Cytochrome P450 2D (CYP2D) enzyme dysfunction associated with aging and serotonin deficiency in the brain and liver of female Dark Agouti rats.

Among the enzymes that support brain metabolism, cytochrome P450 (CYP) enzymes occupy an important place. These enzymes catalyze the biotransformation pathways of neuroactive endogenous substrates (neurosteroids, neurotransmitters) and are necessary for the detoxification processes. The aim of the present study was to assess changes in the CYP2D activity and protein level during the aging process and as a result of serotonin deficiency in the female brain. The CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) female rats (mature 15-week-old and senescent 18-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent female rats. The CYP2D activity in mature WT Dark Agouti females was independent of the changing phases of the estrous cycle. In senescent WT females rats, the CYP2D activity and protein level were decreased in the cerebral cortex, hippocampus, cerebellum and liver, but increased in the brain stem. In the other examined structures (frontal cortex, hypothalamus, thalamus, striatum), the enzyme activity did not change. In aging TPH2-deficient females, the CYP2D activity and protein levels were decreased in the frontal cortex, hypothalamus and brain stem (activity only), remaining unchanged in other brain structures and liver, relative to senescent WT females. In summary, the aging process and TPH2 deficit affect the CYP2D activity and protein level in female rats, which may have a negative impact on the compensatory capacity of CYP2D in the synthesis of serotonin and dopamine in cerebral structures involved in cognitive and emotional functions. In the liver, the CYP2D-catalyzed drug metabolism may be diminished in elderly females. The results in female rats are compared with those obtained previously in males. It is concluded that aging and serotonin deficiency exert sex-dependent effects on brain CYP2D, which seem to be less favorable in females concerning CYP2D-mediated neurotransmitter synthesis, but beneficial regarding slower neurosteroid metabolism.

The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer's Disease.

BACKGROUND: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer's disease (AD). However, 5-HT'ergic signaling is also suggested to reduce the production of pathogenic amyloid-ß (Aß). OBJECTIVE: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice. METHODS: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (-/-) were allowed to survive until 6 months old with APP/PS1, Tph2-/-, and wildtype mice. Survival and weight were recorded. Levels of Aß42/40/38, soluble APPα (sAßPPα) and sAßPPß, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aß were visualized histologically. RESULTS: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aß42 and Aß40 in neocortex and hippocampus, and with only mild changes of soluble Aß42/Aß40. However, sAßPPα and sAßPPß in hippocampus and Aß38 and Aß40 in cerebrospinal fluid were reduced. 3xTg-/-mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2-/- mice. Microglia clustered around Aß plaques regardless of genotype. CONCLUSION: The results suggest that Tph2 inactivation influences AßPP processing, at least in the hippocampus, although levels of Aß are unchanged. The reduced viability of 3xTg-/-mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

Serotonin (5-HT) influences brain development and has predominantly excitatory neuromodulatory effects on the neural respiratory control circuitry. Infants that succumb to sudden infant death syndrome (SIDS) have reduced brainstem 5-HT levels and Tryptophan hydroxylase 2 (Tph2). Furthermore, there are age- and sex-dependent risk factors associated with SIDS. Here we utilized our established Dark Agouti transgenic rat lacking central serotonin KO to test the hypotheses that CNS 5-HT deficiency leads to: (1) high mortality in a sex-independent manner, (2) age-dependent alterations in other CNS aminergic systems, and (3) age-dependent impairment of chemoreflexes during post-natal development. KO rat pups showed high neonatal mortality but not in a sex-dependent manner and did not show altered hypoxic or hypercapnic ventilatory chemoreflexes. However, KO rat pups had increased apnea-related metrics during a specific developmental age (P12-16), which were preceded by transient increases in dopaminergic system activity (P7-8). These results support and extend the concept that 5-HT per se is a critical factor in supporting respiratory control during post-natal development.

Serotonin Deficiency Is Associated With Delayed Gastric Emptying.

