Venlafaxine alters microvascular perfusion, [I]-beta-CIT binding and BDI scores in flushing postmenopausal women

Background

Although 70% of postmenopausal women suffer from hot flashes the pathophysiology is poorly understood. The serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine provides relief of flushing although the mechanism is unknown and could involve a central effect and/or a peripheral effect. Using single photon emission computed tomography (SPECT) we studied the central serotonin transporter (SERT) in vivo using [¹²³I]-beta-carbomethoxy-3-β-(4-iodophenyl)tropane (beta-CIT) and, as previous studies have shown that reactivity of the skin blood vessels is enhanced in those who flush, we examined cutaneous microvascular perfusion.

Methods

Cutaneous microvascular perfusion was assessed in 31 postmenopausal women, with flushing, using laser Doppler imaging with iontophoresis (LDI + ION), before and after 8 weeks of treatment with venlafaxine. A sub-group of 14 of these women also had SPECT imaging at both time points to evaluate the availability of SERT in the brain. Flush frequency and score was recorded, and Beck Depression Inventory (BDI) II scores were assessed before and after treatment.

Results

Following treatment with venlafaxine, there was a significant reduction in the [¹²³I]-beta-CIT binding ratio, BDI scores, flushing and endothelial dependent perfusion response. [¹²³I]-Beta-CIT reduction was associated with BDI reduction (r² = 0.54; F = 8.8; p = 0.004), but not flushing reduction or perfusion reduction.

Conclusions

Venlafaxine resulted in a decrease in BDI II scores with an associated reduction in [¹²³I]-beta-CIT binding in a group of non-depressed women. It also improved flush frequency and severity which may be as a result of decreases seen in enhanced cutaneous microvascular perfusion.     

胚胎期缺氧后肾脏内肾上腺素与去甲肾上腺素的含量变化

本文用高效液相色谱电化学检测方法(HPLC-EC)研究胎儿期缺氧后,在新生鼠肾脏内肾上腺素(E)和去甲肾上腺索(NA)含量的变化。发现块氧组肾脏内E的含量生后第一天高于对照组,以后逐渐下降与对照组相接近。NA含量在生后第一天低于对照组,五天后显著上升。.肾重与体重之比值缺氧组高于对照组,有统计学意义。     

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity,stress, anxiety,mood, and drug dependence

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.     

The Effect of an Academic Examination on Salivary Norepinephrine and Immunoglobulin Levels

Abstract

Forty-six college students provided saliva samples just after taking an examination, one hour and 45 minutes later, and several days later, at a period of rest. As compared with baseline levels, the power stress of an examination was associated with an increase in salivary immunoglobulin A (S-IgA), a measure of B-cell immune function, and with an increase in norepinephrine (NE) concentrations in the saliva. The increase in NE was greater for those for whom n power was greater than n affiliation rather than for those for whom the reverse was true. Greater increases in, and levels of, NE at the examination and after were associated with greater subsequent drops in S-IgA, which reached below baseline levels for those for whom n power was stronger. The examination stimulated adrenergic activity, which in the long run depressed immune function for those with a strong power motive who had been most aroused adrenergically by the examination.     

Somatosensory stimuli evoke norepinephrine release in the anterior ventromedial hypothalamus of sexually receptive female rats

We used in vivo brain microdialysis to determine the role of specific copulatory stimuli in mating-induced release of norepinephrine in the lateral ventromedial hypothalamus (VMH) of hormone-treated, sexually receptive female rats. Ovariectomized rats implanted with a unilateral guide cannula aimed at the ventrolateral VMH received systemic injections of estradiol benzoate daily for 2 days before and progesterone 4 h before the initiation of a 1-h behavioural test. Dialysis probes were lowered immediately after progesterone administration, and 20-min dialysis samples were collected until 1 h after the termination of behavioural testing. Norepinephrine content of dialysates was quantified by high performance liquid chromatography with electrochemical detection. During mating tests with male rats, dialysate levels of norepinephrine increased significantly over baseline in sexually receptive females with probe placements in the anterior but not posterior VMH. Norepinephrine levels were unchanged if rats were nonreceptive, even if males mounted vigorously and probes were located in the anterior VMH. Hormone-treated females that were placed on male-soiled bedding for 1 h showed no changes in dialysate levels of norepinephrine. Similarly, females in which vaginocervical stimulation was prevented by a vaginal mask failed to show increased levels of norepinephrine in dialysates collected from the anterior VMH, even if they displayed high levels of lordosis behaviour. Thus, the release of norepinephrine is not a result of executing the lordosis posture. The findings suggest that mating-induced increases in norepinephrine release in hormone-treated, sexually receptive rats are confined to the anterior VMH and that somatosensory rather than chemosensory stimuli evoke norepinephrine release. Moreover, experiments with vaginal masks indicate that vaginocervical stimulation is necessary for mating-evoked norepinephrine release in the anterior VMH.     

