Anxiolysis followed by anxiogenesis relates to coping and corticosterone after medial prefrontal cortical damage in rats

Medial prefrontal cortex (MPFC) damage causes profound behavioral and neuroendocrine alterations. However, many reports have been inconsistent regarding the direction of these effects. We hypothesized that the lesion recovery stage might be a key factor generating discrepancies. To examine changes over time following ibotenic acid lesion in the ventral part of the MPFC, behavioral and endocrine testing was conducted on the second and the fifth week after lesioning. On the second post-lesion week, bilaterally lesioned animals increased social interaction and swimming scores and their corticosterone response to restraint was exaggerated as compared with shams. On the fifth post-lesion week, social interaction and swimming scores were diminished in bilaterally lesioned animals; their basal plasma corticosterone was enhanced, while their corticosterone increase under restraint was blunted relative to shams. These results reveal that the emotional and endocrine responses to stress vary as a function of time following MPFC lesion, which may help to reconcile conflicting reports on effect direction. The role of the MPFC in anxiety, ability to cope with stress and adrenal regulation is also discussed.     

The role of the dorsomedial part of the prefrontal cortex serotonergic innervation in rat responses to the aversively conditioned context: behavioral, biochemical and immunocytochemical studies

In this study we have explored differences in animal reactivity to conditioned aversive stimuli using the conditioned fear test (a contextual fear-freezing response), in rats subjected to the selective lesion of the prefrontal cortex serotonergic innervation, and differing in their response to the acute painful stimulation, a footshock (HS--high sensitivity rats, and LS--low sensitivity rats, selected arbitrarily according to their behavior in the 'flinch-jump' pre-test). Local administration of serotonergic neurotoxin (5,7-dihydroxytryptamine) to the dorsomedial part of the prefrontal cortex caused a very strong, structure and neurotransmitter selective depletion of serotonin concentration. In HS rats, the serotonergic lesion significantly disinhibited rat behavior controlled by fear, enhanced c-Fos expression in the dorsomedial prefrontal area, and increased the concentration of GABA in the basolateral amygdala, measured in vivo after the testing session of the conditioned fear test. The LS animals revealed an opposite pattern of behavioral and biochemical changes after serotonergic lesion: an increase in the duration of a freezing response, and expression of c-Fos in the basolateral and central nuclei of amygdala, and a lower GABA concentration in the basolateral amygdala. In control conditions, c-Fos expression did not differ in LS and HS, na?ve, not conditioned and not exposed to the test cage animals. The present study adds more arguments for the controlling role of serotonergic innervation of the dorsomedial part of the prefrontal cortex in processing emotional input by other brain centers. Moreover, it provides experimental data, which may help to better explain the anatomical and biochemical basis of differences in individual reactivity to stressful stimulation, and, possibly, to anxiolytic drugs with serotonergic or GABAergic profiles of action.     

立体定向毁损大鼠杏仁核及隔核对脑内单胺类递质含量的影响

目的 :探讨杏仁核及隔核毁损后AMP模型大鼠脑内单胺类递质含量的变化。方法 :经腹腔注射苯丙胺 (amphetamine ,AMP)制作精神分裂症动物模型 ,用立体定向技术电极毁损大鼠杏仁核及隔核 ,采用荧光分光光度法和放射免疫法测定大鼠前额叶、间脑和脑干多巴胺 (DA)、5 羟色胺 ( 5 HT)和去甲肾上腺素 (NE)的含量。结果 :杏仁核及隔核毁损组前额叶DA低于模型组 (P <0 0 1) ,5 HT、NE均高于模型组 (P <0 0 1) ;杏仁核及隔核毁损组间脑DA、NE均低于模型组 (P <0 0 1) ,5 HT高于模型组 (P <0 0 1) ;脑干DA、NE均低于模型组 (P <0 0 1) ,5 HT高于模型组 (P <0 0 1)。结论 :AMP模型大鼠前额叶和脑干DA含量增高、5 HT和NE含量下降 ,间脑DA、NE含量增高、5 HT含量下降 ,立体定向毁损杏仁核及隔核能够改变脑内单胺类递质的水平。     

Enhancement of conditioned fear extinction by infusion of the GABA(A) agonist muscimol into the rat prefrontal cortex and amygdala

