive neurophysiological indicator of central serotonergic function. This review focuses on recent studies providing evidence for the validity of LD as an indirect serotonergic marker and highlights data on the clinical application in terms of prediction of treatment response in patients with depression.

Flumazenil-Induced Improvement of the Central Dopaminergic System in Rats with Acute Hepatic Failure

Several reports have demonstrated the alleviation of hepatic encephalopathy by flumazenil, an antagonist of benzodiazepine receptors. As changes in central monoaminergic activity are involved in the mechanisms for hepatic encephalopathy, the effects of flumazenil on central monoaminergic activity were evaluated in acute hepatic failure produced by ischemia-reperfusion injury in rats. Eighteen male Wistar rats were evenly assigned to three groups: sham-operated group given saline, liver-ischemic group given saline, and liver-ischemic group given flumazenil. Flumazenil (1 mg/kg) or saline (10 mL/kg) was intraperitoneally administered three times, at 1, 6, and 24 hours after 90 minutes of liver ischemia produced by occlusion of the left portal vein. The extracellular concentrations of neurotransmitter amino acids, monoamines, and their metabolites were determined in the striatum using a microdialysis procedure. Another set of 12 rats was subjected to liver ischemia, and the effect of flumazenil on spontaneous motor activity was examined after 24 hours. The extracellular concentration of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 39% of that in sham-operated animals 24 hours after surgery (P < 0.05), although the dopamine level did not change. The treatment with flumazenil completely abolished the decrease in the metabolite (P < 0.05). Although the glutamate level in the injured animals decreased to 42% of that in sham-operated animals (P < 0.05), no remarkable increase in the glutamate level was observed in animals treated with flumazenil. Spontaneous motor activity decreased 24 hours after surgery in animals subjected to liver ischemia. Flumazenil led to improvement of spontaneous motor activity 5 minutes after administration, but this effect was not observed after 30 minutes. The restoration of the central dopaminergic function may be a contributing factor in the improvement of hepatic encephalopathy.

Panic disorder: Psychobiological aspects of personality dimensions

Attempts to understand the underlying mechanisms of association between psychological factors and panic disorder have been mostly based on psychodynamic description. Evidence of the importance of serotonergic (5-HT) system in panic disorder (PD), however, has substanti ally increased in recent years. The objective of our study was to determine whether there was a specific personality profile of panic disorder patients and how it was related to possible neurobiological mechanisms underlying personality dimensions. Sample consisted of 14 inpatients with ICD-X diagnosis of panic disorder and 34 healthy control subjects. Personality dimensions were assessed by Minnesota Multiphasic Personality Inventory (MMPI-201) and Tridimensional Personality Questionnaire (TPQ). To assess central 5-HT function, platelet monoamine-oxidase (MAO) activity was measured. In panic disorder group, higher scores of histrionic, depressive and hypochondriac subscales and significant increase of harm avoidance (HA) scale as well as low MAO activity were found. Negative correlation was established between MAO activity and psychopathic deviance MMPI scale. The obtained results might indicate a specific personality profile of patients with panic disorder, which is characterized by high neuroticism, fearfulness, inhibition, shyness and apprehensive worry. Low MAO activity and high HA scores possibly indicate underlying hyperserotonergic state. The observed correlation between personality traits and MAO activity provide additional support for the hypothesized functional relationship between underlying central monoaminergic activity and temperament traits associated with anxiety, depression and impulsivity.

Effects of l-DOPA on aggressive behavior and central monoaminergic activity in the lizard Anolis carolinensis, using a new method for drug delivery

The dopamine (DA) precursor, l-DOPA (500 μg), was injected into living crickets, which were ingested (one each) by adult male Anolis carolinensis. This method of delivery elevated plasma l-DOPA and DA concentrations by ∼1000-fold. In contrast, plasma epinephrine (Epi) and norepinephrine (NE) were not influenced by l-DOPA treatment, although they were elevated following the consumption of the cricket. Lizards that ingested l-DOPA treated crickets had elevated l-DOPA in all brain regions measured, with DA and/or DOPAC also increased significantly in most brain regions studied. Despite increased DA levels in the striatum and nucleus accumbens as a response to l-DOPA, the treatment had no influence on general motor activity. Central serotonin, NE, and Epi systems were not affected in any brain region by oral l-DOPA treatment. In addition, aggression was inhibited by this dose of l-DOPA, even though there was no effect on serotonergic systems. This is surprising because controlling aggressive behavior is usually considered the province of serotonergic activity. Aggression was measured before and after treatment, and while saline-treated lizards retained the full vigor of aggressive activity, those fed a cricket injected with l-DOPA were only one-third as aggressive after treatment. As l-DOPA treatment did not affect general motor activity, the effect appears to be directly associated with aggression. This is supported by the observation that l-DOPA treatment delayed latency to eyespot darkening, which predicts the latency to aggression.