Brainstem projections to the normal and noradrenergically hyperinnervated trigeminal motor nucleus

The noradrenergic innervation of the trigeminal motor nucleus of the rat can be increased severalfold by neonatal treatment with the neurotoxin, 6-hydroxydopamine. The brainstem projections to the nucleus were studied by injecting HRP into the nucleus of normal and noradrenergically hyperinnervated rats. In order to identify the source of the noradrenergic innervation, the fluorescent dye, True Blue, was used as a retrograde tracer in combination with the glyoxylic acid histofluorescence method for catecholamines. In both control and neonatally treated rats, the noradrenergic innervation of the motor nucleus was shown to arise from an ipsilateral group of cells located among the fibers of the lateral lemniscus just rostral to the motor nucleus. Our results confirmed the high degree of specificity of noradrenergic innervation, which arises exclusively from this lateral tegmental noradrenergic cell group. During the process of sprouting, this specificity is maintained since only those noradrenergic cells normally innervating the nucleus were retrogradely labeled in neonatally treated animals. Other noradrenergic projections which are also increased in these animals, such as the nearby locus ceruleus innervation of the main sensory trigeminal nucleus, do not spread to the motor trigeminal nucleus. HRP-labeled nonadrenergic cells were concentrated dorsally, with scattered cells surrounding the nucleus. A similar distribution was observed contralateral to the injection site. The mesencephalic trigeminal nucleus was labeled only ipsilateral to the injection. The motor nucleus also receives an extensive bilateral input from the pontine and medullary reticular formation. The medial reticular formation nuclei, including nucleus pontis caudalis, nucleus gigantocellularis, and nucleus reticularis ventralis contained large labeled cells, which were especially numerous in the retrotrigeminal area. Smaller, lateral reticular formation neurons were concentrated rostrally and ipsilaterally in the nucleus pontis lateralis. HRP retrograde labeling revealed no obvious change in the overall pattern of cells innervating the trigeminal motor nucleus following noradrenergic hyperinnervation.     

Age-related alterations in dopamine and norepinephrine activity within microdissected brain regions of ovariectomized long evans rats

The ability of several stimuli which augment central catecholamine (CA) neuronal activity to reinitiate estrous cycles in old constant estrous (CE) rats suggests CA neuronal function is impaired with advanced age. We examined the effects of age on dopamine (DA) and norepinephrine (NE) levels and turnover rates within microdissected brain regions of previously normally cycling young (3-4 months old) and middle-aged (10 months old) and CE old (20-22 months old) Long Evans 2 weeks after ovariectomy. Steady-state DA concentrations were significantly decreased in old compared to young rats in the nucleus accumbens (34%), anterior hypothalamic nucleus (54%, NHA ), neurointermediate pituitary lobe (51%, NIL) and median eminence (74%, ME). The rate constant of DA loss, an estimate of neuronal activity, decreased in old versus young rats only in the preoptic area suprachiasmatica (60%, POAs ) and NHA (60%) and was unchanged or augmented in the 7 other regions. In contrast, a decline in DA turnover rate of 29-67% was observed in 6 of 9 regions in middle-aged rats and 45-81% in 5 of 9 regions in old rats. Steady-state NE concentrations similarly were significantly decreased in old versus young rats in the POAs (54%), medial forebrain bundle (44%), nucleus suprachiasmatica (49%) and ME (59%). The rate constant of NE loss progressively decreased with increasing age only in the POAs and was unchanged or augmented in other regions. Turnover rate of NE was decreased from 21 to 98% in 4 of 8 regions from old animals. A strong positive correlation was noted between the rate constant of NE (but not DA) loss measured in young rats and the magnitude of the age-related depletion in NE concentrations within specific brain regions. Collectively these data indicate that with increasing age: CA neuronal function is differentially altered in nuclei located along the preoptico-tuberal pathway; substantial declines in both DA and NE concentrations are the primary contributor to the reduced amine turnover noted in several of these regions; and the observed age-related alterations in CA turnover may contribute to impaired LH response and the persistent hyperprolactinemia in old CE rats.     

