Gender,personality, and serotonin-2A receptor binding in healthy subjects

The vulnerability to mood disorders, impulsive-aggression, eating disorders, and suicidal behavior varies greatly with gender, and may reflect gender differences in central serotonergic function. We investigated the relationships of gender, mood, impulsivity, aggression and temperament to 5HT_2A receptor binding in 21 healthy subjects using [¹⁸F]altanserin and PET neuroimaging. Binding potentials in pre-defined regions-of-interest (ROI) were calculated using the Logan graphical method, corrected for partial volume effects, and compared by gender with age co-varied. SPM analysis was used for voxel level comparisons. Altanserin binding (BP_P) was greater in male than female subjects in the following nine ROIs: hippocampus (HIP) and Lt. HIP, lateral orbital frontal cortex (LOF) and Lt.LOF, left medial frontal cortex (Lt.MFC), left medial temporal cortex (Lt. MTC), left occipital cortex (Lt. OCC), thalamus (THL) and Lt. THL. Differences in Lt. HIP and Lt. MTL remained significant after Bonferroni correction. Gender differences were noted in the co-variation of psychological traits with BP_P values in specific ROIs. Among males alone, aggression was negatively correlated with BP_P values in Lt. LOF and Lt. MFC, and Suspiciousness positively correlated in LOF, Lt. LOF and Lt. MFC. Among female subjects alone, Negativism was positively correlated with BP_P values in HIP, and Verbal Hostility in Lt. HIP. Altanserin binding in Lt. MTC was positively correlated with Persistence, with no significant gender effect. Gender differences in 5HT_2A receptor function in specific ROIs may mediate expression of psychological characteristics such as aggression, suspiciousness and negativism. Future studies of 5HT_2A receptor function and its relationship to behavior should control for gender.     

Regulation of serotonin-1A receptor function in inducible brain-derived neurotrophic factor knockout mice after administration of corticosterone.

BACKGROUND: We examined the effects of a forebrain-specific reduction in brain-derived neurotrophic factor (BDNF) on the regulation of serotonin-1A (5-HT1A) receptor function in serotonergic cell body areas as well as in limbic and cortical structures of mice chronically treated with corticosterone. METHODS: 5-HT1A receptor function, at the level of receptor-G protein interaction, was assessed with quantitative autoradiography of [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT. 5-HT1A receptor number was assessed by measuring the binding of the antagonist radioligand [3H] WAY100635. RESULTS: We observed a significant attenuation of 5-HT1A receptor function, in the absence of a change in receptor number, in the dorsal hippocampus of BDNF knockout versus control mice. There was no difference between control and BDNF knockout mice in 5-HT1A receptor number or function in the dorsal or median raphe nuclei or medial prefrontal cortex or anterior cingulate cortex. Corticosterone treatment of control mice decreased 5-HT1A receptor function in the dorsal and median raphe but not in hippocampus or frontal cortical areas. The regulation of 5HT1A receptor number or function in the dorsal and median raphe by corticosterone was lost in BDNF knockout mice. CONCLUSIONS: Attenuation of BDNF expression in forebrain regions produces differential effects on distinct 5-HT1A receptor populations and on the regulation of these receptor populations by corticosterone.     

Effect of sleep deprivation on dopamine receptor function in normal subjects

Summary Twenty-four hours sleep deprivation significantly decreased the growth hormone response to the dopamine receptor agonist, apomorphine HCl, in five normal men (0.5 mg s.c.) and one woman (0.75 mg s.c.) but had no effect on basal or post-apomorphine prolactin concentrations. These results suggest that sleep deprivation decreases the sensitivity of certain central dopamine receptors. The relevance of this finding to the antidepressant effect of sleep deprivation is unclear.     

Daytime variability in carotid baroreflex function in healthy human subjects

Variability of blood pressure is limited by arterial baroreceptors, yet blood pressure still shows circadian changes. This study was undertaken to examine if the responses to the carotid baroreflex also change throughout the day. Responses of cardiac interval (RR), mean arterial pressure (MAP) and vascular resistance (VR) to carotid baroreflex stimulation and inhibition using pressures and suction applied to a neck chamber, were measured in 14 healthy, normotensive subjects. Studies were carried out at three hourly intervals between 09:00 and 21:00 hours. Stimulus-response curves were defined and the first differential of the curve was calculated to establish reflex sensitivity (maximal slope) and “operating” point (estimated carotid sinus pressure at point of maximum slope, OP). The principal findings are: (1) baroreflex sensitivity for the control of VR was at its highest at 09:00 (−3.4 ± 0.6 units) compared to 12:00 (−1.9 ± 0.4 units), 15:00 (−2.0 ± 0.4 units) and 18:00 (−1.9 ± 0.3 units) (all P < 0.05); (2) baroreflex OP for the control of MAP was at its lowest at 09:00 (P < 0.01); (3) baroreflex sensitivity for control of VR was significantly correlated with prevailing mean pressure (P < 0.05) and OP for the control of MAP (P < 0.02); (4) OP for control of RR, MAP and VR are all highly correlated to prevailing MAP (P < 0.0001). Our results suggest that baroreflex function varies throughout the day and this favors higher sensitivity and lower blood pressure in the mornings. We speculate that this may be of importance in long-term blood pressure regulation.     

