Regional changes in monoamine metabolism in the aging constant estrous rat

Studies were undertaken to determine levels of monoamines and their metabolites in brain regions in young (3–4 months) normally cycling and old (25–26 month) constant estrous female rats. Dopamine (DA) concentrations were reduced in old rats in the median eminence (ME), medial basal hypothalamus (MBH), preoptic area-anterior hypothalamus (POA-AH) and the striatum. Similarly, concentrations of dihydroxyphenylacetic acid (DOPAC), the major acid metabolite of DA, were reduced significantly in all 4 regions. In the ME, a strong positive correlation was observed between DA and DOPAC concentrations in both young and old rats. Concentrations of norepinephrine (NE) were reduced in old rats in the MBH and POA-AH but not in the ME or striatum. Concentrations of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA) were generally unchanged with age in all of the regions examined. These studies indicate the age-related regional alterations in DA and 5HT metabolism can be monitored by methods which quantitate monoamines and their metabolites.     

Chronic social stress: effects on limbic brain structures

Different types of stressors are known to activate distinct neuronal circuits in the brain. Acute physiological stimuli that are life threatening and require immediate reactions lead to a rapid stimulation of brainstem and hypothalamus to activate efferent visceral pathways. In contrast, psychological stressors activate higher-order brain structures for further interpretations of the perceived endangerment. Common to the later multimodal stressors is that they need cortical processing and, depending on previous experience or ongoing activation, the information is assembled within limbic circuits connecting, e.g., the hippocampus, amygdala and prefrontal cortex to induce neuroendocrine and behavioral responses. In view of the fact that stressful life events often contribute to the etiology of psychopathologies such as depressive episodes, several animal models have been developed to study central nervous mechanisms that are induced by stress. The present review summarizes observations made in the tree shrew chronic psychosocial stress paradigm with particular focus on neurotransmitter systems and structural changes in limbic brain regions.     

Hyperbaric oxygenation mitigates focal cerebral injury and reduces striatal dopamine release in a rat model of transient middle cerebral artery occlusion

The usefulness of the administration of hyperbaric oxygen (HBO) in the treatment of acute focal cerebral ischemia remains debatable. A significant association exists between focal cerebral injury and an excessive release of extracellular dopamine (DA). In vivo microdialysis was used in the present study to examine the effect of HBO on DA release in the striatum during ischemia and reperfusion in rats. The histological changes occurring were also evaluated. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCA) using a surgically placed intraluminal filament. Control rats (n=8) were subjected to 1 h of ischemia, whilst the study rats (n=8) were in addition treated with HBO (2.8 atmospheres of absolute pressure 100% O₂) during ischemia. Both groups were returned to breathing room air at normal pressure during reperfusion. Microdialysis samples were continuously collected at 15 min intervals at 2 μl·min^–1. The [mean (SE)] increase in release of striatal DA attained significance after 30 min of occlusion of MCA [170 (24)%], and continued to increase [268 (26)% at 45 min] reaching a peak level at 60 min [672 (59)%] before returning to the baseline level during the late reperfusion phase. There was no significant change in the level of DA in HBO treated rats during the period of ischemia. A significant reduction in edema and neuronal shrinkage were observed by histological examination in HBO treated rats when compared to the control rats. The results showed that HBO, when administered during ischemia, offered significant neuroprotection in our experimental model of transient focal cerebral ischemia in the rat. The mechanism seems to imply, at least in part, a reduced level of DA. Electronic Publication     

Effects of dopamine agonists on hypothalamic defensive attack in cats

The effects of methamphetamine (MAT) and apomorphine (APO), dopamine agonists, were studied in 16 cats to evaluate their effects on threshold for defensive attack behavior elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VMH). Directed attack and hissing were selected from elementary responses as constituting a defensive attack. Hissing threshold was measured in two situations, one with human provocation and the other without provocation. MAT administered systemically lowered the thresholds for all three types of responses in a dose-related manner (0.5, 1.0, and 3.0 mg/kg). The effects of 1.0 mg/kg of APO were almost identical to those observed with 0.5 or 1.0 mg/kg of MAT. These results suggest that MAT-induced aggressive behavior may be mediated by a dopamine-induced increase in the excitability of the VMH.     

