Central Neurotransmitter Systems Research Articles

Antidepressant-like effect of low molecular proanthocyanidin in mice: Involvement of monoaminergic system

Proanthocyanidin is a phenolic product present in plants which has antioxidant, antinociceptive and neuroprotective properties, without inducing significant toxicological effects. The present study tested the hypothesis that low molecular proanthocyanidin from grapes that has optimized bioavailability, would exert antidepressant-like activities in behavioral despair tests. The results suggested that oral administration proanthocyanidin at doses of 25 and 50 mg/kg for 7 days significantly reduced the duration of immobility in both the tail suspension and forced swimming tests. The doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical and neuropharmacological assays showed that proanthocyanidin produced a marked increase of 5-HT levels at 25 and 50 mg/kg in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased when higher dose of proanthocyanidin (50 mg/kg) administration both in the frontal cortex and hippocampus. These effects were similar to those observed for the classical antidepressant imipramine (10 mg/kg, i.p.). Moreover, Our study suggested that proanthocyanidin (12.5, 25 and 50 mg/kg) dose dependently inhibited monoamine oxidase-A (MAO-A) activity, while MAO-B inhibitory activity was also found at higher doses (25 and 50 mg/kg) after 7 days administration. MAO-A selective inhibitor, moclobemide (20 mg/kg, i.g.) produced MAO-A inhibition of 70.5% in the mouse brain. These findings suggest that the antidepressant-like effects of proanthocyanidin may involve the central monoaminergic neurotransmitter systems.

Aberrant amino acid transport in fibroblasts from patients with bipolar disorder

Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder ( n = 10) and healthy controls ( n = 10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity ( V max ) and affinity constant ( K m ) were determined. A significantly lower V max for tyrosine ( p = 0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K m for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V max ) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.

Sexual dysfunction and hormonal changes in first episode psychosis patients on olanzapine or risperidone

Atypical antipsychotics interfere with central and peripheral neurotransmitter systems and with hormonal production. In this study we compared the effect of olanzapine and risperidone on hormonal state and sexual function (by using the Questionnaire for Sexual Dysfunction, QSD) in 40 patients with a first episode psychosis. Results were compared to those of 34 healthy controls. Patients using risperidone had significant higher prolactin levels than patients using olanzapine. Patients using olanzapine had significantly higher 17beta-estradiol levels than patients using risperidone. Overall satisfaction with sexuality was less in patients compared to controls, but not different between patients using olanzapine and those using risperidone. Problems with sexual arousal were significantly higher in patients using olanzapine compared to patients using risperidone. A significantly higher frequency of problems with ejaculation and problems with insensibility of genitals were found in patients compared to healthy controls. We found no relation between medication, prolactin and 17beta-estradiol levels, frequency of sexual activity, overall satisfaction with sexuality and any of the 18 sexual dysfunctions we investigated. Our results suggests that sexual dysfunction in patients with first episode psychosis might occur despite normal prolactin levels. Also, sexual dysfunction is highly prevalent in healthy controls. Awareness should be raised of potential sexual problems in young adults.

Stress, depression and cardiovascular dysregulation: A review of neurobiological mechanisms and the integration of research from preclinical disease models

Bidirectional associations between mood disorders and cardiovascular diseases are extensively documented. However, the precise physiological and biochemical mechanisms that underlie such relationships are not well understood. This review focuses on the neurobiological processes and mediators that are common to both mood and cardiovascular disorders. The discussion places an emphasis on the role of exogenous stressors in addition to: (a) neuroendocrine and neurohumoral changes involving dysfunction of the hypothalamic-pituitary-adrenal axis and the activation of the renin-angiotensin-aldosterone system, (b) immune alterations including activation of pro-inflammatory cytokines, (c) autonomic and cardiovascular dysregulation including increased sympathetic drive, withdrawal of parasympathetic tone, cardiac rate and rhythm disturbances, and altered baroreceptor reflex function, (d) central neurotransmitter system dysfunction involving the dopamine, norepinephrine and serotonin systems, and (e) behavioral changes including fatigue and physical inactivity. The review also discusses experimental investigations using preclinical disease models to elucidate the neurobiological mechanisms underlying the link between mood disorders and cardiovascular disease. These include: (a) the chronic mild stress model of depression, (b) a model of congestive heart failure, (c) a model of cardiovascular deconditioning, (d) pharmacological manipulations of body fluid and sodium balance, and (e) pharmacological manipulations of the central serotonergic system. In combination with an extensive human research literature, the investigation of mechanisms underlying mood and cardiovascular regulation using animal models will enhance understanding the association between depression and cardiovascular disease. This will ultimately promote the development of better treatments and interventions for individuals with co-morbid psychological and somatic pathologies.