BACKGROUND & AIMS: Gastrointestinal (GI) motility is regulated by serotonin (5-hydroxytryptamine [5-HT]), which is primarily produced by enterochromaffin (EC) cells in the GI tract. However, the precise roles of EC cell-derived 5-HT in regulating gastric motility remain a major point of conjecture. Using a novel transgenic mouse line, we investigated the distribution of EC cells and the pathophysiologic roles of 5-HT deficiency in gastric motility in mice and humans. METHODS: We developed an inducible, EC cell-specific Tph1CreERT2/+ mouse, which was used to generate a reporter mouse line, Tph1-tdTom, and an EC cell-depleted line, Tph1-DTA. We examined EC cell distribution, morphology, and subpopulations in reporter mice. GI motility was measured in vivo and ex vivo in EC cell-depleted mice. Additionally, we evaluated 5-HT content in biopsy and plasma specimens from patients with idiopathic gastroparesis (IG). RESULTS: Tph1-tdTom mice showed EC cells that were heterogeneously distributed throughout the GI tract with the greatest abundance in the antrum and proximal colon. Two subpopulations of EC cells were identified in the gut: self-renewal cells located at the base of the crypt and mature cells observed in the villi. Tph1-DTA mice displayed delayed gastric emptying, total GI transit, and colonic transit. These gut motility alterations were reversed by exogenous provision of 5-HT. Patients with IG had a significant reduction of antral EC cell numbers and 5-HT content, which negatively correlated with gastric emptying rate. CONCLUSIONS: The Tph1CreERT2/+ mouse provides a powerful tool to study the functional roles of EC cells in the GI tract. Our findings suggest a new pathophysiologic mechanism of 5-HT deficiency in IG.

Serotonin depletion reduces both acquisition and expression of context-conditioned fear.

OBJECTIVE: Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. METHODS: Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. RESULTS: The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. CONCLUSION: Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

Ursolic acid enhances stress resistance, reduces ROS accumulation and prolongs life span in C. elegans serotonin-deficient mutants.

INTRODUCTION: Depression and anxiety disorders contribute to the global disease burden. Ursolic acid (UA), a natural compound present in many vegetables, fruits and medicinal plants, was tested in vivo for its effect on (1) enhancing resistance to stress and (2) its effect on life span. METHODS: The compound was tested for its antioxidant activity in C. elegans. Stress resistance was tested in the heat and osmotic stress assay. Additionally, the influence on normal life span was examined. RT-PCR was used to assess possible serotonin targets. RESULTS: UA prolonged the life span of C. elegans. Additionally, UA significantly lowered reactive oxygen species (ROS). Molecular docking studies, PCR analysis and microscale thermophoresis (MST) supported the results that UA acts through serotonin receptors to enhance stress resistance. DISCUSSION: Considering the urgent need for new and safe medications in the treatment of depression and anxiety disorders, our results indicate that UA may be a promising new drug candidate.

Neonatal Serotonin Depletion Induces Hyperactivity and Anxiolytic-like Sex-Dependent Effects in Adult Rats.

The serotoninergic system plays an important role in the ontogeny of the mammalian central nervous system, and changes in serotonin production during development may lead to permanent changes in brain cytoarchitecture and function. The present study investigated the programming effects of neonatal serotonin depletion on behavior and molecular components of the serotoninergic system in adult male and female rats. Subcutaneous para-chlorophenylalanine (pCPA) administration (100 mg kg-1) was performed daily on postnatal days 8-16 to deplete brain serotonin content. During adulthood, elevated plus-maze, open field, social interaction, forced swimming, and food, saline, and sucrose intake tests were performed. Relative expression of serotonin neurotransmission components in several brain areas was determined by qPCR. Additionally, serotonin immunofluorescence and neuropeptide mRNA expression were assessed in dorsal raphe (DRN) and paraventricular (PVN) nuclei, respectively. Rat performance in behavioral tests demonstrated a general increase in locomotor activity and active escape behavior as well as decreased anxiety-like behavior after neonatal brain serotonin depletion. The behavioral programming effects due to neonatal serotonin depletion were more pronounced in females than males. At the gene expression level, the mRNA of Tph1 and Tph2 were lower in DRN while Htr2c was higher in the amygdala of pCPA-treated males, while Htr1a, Htr2c, Oxt, Avp, Crh, and Trh were not different in any treatments or sex in PVN. The results indicate that neonatal serotonin depletion has long-term consequences on locomotion and anxiety-like behavior associated with long-lasting molecular changes in the brain serotoninergic system in adult rats.

The effect of ageing and cerebral serotonin deficit on the activity of cytochrome P450 2D (CYP2D) in the brain and liver of male rats.