高效毛细管电泳法分离多巴胺和5-羟色胺

建立毛细管电泳分离分析多巴胺和 5一羟色胺的方法。采用自由区带电泳法 (CZE) ,4 0mmol/L硼砂缓冲液 2 0PSI气压进样 5s ,定电流 75 μA分离 10min ,二极管阵列PDA检测器检测 ,应用 2 0 0nm检测波长 ,结果显示两种物质完全分离。     

Differential involvement of GABA system in mediating behavioral and neurochemical effect of acupuncture in ethanol-withdrawn rats

In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague–Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72 h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1 min. The selective GABA_A antagonist bicuculline and the selective GABA_B antagonist SCH 50911 were injected intraperitoneally 20 min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABA_B receptor system in ethanol-withdrawn rats.     

Injection of substance P (SP) N-terminal fragment SP(1-7) into the ventral tegmental area modulates the levels of nucleus accumbens dopamine and dihydroxyphenylacetic acid in male rats during morphine withdrawal

The biologically active substance P (SP) N-terminal metabolite SP_1–7 has been reported to modulate several neural processes such as learning, locomotor activity and reaction to opioid withdrawal. Although all these processes are believed to be associated with dopaminergic transmission no evidence of an interaction between SP_1–7 and dopamine in the case of morphine withdrawal has so far been reported. Therefore, in this work we applied in vivo microdialysis to investigate the effect of SP_1–7 injection into the ventral tegmental area on dopamine release in nucleus accumbens of male rats during naloxone precipitated morphine withdrawal. The result showed that the heptapeptide enhances dopamine release and also elevates the level of the dopamine metabolite dihydroxyphenylacetic acid in this brain area. It was suggested that the observed action of the SP fragment on the dopamine system represents the underlying mechanism for a previously observed ability of SP_1–7 to counteract the aversion response to morphine withdrawal.     

The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD

ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282–284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n=61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.Mark Bellgrove and Katharina Domschke contributed equally to this work and should therefore both be considered first authors. The work reported herein was supported by a grant from the Irish Health Research Board.     

Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits

The human dopamine D4 receptor (DRD4) is of major interest in molecular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (−768G>A in the negative modulator region; −521C>T, −376C>T, and −291C>T in the cell type-specific promoter region; and −616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The −768G>A polymorphism was significantly associated with reward dependence (P = 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene. Received: August 28, 2000 / Accepted: October 25, 2000     

Projections from the ventral tegmental area and mesencephalic raphe to the dorsal raphe nucleus in the rat

Summary The origins of the dopaminergic innervation of the rat dorsal raphe nucleus (NRD) have been investigated using a combination of fluorescent retrograde tracing and fluorescence histochemistry. Stereotaxic microinjections of True Blue were placed in the central, caudal and lateral portions of the NRD, and after 6–12 days survival the brains were processed for fluorescence histochemical detection of catecholamines. Retrogradely labeled neurons were searched for in the diencephalic A11 and A13 dopaminergic cell groups, substantia nigra, ventral tegmental area (VTA) and the linear, central superior and dorsal raphe nuclei. The various NRD injections consistently resulted in retrograde labeling of a small number of catecholamine-containing, presumed dopaminergic cell bodies, confined mainly to three regions: the VTA, the linear and central superior raphe nuclei and the NRD itself. The present findings indicate that not only dopaminergic neurons in the VTA but also the system of catecholamine-containing cells, extending dorsally and caudally from the VTA within the midline raphe area, project to the NRD. Although often similar in size, shape and distribution to the catecholaminergic neurons the majority of retrogradely labeled cells in these regions were, however, found to be non-catecholaminergic.Abbreviations 3 Principal oculomotor nucleus - 4 Trochlear nucleus - Aq Cerebral aqueduct - cp cerebral peduncle - cst cortico-spinal tract - dscp decussation of the superior cerebellar peduncle - DTg Dorsal tegmental nucleus - fr fasciculus retroflexus - IF Interfascicular nucleus - IP Interpeduncular nucleus - LL nucleus of the lateral lemniscus - ml medial lemniscus - mlf medial longitudinal fasciculus - mNV mesencephalic trigeminal nucleus - NLC Nucleus linearis caudalis - NLR Nucleus linearis rostralis - NRD Dorsal raphe nucleus - PAG Periaqueductal grey - PN Pontine nucleus - PRN Pontine raphe nucleus - R Red nucleus - RCS Nucleus raphe centralis superior - SN Substantia nigra - VTA Ventral tegmental area - VTg Ventral tegmental nucleus