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Preclinical evidence suggests that non-cannabinoid neurotransmitter systems are involved in the behavioral and physiological effects of cannabinoids, but relatively little research has been conducted in humans. The aims of this study were to assess whether oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Delta(9)-THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., > or =80% drug-appropriate responding for four consecutive sessions), multiple doses of Delta(9)-THC, the GABA(A) positive modulator triazolam, the micro-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Delta(9)-THC. Eight subjects (N = 8) accurately discriminated Delta(9)-THC and completed the study. The training dose of Delta(9)-THC functioned as a discriminative stimulus and produced prototypical subject-rated drug effects. All of the drugs tested produced significant effects on the self-report questionnaires, but only Delta(9)-THC substituted for the training dose. These results suggest that the discriminative-stimulus effects of Delta(9)-THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study.

Higher BDNF concentrations in the hippocampus and cortex of an aggressive mouse strain

Although genetically closely related AB-Halle (ABH) and AB-Gatersleben (ABG) mice inbred strains differ in activity and aggressive behaviour. These behavioural traits have been observed especially in response to social challenges, where ABH mice develop a highly aggressive and active behaviour, which cannot be observed in their ABG counterparts. In contrast to ABG mice, basal brain serotonin, dopamine and noradrenaline concentrations in ABH mice are low but highly stimulated by social challenges. Since brain-derived neurotrophic factor (BDNF) modulates central neurotransmitter systems and has been involved in aggressive and activity behaviour, we studied specific concentrations of BDNF and NGF protein in several brain regions of ABG and ABH mice. A significant higher concentration of BDNF protein was found in the hippocampus of 5 weeks and 5 months old ABH mice, when compared to ABG mice. BDNF was also higher in the cortex of 5 weeks and 5 months old ABH mice. Moreover BDNF concentrations were higher in the striatum of 5 months old ABH mice when compared to ABG mice. NGF concentrations in ABH mice were not changed in all measured brain regions but higher in older age in the hippocampus of ABG mice as compared to ABH mice. We hypothesize, that BDNF might be involved in the behavioural and neurochemical mechanisms of aggressive behaviour.

Positron emission tomography ligand activation studies in the sports sciences: Measuring neurochemistry in vivo

Functional neuroimaging with magnetic resonance imaging (fMRI) or positron emission tomography (PET) provides the methodology to unravel some of the fascinating, but hitherto largely unresolved interactions between physical exercise and brain function. Phenomena such as raised mood, pain modulation, and sport addiction associated with physical exercise are highly interesting psychophysical models that require further in depth understanding at the neurotransmitter level. PET ligand displacement studies allow in vivo monitoring of endogenous transmitter trafficking in the entire brain and, thereby, to identify the link between exercise-induced behavioral measures and the endogenous neurotransmitter release. This review focuses on the methodology of ligand displacement in the opioidergic system, which together with the dopaminergic system has been considered as a central neurotransmitter system underlying diverse sport-induced psychophysical effects. Understanding the basic principles of exercise-induced transmitter release in the brain will potentially aid clinical applications of endurance training, both as a preventative or therapeutic intervention.

Antidepressant‐like effect of ethanol extract from Paeonia lactiflora in mice

The present study investigated the antidepressant effect of ethanol extract of Paeonia lactiflora (EPL) in mice using forced swim test, tail suspension test, open-field test and reserpine test. Our results showed that intragastric administration of EPL at the doses of 250 and 500 mg/kg for seven days significantly reduced the duration of immobility in both forced swim test and tail suspension test. EPL at the dose of 500 mg/kg was as effective as the positive control (chlorimipramine, 20 mg/kg) in these tests. However, these treatments did not affect the number of crossing and rearing in the open-field test. Treating mice with EPL at the doses of 250 and 500 mg/kg significantly antagonized reserpine-induced ptosis and hypothermia. However, at the dose of 125 mg/kg, EPL antagonized only the hypothermia but not ptosis induced by reserpine. The results clearly demonstrated the antidepressant effect of Paeonia lactiflora in animal models of depression. The action of Paeonia lactiflora may be mediated via the central monoaminergic neurotransmitter system.