Brain cytochrome P450 (CYP) contributes to the local metabolism of endogenous substrates and drugs. The aim of present study was to ascertain whether the cytochrome P450 2D (CYP2D) activity changes with ageing and in cerebral serotonin deficit. Kinetics of 5-methoxytryptamine O-demethylation to serotonin was studied and the CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) rats (mature 3.5-month-old and senescent 21-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent rats. The CYP2D activity and protein level decreased in the frontal cortex of senescent WT rats, but increased in senescent TPH2-deficient rats (compared to senescent WT). In contrast, in the hippocampus, hypothalamus and striatum the CYP2D activity/protein level increased with ageing, but did not change in senescent TPH2-deficient animals (compared to senescent WT). The activity and protein level of liver CYP2D was lower in senescent WT rats than in the mature animals and further decreased in senescent TPH2-deficient rats. In conclusion, ageing and TPH2-deficit affect the CYP2D activity and protein level, which may have a positive impact on neurotransmitter synthesis in brain structures involved in cognitive, emotional or motor functions, but a negative effect on drug metabolism in the liver.

RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis.

Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.

Mice Lacking Brain-Derived Serotonin Have Altered Swallowing Function.

The intricate sensorimotor neural circuits that control swallowing are heavily reliant on serotonin (5-hydroxytryptamine [5-HT]); however, the impact of 5-HT deficiency on swallow function remains largely unexplored. We investigated this using mice deficient in tryptophan-hydroxylase-2 (TPH2), the enzyme catalyzing the rate-limiting step in 5-HT synthesis. Videofluoroscopy was utilized to characterize the swallowing function of TPH2 knockout (TPH2-/-) mice as compared with littermate controls (TPH2+/+). Results showed that 5-HT deficiency altered all 3 stages of swallowing. As compared with controls, TPH2-/- mice had significantly slower lick and swallow rates and faster esophageal transit times. Future studies with this model are necessary to determine if 5-HT replacement may rescue abnormal swallowing function. If so, supplemental 5-HT therapy may have vast applications for a large population of patients with a variety of neurologic disorders resulting in life-diminishing dysphagia, particularly amyotrophic lateral sclerosis and Parkinson's disease, for which 5-HT deficiency is implicated in the disease pathogenesis.

Enhancement of Aggression Induced by Isolation Rearing is Associated with a Lack of Central Serotonin.

Isolation rearing (IR) enhances aggressive behavior, and the central serotonin (5-hydroxytryptamine, 5-HT) system has been linked to IR-induced aggression. However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/- and Lmx1b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1b-/- mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1b-/- mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1b-/- mice. Our results link the serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.

Brain serotonin deficiency affects female aggression.

The neurotransmitter serotonin plays a key role in the control of aggressive behaviour. While so far most studies have investigated variation in serotonin levels, a recently created tryptophan hydroxylase 2 (Tph2) knockout mouse model allows studying effects of complete brain serotonin deficiency. First studies revealed increased aggressiveness in homozygous Tph2 knockout mice in the context of a resident-intruder paradigm. Focussing on females, this study aimed to elucidate effects of serotonin deficiency on aggressive and non-aggressive social behaviours not in a test situation but a natural setting. For this purpose, female Tph2 wildtype (n = 40) and homozygous knockout mice (n = 40) were housed with a same-sex conspecific of either the same or the other genotype in large terraria. The main findings were: knockout females displayed untypically high levels of aggressive behaviour even after several days of co-housing. Notably, in response to aggressive knockout partners, they showed increased levels of defensive behaviours. While most studies on aggression in rodents have focussed on males, this study suggests a significant involvement of serotonin also in the control of female aggression. Future research will show, whether the observed behavioural effects are directly caused by the lack of serotonin or by potential compensatory mechanisms.

Increased central cholinergic drive contributes to the apneas of serotonin-deficient rat pups during active sleep.