Smoking only explains part of the associations between platelet monoamine oxidase activity and personality.

Platelet monoamine oxidase (MAO) activity has been shown to be inversely associated with personality traits such as sensation seeking, impulsiveness and extraversion. Those personality traits have also been linked to vulnerability for substance abuse, e.g. tobacco smoking and early onset or "type 2" alcoholism. Compounds in cigarette smoke have been shown to be inhibitors of MAO, which has led several authors to claim that there is no association between alcoholism, which is the most studied psychiatric condition, and platelet MAO if the effect of smoking is removed. With regard to the association between personality and platelet MAO, authors have in general been cautious. In the present paper we describe a number of results which show that there is such an association, both in clinical series if the effect of smoking is removed and in series where smoking have never taken place. A cornerstone in this regard is the significant association between platelet MAO activity and both behaviour/personality, voluntary alcohol intake and biochemical measures of CNS serotonergic activity in non-human primates. Strong evidence that the regulation of platelet MAO activity takes place on a transcriptional level with an involvement of transcription factors, likely to also regulate central monoaminergic activity, are presented.

Serotonergic Responses to Corticosterone and Testosterone in the Limbic System

Glucocorticoids secreted peripherally during stressful events act on central monoaminergic systems. In particular, serotonergic mediation of social behavior, such as aggression and reproduction, may be affected by glucocorticoids. This study was undertaken to determine if systemically administered corticosterone would rapidly affect central monoaminergic activity. Male Anolis carolinensis (N = 8 each group) were injected intraperitoneally with 10 or 100 μg corticosterone, 10 μg testosterone, or saline. Twenty minutes after treatment, brains were rapidly dissected and frozen and then microdissected (punch diameter 300 μm) and analyzed by high-performance liquid chromatography. Serotonergic turnover (estimated by 5-hydroxyindoleacetic acid/serotonin) in the hippocampus and medial amygdala was significantly enhanced by systemic corticosterone. Both of these regions of the brain have been associated with social stress. Testosterone also enhanced turnover in the hippocampus. The effect of corticosterone and testosterone may be to modulate socially induced differences in serotonergic response. Rapid, but short-lived, glucocorticoid stimulation of serotonin release suggests a possible mechanism for mediation of changing social behavioral events.

Cerebrospinal Fluid Monoaminergic Metabolites Differ in Wild Anubis and Hybrid (Anubis hamadryas) Baboons: Possible Relationships to Life History and Behavior

This article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = −60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance.

CSF Monoamines, Age and Impulsivity in Wild Grivet Monkeys (Cercopithecus aethiops aethiops)

Brain monoaminergic activity has been associated with behaviors, such as impulsive risk-taking, that tend to peak during adolescence in humans and nonhuman primates. This study was designed to assess natural variation in monoamine neurotransmitter metabolism in relation to age and behavioral impulsivity in grivet monkeys (Cercopithecus aethiops aethiops) living in their native habitat and subject to natural ecological pressures. Cisternal cerebrospinal fluid, collected from 22 animals living in the Awash National Park, Ethiopia, was assayed for the major metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MHPG). Concentrations of HVA declined significantly from one year of age to older adulthood. Further, a significant curvilinear relationship was identified between age and the 5-HIAA/HVA ratio, with the trough coinciding with the period of adolescence. Finally, behavioral impulsivity, as measured by re-entering baited traps a second time after the animal had already been captured and sampled for CSF, was related to lower levels of MHPG. The results suggest that normal variation in central monoaminergic activity may have functional consequences in wild populations.