Antidepressant-like behavioral and neurochemical effects of the citrus-associated chemical apigenin

Apigenin is one type of bioflavonoid widely found in citrus fruits, which possesses a variety of pharmacological actions on the central nervous system. A previous study showed that acute intraperitoneal administration of apigenin had antidepressant-like effects in the forced swimming test (FST) in ddY mice. To better understand its pharmacological activity, we investigated the behavioral effects of chronic oral apigenin treatment in the FST in male ICR mice and male Wistar rats exposed to chronic mild stress (CMS). The effects of apigenin on central monoaminergic neurotransmitter systems, the hypothalamic–pituitary–adrenal (HPA) axis and platelet adenylyl cyclase activity were simultaneously examined in the CMS rats. Apigenin reduced immobility time in the mouse FST and reversed CMS-induced decrease in sucrose intake of rats. Apigenin also attenuated CMS-induced alterations in serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA) levels and 5-HIAA/5-HT ratio in distinct rat brain regions. Moreover, apigenin reversed CMS-induced elevation in serum corticosterone concentrations and reduction in platelet adenylyl cyclase activity in rats. These results suggest that the antidepressant-like actions of oral apigenin treatment could be related to a combination of multiple biochemical effects, and might help to elucidate its mechanisms of action that are involved in normalization of stress-induced changes in brain monoamine levels, the HPA axis, and the platelet adenylyl cyclase activity.

Changes in endocrine and neurochemical profiles in neonatal pigs prenatally exposed to increased maternal cortisol

Early life environmental factors are able to influence prenatal development and may cause structural and functional effects on hypothalamic-pituitary-adrenal (HPA) axis and neurotransmitter systems in the offspring. These effects seem to be species specific and may depend on the period of gestation when the factors are effective. Elevated maternal cortisol levels are assumed to play a crucial role as a programming factor during prenatal development. Thus, the present study was performed in order to examine the effects of increased maternal cortisol levels during mid- and late gestation on central and peripheral alterations of the HPA axis and brain neurotransmitter profiles in piglets. Endogenous cortisol release was induced by i.m. administration of ACTH to sows every second day either during mid- (day 49 until 75) or late gestation (day 85 until 107). Controls received injections of saline. ACTH treatment of sows during mid- and late gestation had no effects on the gestation length, the number of total born and the frequency of stillborn piglets. However, ACTH treatment during late gestation caused an increase of birth weight (P < 0.04) and affected the organ:body weight ratios (brain and adrenal) in the offspring. There was an impact of increased maternal cortisol on the HPA axis and on central neurotransmitter systems in the offspring. ACTH treatment during mid gestation caused a significant decrease of plasma corticosteroid-binding globulin (CBG; P < 0.03) and an increase of the noradrenergic activity in the locus coeruleus (LC) region (P < 0.02). Elevated maternal cortisol during late gestation also produced a significant decrease of plasma CBG (P < 0.05), but significantly increased the plasma noradrenaline (NA) concentration (P < 0.02) and decreased the serotonergic activity in the LC at both postnatal day 1 (P < 0.016) and day 28 (P < 0.003). Furthermore, there were sex-specific effects of ACTH treatment on plasma CBG, NA and brain monoamine turnover, with more pronounced changes in male offspring. In conclusion, elevated maternal cortisol levels during mid- and late gestation in pigs affect growth, HPA axis and brain neurotransmitter systems in the offspring in a sex-specific manner. The observed alterations in endocrine and neurotransmitter systems are dependent on the gestational period. Late gestation appears to be a more sensitive phase for cortisol-induced programming in pigs. Moreover, the present data show that there are marked developmental differences between laboratory animals and domestic pigs, and highlight the importance of species-specific studies on prenatal influences.