Infant rat pups lacking central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT) have unstable breathing during prolonged periods of active sleep. Given that cholinergic neurons are drivers of active sleep and project to respiratory patterning regions in the brainstem, we hypothesized that 5-HT preserves respiratory stability in active sleep by dampening central cholinergic drive. We used whole-body plethysmography coupled with nuchal electromyography to monitor the breathing pattern of 2-wk-old tryptophan hydroxylase 2 (TPH2)+/+ and TPH2-deficient (TPH2-/-) pups in active sleep, before and after muscarinic blockade. For the group 1 experiment we injected methylatropine (Ap-M), a CNS-impermeant form of atropine, followed ~30 min later by an injection of atropine sulfate (Ap-S), the CNS-permeant form (both 1 mg/kg, 10 µl bolus iv); both injections occurred within an active sleep episode. We analyzed the effect of each drug on the coefficient of variation of the respiratory period (CV-P) during active sleep. For the group 2 experiment rats were cycled through several episodes of active and quiet sleep before administration of Ap-S (1 mg/kg, 200 µl ip) or vehicle. We assessed the effect of Ap-S on the apnea indices of both genotypes during quiet and active sleep. In group 1 Ap-S significantly reduced the CV-P of TPH2-/- pups (P = 0.03), an effect not observed in TPH2+/+ pups or following Ap-M. In group 2 the apnea index of TPH2-/- pups was significantly reduced following Ap-S injection (P = 0.04), whereas the apnea index of TPH2+/+ littermates was unaffected (P = 0.58). These findings suggest that central 5-HT reduces apnea and stabilizes breathing by reducing cholinergic signaling through muscarinic receptors. NEW & NOTEWORTHY Serotonin in the central nervous system (CNS) is necessary for maintaining the stability of breathing in the early postnatal period, particularly during active sleep. Here we show that the administration of atropine to the CNS selectively stabilizes the respiratory pattern of tryptophan hydroxylase 2-deficient rat pups and reduces their apneas. This suggests that CNS serotonin stabilizes breathing at least in part by reducing central cholinergic drive.

Priming of LTP in amygdala and hippocampus by prior paired pulse facilitation paradigm in mice lacking brain serotonin.

This study focuses on analyzing long-term potentiation (LTP) changes in the lateral nucleus of the amygdala (LA) and in the CA1 region of the hippocampus in slices derived from mice deficient in tryptophan hydroxylase 2 (TPH2-/- ), the rate-limiting enzyme for 5-HT synthesis in the brain. We found a reduced LTP in both brain structures in TPH2-/- mice. However, we found no changes in the magnitude of LTP in TPH2-/- mice compared to wildtype mice when it was preceded by a paired pulse protocol. Whereas the magnitude of long-term depression (LTD) did not differ between wildtype and TPH2-/- mice, priming synapses by LTD-induction facilitated subsequent CA1-LTP in wildtype mice to a greater extent than in TPH2-/- mice. In the LA we found no differences between the genotypes in this protocol of metaplasticity. These data show that, unlike exogenous 5-HT application, lack of 5-HT in the brain impairs cellular mechanisms responsible for induction of LTP. It is supposed that suppression of LTP observed in TPH2-/- mice might be compensated by mechanisms of metaplasticity induced by paired pulse stimulation or low frequency stimulation before the induction of LTP.

Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment.

Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.

A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary- adrenal axis

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Differential anxiety-related behaviours and brain activation in Tph2-deficient female mice exposed to adverse early environment.

Anxiety disorders represent one of the most prevalent mental disorders in today's society and early adversity has been identified as major contributor to anxiety-related pathologies. Serotonin (5-hydroxytryptamine, 5-HT) is implicated in mediating the effects of early-life events on anxiety-like behaviours. In order to further elucidate the interaction of genetic predisposition and adversity in early, developmental stages on anxiety-related behaviours, the current study employed tryptophan hydroxylase 2 (Tph2)-deficient female mice, as a model for lifelong brain 5-HT synthesis deficiency. Offspring of this line were exposed to maternal separation (MS) and tested, in the open-field (OF) or the dark-light box (DLB). Subsequently, neural activity was assessed, using c-Fos immunohistochemistry. In the DLB, MS rescued the observed decrease in activity in the light compartment of homozygous Tph2-deficient mice and furthermore increased the incidence of escape-related jumps in animals of the same genotype. In the OF, MS increased escape-related behaviours in homo- and heterozygous Tph2-deficient offspring. On the neural level, both behavioural tests evoked a distinct activation pattern, as shown by c-Fos immunohistochemistry. Exposure to the DLB resulted in Tph2-dependent activation of paraventricular nucleus and basolateral amygdala, while OF exposure led to a specific activation in lateral amygdala of maternally separated animals and a Tph2 genotype- and MS-dependent activation of the ventrolateral and dorsolateral periaqueductal grey. Taken together, our findings suggest that MS promotes active responses to aversive stimuli, dependent on the availability of brain 5-HT. These effects might be mediated by the distinct activation of anxiety-relevant brain regions, due to the behavioural testing.

Pre- and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin-deficient rat neonates.