Immunocytochemical distribution of catecholamine-synthesizing neurons in the hypothalamus and pituitary gland of pigs: Tyrosine hydroxylase and dopamine-β-hydroxylase

This study describes the distribution of catecholaminergic neurons in the hypothalamus and the pituitary gland of the domestic pig, Sus scrofa, an animal that is widely used as an experimental model of human physiology in addition to its worldwide agricultural importance. Hypothalamic catecholamine neurons were identified by immunocytochemical staining for the presence of the catecholamine synthesizing enzymes, tyrosine hydroxylase and dopamine-β-hydroxylase. Tyrosine hydroxylase-immunoreactive perikarya were observed in the periventricular region throughout the extent of the third ventricle, the anterior and retrochiasmatic divisions of the supraoptic nucleus, the suprachiasmatic nucleus, the ventral and dorsolateral regions of the paraventricular nucleus and adjacent dorsal hypothalamus, the ventrolateral arcuate nucleus, and the posterior hypothalamus. Perikarya ranged from parvicellular (10–15 μm) to magnocellular (25–50 μm) and were of multiple shapes (rounded, fusiform, triangular, or multipolar) and generally had two to five processes with branched arborization. No dopamine-β-hydroxylase immunoreactive perikarya were observed within the hypothalamus or in the adjacent basal forebrain structures. Both tyrosine hydroxylase- and dopamine-β-hydroxylase-immunoreactive fibers and punctate varicosities were observed throughout areas containing tyrosine hydroxylase perikarya, but dopamine-β-hydroxylase immunoreactivity was very sparse within the median eminence. Within the pituitary gland, only tyrosine hydroxylase fibers, and not dopamine-β-hydroxylase immunoreactive fibers, were located throughout the neurohypophyseal tract and within the posterior pituitary in both pars intermedia and pars nervosa regions. Generally, the location and patterns of both catecholamine-synthesizing enzymes were similar to those reported for other mammalian species except for the absence of the A15 dorsal group and the very sparse dopamine-β-hydroxylase immunoreactive fibers and varicosities in the median eminence in the pig. These findings provide an initial framework for elucidating behavioral and neuroendocrine species differences with regard to catecholamine neurotransmitters. © 1996 Wiley-Liss, Inc.     

Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding

Dopamine signaling is an important component of many goal-directed behaviors, such as feeding. Acute disruption of dopamine signaling using pharmacological agents tends to inhibit normal feeding behaviors in rodents. Likewise, genetically engineered dopamine-deficient (DD) mice are unable to initiate sufficient feeding and will starve by approximately 3 weeks of age if untreated. Adequate feeding by DD mice can be achieved by daily administration of L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, which can be taken up by dopaminergic neurons, converted to dopamine, and released in a regulated manner. In contrast, adequate feeding cannot be restored with apomorphine (APO), a mixed agonist that activates D1 and D2 receptors. Viral restoration of dopamine production in neurons that project to the dorsal striatum also restores feeding in DD mice. Administration of amphetamine (AMPH) or nomifensine (NOM), drugs which increase synaptic dopamine concentration, inhibits food intake in virally rescued DD mice (vrDD) as in control animals. These results indicate that the dysregulation of dopamine signaling in the dorsal striatum is sufficient to induce hypophagia and suggest that regulated release of dopamine in that brain region is essential for normal feeding and, probably, many other goal-directed behaviors.