Antidepressant-Like Effects of Sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae)

The aim of this study was to investigate the effects of sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae) on the forced swimming test, and the central noradrenergic, dopaminergic and serotonergic activities in mice. Our results showed that sarsasapogenin treatment at 12.5, 25 and 50 mg/kg (p.o.) for 14 d significantly reduced the duration of immobility in the forced swimming test. These doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical assays showed that sarsasapogenin produced a marked increase of noradrenaline and serotonin levels at 50 mg/kg in both the hypothalamus and the hippocampus. Moreover, sarsasapogenin showed a monoamine oxidase inhibitory activity in the mouse brain. These findings suggest that the antidepressant activity of sarsasapogenin may involve the central monoaminergic neurotransmitter systems.

Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and we hypothesized that curcumin would have an influence on depressive-like behaviors. The purpose of the present study was to confirm the putative antidepressant effect of chronic administrations of curcumin (1.25, 2.5, 5 and 10 mg/kg, p.o.) in the forced swimming test and bilateral olfactory bulbectomy (OB) models of depression in rats. In the first study, chronic treatment with curcumin (14 days) reduced the immobility time in the forced swimming test. In the second experiment, curcumin reversed the OB-induced behavioral abnormalities such as hyperactivity in the open field, as well as deficits in step-down passive avoidance. In addition, OB-induced low levels of serotonin (5-HT), noradrenaline (NA), high 5-hydroxyindoleacetic acid (5-HIAA) and 4-dihydroxyphenylacetic acid (DOPAC) in the hippocampus were observed, and were completely reversed by curcumin administration. A slight decrease in 5-HT, NA and dopamine (DA) levels was found in the frontal cortex of OB rats which was also reversed by curcumin treatment. These results confirm the antidepressant effects of curcumin in the forced swim and the OB models of depression in rats, and suggest that these antidepressant effects may be mediated by actions in the central monoaminergic neurotransmitter systems.

The effects of curcumin on depressive-like behaviors in mice

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used effectively to treat depression-related diseases in China. There is no information available about the antidepressant activity of curcumin, the active component of curcuma longa. In the present study, we analyzed the effects of curcumin on depressive-like behaviors in mice, using two animal models of depression. Our results showed that curcumin treatment at 5 and 10 mg/kg (p.o.) significantly reduced the duration of immobility in both the tail suspension and forced swimming tests. These doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical assays showed that curcumin produced a marked increase of serotonin and noradrenaline levels at 10 mg/kg in both the frontal cortex and hippocampus. Dopamine levels were also increased in the frontal cortex and the striatum. Moreover, curcumin was found to inhibit monoamine oxidase activity in the mouse brain. These findings suggest that the antidepressant-like effects of curcumin may involve the central monoaminergic neurotransmitter systems.

Platelet monoamine oxidase B (MAO-B) activity and its relationship to DL-fenfluramine-induced prolactin response in healthy men

Several techniques are used to assess central serotonergic neurotransmission in man, e.g. challenge tests (hormonal and physiological responses to serotonin active drugs), platelet MAO-B activity as well as brain imaging techniques. Little is known about how these tests relate to each other. The aim of the present study was therefore to investigate if platelet MAO-B activity could be related to hormonal and temperature responses to the serotonin active drug DL-fenfluramine in healthy men. Twelve male subjects without any history of psychiatric disorders or drug abuse/dependencies were recruited. Prior to the challenge with 60 mg DL-fenfluramine, which was given orally, blood for determination of platelet MAO-B activity was drawn. Blood samples for determination of serum prolactin and serum cortisol were drawn at baseline and thereafter every hour for the following six hours. In addition, body temperature was measured at the same time-points. Delta-values were calculated as the difference between the baseline values and the highest (prolactin and cortisol) or lowest value (temperature) thereafter. There was a strong positive correlation (r = 0.75, p < 0.02) between platelet MAO-B activity and Delta-prolactin. No correlations were found to Delta-cortisol, Delta-temperature or any of the baseline values. The results support the notion that the peripheral marker platelet MAO-B activity is related to the function of the central serotonergic neurotransmitter system as assessed by the prolactin response to 60 mg DL-fenfluramin.

Behavioral Pharmacology of σ-Ligands

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.

Genetic risk factors in eating disorders.

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.