Effects of long-lasting voluntary running on the cerebral levels of dopamine, serotonin and their metabolites in the spontaneously hypertensive rat

The brain regional dopamine (DA) and serotonin (5-HT) levels and turnover were studied in the spontaneously hypertensive rat (SHR), following voluntary, long-lasting (7 weeks) wheel-running exercise. Groups of rats were sacrificed 1–2 h, 23–24 h or 47–48 h after termination on the last running session, and the cerebral tissue levels of 5-HT, 5-HIAA, DA and DOPAC were determined and compared to corresponding levels obtained in sedentary controls. In the exercised animals, there was a selective decrease in the limbic forebrain levels of DOPAC in the immediate post-exercise period (1–2 h), while the DA turnover (DOPAC/DA ratio) was not altered. In addition, the 5-HT and 5-HIAA levels in the serotoninergic nerve terminal limbic forebrain and the 5-HT turnover (5-HIAA/5-HT ratio) in the cell body-containing brain stem areas were decreased in the immediate post-exercise period. No significant changes in the DA, DOPAC, 5-HT or 5-HIAA levels, nor in the DA and 5-HT turnover, were obtained in the remainder of the brain regions analyzed, regardless of time after termination of running. Taken together, the present study indicates that voluntary exercise in the SHR gives rise to differentiated regional effects on brain DA and 5-HT levels and turnover, thus supporting the view that changes in central monoaminergic activity are involved in the functional effects of long-term exercise. Interestingly, the psychomotor-associated limbic forebrain areas appeared particularly susceptible.

Ventricular Cerebrospinal Fluid Monoamine Transmitter and Metabolite Concentrations Reflect Human Brain Neurochemistry in Autopsy Cases

Concentrations of dopamine (DA), its metabolites 3-methoxytyramine and homovanillic acid (HVA), noradrenaline (NA), its metabolites normetanephrine (NM) and 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT, serotonin), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in 14 brain regions and in CSF from the third ventricle of 27 human autopsy cases. In addition, in six cases, lumbar CSF was obtained. Monoamine concentrations were determined by reversed-phase liquid chromatography with electrochemical detection. Ventricular/lumbar CSF ratios indicated persistence of rostrocaudal gradients for HVA and 5-HIAA post mortem. Ventricular CSF concentrations of DA and HVA correlated positively with striatal DA and HVA. CSF NA correlated positively with NA in hypothalamus, and CSF MHPG with levels of MHPG in hypothalamus, temporal cortex, and pons, whereas CSF NM concentration showed positive correlations with NM in striatum, pons, cingulate cortex, and olfactory tubercle. CSF 5-HT concentrations correlated positively with 5-HT in caudate nucleus, whereas the concentration of CSF 5-HIAA correlated to 5-HIAA levels in thalamus, hypothalamus, and the cortical areas. These data suggest a specific topographic origin for monoamine neurotransmitters and their metabolites in human ventricular CSF and support the contention that CSF measurements are useful indices of central monoaminergic activity in man.

Monoamine oxidase activity in relation to psychiatric disorders: The state of the art

Monoamine oxidase (MAO; E.C. 1.4.3.4) activity in platelets is one of the few hitherto known biological markers which might be useful in clinical psychiatric practice. Thus, as is discussed in more detail below, there are obvious connections between platelet MAO activity and certain personality traits. In this way, however, low (and possibly high) platelet MAO activity is a marker for “vulnerability” rather than for illness. The present knowledge about relationships between temperament and central monoaminergic activity does not permit any definite conclusions about which monoamine system is involved. Available data, however, favour the notion that the activity of the serotonin system is most closely connected to the personality traits of interest. Thus, the simplest interpretation would be that there is a positive correlation between central serotonergic activity and platelet MAO activity. Such an interpretation is supported by the findings of a positive correlation between CSF levels of 5-HIAA and plate...

Monoamine Metabolite Levels in Rat CSF: Kinetic Studies

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.

In search of the mode of action of antidepressants 5-HTP/tyrosine mixtures in depressions

For a long time antidepressants have been considered to act via enhancement of central monoaminergic activity (due to reuptake or MAO inhibition). An alternative hypothesis holds that their action is based on down-regulation of monoaminergic activity (due to decrease in density or sensitivity of certain receptor populations). In this paper the likelihood of both hypotheses is discussed and the conclusion reached that the first one is the most plausible. The following arguments are discussed: (1) the 5-HT precursor 5-HTP, which is transformed to 5-HT in the brain, has antidepressant properties; (2) there are indications that the same holds true for tyrosine, a catecholamine precursor transformed in the brain to DA and NA; and (3) evidence was found that the effects of 5-HTP in depression are potentiated by tyrosine. Since activation rather than suppression of monoaminergic activity seems to be linked to antidepressant activity, it seems likely that the signs of decreased monoamine metabolism that have been demonstrated in certain types of depression are the expression of a primary metabolic deficit rather than a phenomenon secondary to receptor hypersensitivity. Further clinical studies of 5-HT/CA precursor combinations in depression are justified.