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.     

Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain

Abstract

Objective. Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter. Methods. We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-¹¹C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity). Results. We found a 20–30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days. Conclusions. Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.     

Monosodium glutamate and tranylcypromine administration in healthy subjects

The authors administered 400 to 1600 mg of monosodium glutamate and placebo to five healthy males while they were medication-free and again while they were receiving the monoamine oxidase inhibitor tranylcypromine, after having received the drug daily for at least 2 weeks. Monosodium glutamate produced no consistent changes in either blood pressure or heart rate in subjects receiving tranylcypromine. Spontaneous hypertensive episodes were observed in two subjects. These blood pressure increases also occurred with tranylcypromine alone and were unrelated to monosodium glutamate administration. Diet was not violated during these episodes.     

Synergistic interaction between serotonin-2 receptor and dopamine D1 receptor stimulation on striatal preprotachykinin mRNA expression in the 6-hydroxydopamine lesioned rat.

The regulation of striatal preprotachykinin (PPT) mRNA expression can be mediated through both dopamine (DA) D1 and serotonin (5-HT) 5-HT2A/2C receptors. In the present study, we used in situ hybridization to examine possible synergistic interactions between 5-HT2A/2C and D1 receptor-mediated regulation of striatal PPT mRNA levels in the rat depleted of DA with 6-hydroxydopamine. Acute administration of the 5-HT2A/2C receptor agonist DOI (2 mg/kg) significantly increased (+75%) PPT mRNA levels in the dorsal striatum. Acute administration of the D1 receptor agonist SKF-38393 (2 mg/kg) did not significantly alter PPT mRNA levels in the dorsal striatum. However, the co-administration of SKF-38393 and DOI produced a significant increase (+300%) in striatal PPT mRNA expression restricted to the periventricular region of the dorsal-medial striatum. This synergistic interaction was not observed in the remaining aspect of the dorsal striatum where DOI alone increased PPT mRNA expression. These data show that 5-HT2A/2C and D1 receptors can act in a synergistic manner to regulate striatal PPT mRNA in a subregion of the DA-depleted striatum.     

The effect of sodium valproate on serum cortisol levels in healthy subjects and depressed patients

In nine healthy subjects the i.v. injection of 800 mg of the GABA-transaminase inhibitor sodium valproate (SV) was able to suppress serum cortisol significantly when compared to saline. Three and a half hours after the administration of SV, serum cortisol was reduced to less than 50% of the basal value in each of the subjects. Among 17 depressed patients serum cortisol was reduced to less than 50% of basal value 3 1/2 h after SV in only two patients. No difference was found between nine patients with endogenous depression and eight with non-endogenous depression. The dexamethasone suppression test was abnormal in four out of 17 patients. These four patients had endogenous depression, and also an abnormal response to SV. A positive correlation was found between the effect of SV on serum cortisol, and age (r = 0.55), but not between the percentual decrease of serum cortisol and the severity of depression. The effect of SV on serum cortisol was significantly less pronounced in depressed patients than in controls but no difference was found between patients with endogenous and non-endogenous depression.     

Effects of levetiracetam and valproate on reproductive endocrine function studied in human ovarian follicular cells