Cholinergic mechanisms mediating anesthetic induced altered states of consciousness

A host of central neurotransmitter systems subserving γ -aminobutyric acid (GABA)ergic, glutamatergic, adrenergic, serotonergic, and cholinergic transmission are likely affected by anesthetics. Anesthetic drugs interfere with cholinergic processes associated with altered states of consciousness. For example, administration of opiates, halothane, isoflurane, and enflurane are associated with decreased acetylcholine (ACh) release from neurones in the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei projecting to the medial pontine reticular formation. Conversely, drugs that directly affect cholinergic activity also influence minimum alveolar concentration (MAC). There is one possibility that general anesthetics interfere directly with cholinergic transmission to produce unconsciousness. A series of experiments presented focuses on a hypothesis that the loss of consciousness produced by anesthetic drugs involves depression, directly or indirectly, of central cholinergic transmission. It was investigated whether physostigmine, a centrally-acting anticholinesterase, reverses the loss of consciousness produced by continuous administration of anesthetic drugs. In addition, it was determined whether the reversal was blocked by scopolamine, a nonselective centrally-acting muscarinic antagonist.

Perturbations in brain monoamine systems during stress.

Monoamines modulate the activity of many neurons and there is evidence that a balanced synthesis of central nervous monoamines is a prerequisite for normal brain functioning. Stress accelerates both release and turnover of brain monoamines and the resulting fluctuations in concentrations affect various parameters within neurotransmitter systems. Acute stress leads to only transient alterations in monoamine systems so that homeostasis can be restored, in contrast, chronic stress accompanied by repetitive and/or prolonged stimulation of monoaminergic neurons can induce a long-lasting imbalance in central nervous neurotransmitter systems. Accordingly, stress-induced changes in brain monoamine systems are suspected to contribute to psychiatric diseases such as depression. The present paper gives a short overview of stress effects on brain monoamines and their receptors.

Cerebrovascular disease and pneumonia in the elderly

Pneumonia is a common cause of death in elderly people. A series of our studies have demonstrated that pneumonia in the elderly is characterized by silent aspiration, impaired swallowing and cough reflex, partly due to cerebral infarctions at basal ganglia. These infarctions probably induce the disruption of the specific central neurotransmitter system including dopamine and substance P, which plays an important role for swallowing and cough reflex. Use of ACE inhibitor and stimulation of the oral cavity by simple oral care, which are effective in increasing substance P. reduced the incidence of aspiration pneumonia. Moreover, use of a dopamine agonist such as amantadine hydrochloride and a folic acid supplement that are known to potentiate dopaminergic neurons also prevented aspiration pneumonia. For patients bedridden due to lowered ADL, it is essential for them to keep an upright position a few hours after meals to prevent aspiration pneumonia caused by the reflux of ingested foods. Also, administration of neuroleptics may cause aspiration pneumonia by suppression of dopaminergic neurons.

Temperature influences the ontogenetic expression of aromatase and oestrogen receptor mRNA in the developing tilapia (Oreochromis mossambicus) brain.

Water temperature has a differential influence on the development of central neurotransmitter systems according to the developmental period in tilapia (Oreochromis mossambicus). Aromatase and oestrogen receptors (ERs) represent important components of the mechanism of brain differentiation. Gene expression of aromatase and ERs is modulated by neurotransmitters in the developing brain. In the present study, the quantitative reverse transcription-polymerase chain reaction method was used to investigate the effects of temperature on the ontogenetic expression of aromatase and ERs in the developing tilapia brain. Before day 10 posthatching, exposure to a higher temperature (32 degrees C) resulted in a significant increase in the expression of brain aromatase; conversely, a lower temperature (20 degrees C) resulted in a decrease. ERalpha expression was depressed in accordance with the decrease of temperature, but ERbeta was unaffected by temperature. Between days 10 and 20, neither brain aromatase nor ERalpha expression was altered by temperature, whereas ERbeta expression was significantly enhanced by exposure to 32 degrees C. Between days 20 and 30, brain aromatase significantly increased at the higher temperature and decreased at 20 degrees C, but neither ERalpha nor ERbeta was affected by temperature. The expression of both brain aromatase and ERs, differentially regulated according to the temperature and to the developmental period, could be related to brain-sex differentiation.