KEY POINTS: Sudden infant death syndrome (SIDS) is one of the leading causes of death during the first year of life and abnormalities linked to serotonin (5-HT) have been identified in many SIDS cases. Cigarette smoking and associated exogenous stressors, e.g. developmental nicotine exposure, may compound these serotonergic defects and any associated defects in cardiorespiratory function. Using neonatal rodent pups subjected to medullary 5-HT deficiency and perinatal nicotine exposure, we examined the impact of this interplay of factors on the neonates' ability to autoresuscitate at specific ages. In perinatal nicotine-exposed 5-HT deficient pups, impaired autoresuscitation along with significantly delayed post-anoxic recovery of normal breathing and heart rate was observed at postnatal day 10 (P10). We found that the interaction between 5-HT deficiency and perinatal nicotine exposure can significantly increase pups' vulnerability to environmental stressors and exacerbate defects in cardiorespiratory protective reflexes to repetitive anoxia during the development period. ABSTRACT: Cigarette smoking during pregnancy increases the risk of sudden infant death syndrome (SIDS), and nicotine replacements, a key ingredient of cigarettes, have been recently prescribed to women who wish to quit smoking during their pregnancy. Serotonin (5-HT) abnormalities have been consistently identified in many SIDS cases. Here we investigated the effects of perinatal nicotine exposure in mild 5-HT deficiency rat neonates on autoresuscitation, a protective cardiorespiratory reflex. The mild 5-HT deficiency was induced by a maternal tryptophan-deficient diet, and nicotine was delivered from embryonic day (E) 4 to postnatal day (P) 10 at 6 mg kg-1  day-1 through an osmotic pump. In P10 rats, nicotine exposure exacerbates autoresuscitation failure (mortality) in mildly 5-HT-deficient rats to a greater extent than in controls (P = 0.029). The recovery of eupnoea and heart rate to baseline values following repetitive anoxic events (which elicit an apnoea accompanied by a bradycardia) is significantly delayed in 5-HT-deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (eupnoea recovery: P = 0.0053; heart rate recovery: P = < 0.0001). Neither 5-HT deficiency nor nicotine exposure alone appears to affect the ability to autoresuscitate significantly when compared among the four treatments. The increased vulnerability to environmental stressors, e.g. severe hypoxia, asphyxia, or anoxia, in these nicotine-exposed 5-HT-deficient neonates during postnatal developmental period is evident.

Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.

Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice. At euthanasia, there was in Pahenu2/enu2 brain a significant reduction in the protein abundance and maximally stimulated activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), the rate limiting enzymes catalyzing neuronal dopamine and serotonin synthesis respectively, in comparison to levels seen in wild type brain. Phenylalanine-reducing treatments initiated during adulthood did not affect brain TH or TPH2 content or maximal activity. Despite this apparent fixed deficit in striatal TH and TPH2 activities, initiation of phenylalanine-reducing treatments yielded substantial correction of brain monoamine neurotransmitter content, suggesting that phenylalanine-mediated competitive inhibition of already constitutively reduced TH and TPH2 activities is the primary cause of brain monoamine deficiency in Pahenu2 mouse brain. We propose that CNS monoamine deficiency may be the cause of the partially reversible adverse behavioral effects associated with chronic HPA in Pahenu2 mice, but that phenylalanine-reducing treatments initiated during adulthood are unable to correct the neuropathology and attendant cognitive deficits that develop during juvenile life in late-treated Pahenu2/enu2 mice.

Inflammation-induced depression: Its pathophysiology and therapeutic implications.

Inflammation is not the only cause of depression and cannot explain its entire pathophysiology, but it is an important pathogenic factor that explains one possible mechanism of depression, with the kynurenine (KYN) pathway of tryptophan at its center. In particular, greater impairment seems to exist in the KYN pathway in inflammation-induced depression related to immunotherapy, autoimmune disease, and infection. In patients with these conditions, immunopharmacology is likely to be an important therapy. To develop this therapy, clear evidence of the immune-KYN pathway must be established via multiple types of experiments. This paper reviews the body of evidence, not only for the action of tryptophan (TRY) and consequent serotonin depletion, but also for the detrimental effects of TRY catabolites and the key enzymes in the KYN pathway that play important roles in the pathophysiology of inflammation-induced depression. In addition, this paper explores a potential treatment strategy for inflammation-induced depression using KYN metabolism.