Purpose:   Recent animal studies have indicated possible reproductive endocrine effects of levetiracetam (LEV). The aim of the present study was to investigate possible reproductive endocrine effects of LEV compared to valproate (VPA) using human ovarian follicular cells.
Methods:   Cell cultures of human granulosa cells were prepared. First, the effect of the drugs on basal and follicle-stimulating hormone (FSH)–stimulated estradiol secretion was investigated at different concentrations of LEV (12, 20, 50, or 80  μ g/ml) or VPA (75, 100, 250, or 350  μ g/ml). Second, the effect of the drugs on CYP19 aromatase activity was studied. Third, the possible effect of the drugs on cell apoptosis was investigated by measuring caspase-3 activity.
Results:   VPA significantly and concentration-dependently decreased basal and FSH-stimulated estradiol secretion. No effects on estradiol secretion were observed for LEV. Neither VPA nor LEV had any effect on CYP19 aromatase activity under basal conditions, but both drugs reduced CYP19 aromatase activity in FSH-stimulated cells at the higher concentrations (VPA 100, 250, and 350 μg/ml; LEV 20, 50, and 80 μg/ml). Both drugs significantly increased caspase-3 activity, the proapoptotic effect of LEV being more pronounced than VPA.
Discussion:   LEV acts differently from VPA on reproductive endocrine function when studied in human ovarian follicular cells. LEV does not affect estradiol secretion, although both drugs affect CYP19 aromatase activity after gonadotropin stimulation. Both drugs act as apoptotic agents in ovarian cells. The proapoptotic effect of LEV was more pronounced than that of VPA.     

Personality traits and striatal dopamine synthesis capacity in healthy subjects

OBJECTIVE: Neuroimaging and genetic studies suggest that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). The authors studied whether presynaptic dopamine function is also associated with personality traits. METHOD: Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [(18)F]fluorodopa in 33 healthy adults, and personality traits were assessed with the Karolinska Scales of Personality. Associations were studied by using a linear regression model controlling for the effects of age and gender on both variables. RESULTS: High scores on two of the anxiety-related personality scales, somatic anxiety and muscular tension, and on one aggressivity-related scale, irritability, were significantly associated with low [(18)F]fluorodopa uptake in the caudate. No statistically significant associations were observed between [(18)F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior (impulsiveness and monotony avoidance). CONCLUSIONS: The results suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects. Together with previous studies, they also indicate differential involvement of various components of the dopaminergic system in normal and pathological personality traits.     

A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function.

BACKGROUND: Norepinephrine and dopamine mediate important aspects of alcoholism and alcohol withdrawal. Dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine. A recent study demonstrated a strong association between variance in plasma DbetaH activity and a novel polymorphism (DBH-1021C-->T) at the structural locus (DBH) encoding DbetaH protein. METHODS: Our study investigated whether the DBH-1021C-->T polymorphism and plasma DbetaH activity were associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal by analyzing 207 German alcoholic and 102 healthy control subjects. We also examined the influence of the polymorphism on enzyme activity. RESULTS: Mean (+SD) plasma DbetaH activity measured in alcoholic subjects abstinent was significantly lower than that observed in control (27.7 + 16.7 vs. 35.6 + 18.8; p =.01). It did not differ between subjects with DT during withdrawal and subjects with mild withdrawal symptoms. The T allele of the DBH-1021C-->T polymorphism was significantly associated with lower plasma DbetaH activity. None of the alleles or genotypes were associated with alcoholism or DT. CONCLUSIONS: The data indicate that the alcoholism-related reduction in plasma DbetaH activity is independent of genotype at DBH-1021C-->T and replicate the finding that DBH-1021C-->T is strongly associated with plasma DbetaH activity in a native Western European population.     

PET measurement of the influence of corticosteroids on serotonin-1A receptor number.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system interact functionally. The modulatory effect of corticosteroids on 5-HT(1A) receptor number and function has been repeatedly demonstrated in preclinical studies suggesting that raised corticosteroid levels decrease 5-HT(1A) receptor number and function in the hippocampus. METHODS: We used positron emission tomography (PET) to quantify the number of 5-HT(1A) receptors in two studies, the first in normal subjects given a single dose of hydrocortisone using a random-order, double-blind, placebo-controlled design and second in patients treated long-term with corticosteroids. RESULTS: We did not find that exposure to elevated levels of corticosteroids in either the short or long term alters 5-HT(1A) receptor binding in the hippocampus or other brain regions examined. CONCLUSIONS: This study does not support the hypothesis that corticosteroids exert a major inhibitory regulatory control over the 5-HT(1A) receptor binding in the human brain.     

Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function

Alcohols and volatile anesthetics affect the function of members of the nicotinic acetylcholine (nACh) superfamily of receptors. Studies on glycine and GABA(A) receptors implicate amino acid residues within transmembrane (TM) regions two and three of these receptors as critical for alcohol and anesthetic enhancement of receptor function. The serotonin-3 (5-HT(3)) receptor is a member of the nicotinic acetylcholine receptor superfamily, sharing sequence and structural homology with the other members. We tested the hypothesis that amino acids of the 5-HT(3) receptor homologous to those shown to affect alcohol and anesthetic potentiation in GABA(A) and glycine receptors also determine the effects of these compounds on the 5-HT(3) receptor. Six 5-HT(3A) mutant cDNAs were generated by site-directed mutagenesis of two amino acids, phenylalanine-269 (14') and lecucine-270 (15') in transmembrane domain two (TM2). When assayed electrophysiologically in Xenopus oocytes, wild-type 5-HT(3) receptors exhibit enhancement of function by enflurane, halothane, isoflurane, chloroform and ethanol, but not by decanol and propofol. Mutations in transmembrane domain two markedly affected alcohol and anesthetic enhancement of 5-HT(3) receptor function. Some mutations had differential effects on the abilities of the isomers enflurane and isoflurane to potentiate 5-HT(3) receptor function.     

Effects of valproate on biogenesis and function of liver mitochondria

The mitochondrial protein content of liver increased, and mitochondria enlarged after prolonged administration of valproic acid (VPA: N-dipropylacetic acid) to rats. The mitochondria showed low specific activities of membrane-bound enzymes, decreased content of cytochrome aa3, and decreased respiration in states 3 and 4. In vitro studies of amino acid incorporation suggested a decrease in protein synthesis in liver mitochondria from VPA-treated rats. Prolonged administration of VPA seems to impair mitochondrial structure and function.     

Enhancement of serotonin-1A receptor dependent responses following withdrawal of haloperidol in rats

Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). In view of a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the elicitation of EPS, the present study concerns pre- and postsynaptic responses to a selective 5-HT-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) following acute and chronic administration of haloperidol in rats. In the acute administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 30 min after single injection of haloperidol (5 mg/kg). In the chronic administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 48 h after withdrawal from repeated (two times a day for 2 weeks) administration of haloperidol (5 mg/kg). The intensity of 5-HT syndrome elicited by 8-OH-DPAT was taken as measure of postsynaptic response. 8-OH-DPAT-induced decreases of 5-HT synthesis were taken as measure of presynaptic response. Results showed that 8-OH-DPAT-induced locomotion was smaller in acute haloperidol-treated rats. Conversely, these effects of 8-OH-DPAT were greater in chronic haloperidol-treated rats. Animals injected acutely or chronically with haloperidol exhibited greater 5-HT synthesis in the striatum. Administration of 8-OH-DPAT did not decrease 5-HT synthesis in the striatum of acute haloperidol-treated rats but decreased it in the striatum of chronic haloperidol-treated rats. The results show an increase in the effectiveness of pre- and postsynaptic 5-HT-1A receptor dependent responses following chronic administration of haloperidol. A causal role of 5-HT-1A receptor responsiveness in the greater incidences of EPS in patients treated with typical neuroleptics such as haloperidol is discussed.     

Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA–dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel ¹¹C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean ± SD) in specific ¹¹C-raclopride binding from baseline for ketamine (11.2 ± 8.9) was greater than for saline (1.9 ± 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean ± SD) in specific ¹¹C-raclopride binding caused by amphetamine (15.5 ± 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in ¹¹C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed. Synapse 29:142–147, 1998. Published 1998 Wiley-Liss, Inc.     

D2 antidopaminergic modulation of frontal lobe function in healthy human subjects.

BACKGROUND: Although the major principles of dopamine (DA) signaling have been well described previously, its precise modulatory impact on the prefrontal cortex (PFC) in humans is poorly understood. Two major neurophysiological models propose segregated functional circuits on the systems level as well as D(1) and D(2) receptor-dependent processing states on the cellular level (two-state model). METHODS: We examined the predictive validity of these models in 10 healthy male volunteers with a haloperidol challenge (HLP). Cortico-striatal-thalamo-cortical (CSTC) motor loop functions were examined during functional magnetic resonance imaging (fMRI) with a sequential finger opposition task. Neuropsychological implications of the two-state model were evaluated with a test battery of D(1)- or D(2)-sensitive prefrontal measures. RESULTS: Analysis of fMRI data revealed a significant HLP-induced blood oxygen level dependent-signal decrease in the sensorimotor striatum and a lateralized activation loss of ipsilateral higher order motor cortices and contralateral cerebellum. Neuropsychological evaluation demonstrated a preferential impairment of D(2)-sensitive functions, whereas D(1) or non-dopaminergic domains were unaffected. CONCLUSIONS: Our data support the hypothesis that mesocortical D(1) and D(2) receptors exert differential influences in the PFC for cognitive function, but the nigrostriatal CSTC network model for the motor domain could not be confirmed.