In auditory fear conditioning, repeated presentation of the tone in the absence of the shock leads to extinction of the acquired fear response. Both the infra limbic prefrontal cortex (IL) and the basolateral amygdala (BLA) are involved in extinction. In this study, we examine the involvement of these two regions in extinction by manipulating the gamma-aminobutyric acid (GABA)ergic system, in the Sprague-Dawley rat. We microinfused a low dose of the GABA(A) agonist muscimol into the IL or BLA. Muscimol infused to IL before extinction training, but not after either a short (five-trials) or long (15-trials) extinction training, resulted in long-term facilitation of extinction. Infusion of muscimol to the BLA following a short (five-trial) extinction session facilitated extinction at least 48-h post-drug infusion. The differences in the temporal parameters of the effects of muscimol in the IL or BLA, suggest differential involvement of these structures in long-term extinction of fear memory. We propose a facilitating role for GABA(A) neurotransmission in the IL in triggering the onset of fear extinction and its maintenance, whereas in the BLA, GABA(A) neurotransmission facilitates extinction consolidation. The involvement of GABA(A) receptors in fear extinction in the prefrontal cortex and amygdala is of particular interest, because of the role of these areas in emotional processes, and the role of the GABA(A) receptors in anxiety states.     

Dynamic amino acid increases in the basolateral amygdala during acquisition and expression of conditioned fear

Glutamate and gamma-aminobutyric acid (GABA) release in the amygdala are thought to be crucial for the acquisition and expression of fear memories, but the time course of amino acid changes during conditioning is unknown. We used rapid-sampling microdialysis with 14 s temporal resolution to address this issue. During auditory fear conditioning, large, rapid and transient increases in glutamate and GABA were detected, but only during the first noise-shock pairing. In contrast, rats receiving unsignaled shocks during contextual fear conditioning showed no changes in GABA and less glutamate release for the initial shock, but increased glutamate release during later shocks. Expression of conditioned fear to either a white noise or the context previously paired with shock produced similar rapid and transient increases in many amino acids in the amygdala. These experiments demonstrate glutamate and GABA levels in the amygdala are differentially modulated during auditory and contextual fear learning, and are transiently increased during the expression of fear memories.     

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.     

Neuropeptide changes following excitotoxic lesion of the insular cortex in rats

Following middle cerebral artery occlusion in Wistar rats, the immunoreactivity of neuropeptide Y increased ipsilaterally in the insular cortex and basolateral nucleus of the amygdala. In addition, the immunoreactivity of leucine-enkephalin, dynorphin, and neurotensin increased in the ipsilateral central nucleus of the amygdala. The amygdalar neurochemical changes are likely the result of damage to the insular cortex, although other cortical areas were also affected by the ischemia. To investigate whether damage to the insular cortex is essential in eliciting these changes, a localized lesion of the right or left insular cortex was produced by microinjection of D,L-homocysteic acid. Control animals received injections of vehicle into the right or left insular cortex or D,L-homocysteic acid into the right primary somatosensory cortex. Neurochemical changes were examined immunohistochemically with the peroxidase antiperoxidase reaction 5 lays after the injection. The immunoreactivity of neuropeptide Y increased locally after excitotoxic damage to the insular cortex or primary somatosenaory cortex. The amygdalar neurochemical changes, including neuropeptide Y increase in the basolateral nucleus and leucine-enkephalin, dynorphin, and neurotensin increase in the central nucleus, were seen only when the ipsilateral insular cortex was lesioned. These neurochemical changes were similar to those seen 5 days after middle cerebral artery occlusion. Our findings indicat that damage to the insular cortex is essential in eliciting the neurochemical changes in the ipsilateral amygdala. In addition, the change in neuropeptide Y in the cortex appears to be a local reaction occurring irrespective of location of the lesion and glutamate receptor activation may be involved. © 1995 Wiley-Liss Inc.     

Effects of prefrontal cortical lesions on neuropeptide and dopamine receptor gene expression in the striatum-accumbens complex

In the rat, neurochemical, behavioral, and anatomical investigations suggest that medial prefrontal cortical input modulates the activity of the basal ganglia. To understand how prefrontal dysfunction might alter striatal-accumbens function, in situ hybridization histochemistry with S³⁵-labeled oligonucleotide probes was used to assess changes in striatal-accumbens gene expression following bilateral excitotoxic ibotenic acid (IA) lesions of the rat medial prefrontal cortex. Quantitative densitometry was used to measure changes in mRNA levels for preproenkephalin A (ENK), D1 dopamine receptor, protachykinin (SubP), glutamic acid decarboxylase (GAD65), and D2 dopamine receptor. No differences were found between sham and lesion groups for ENK, D1, SubP, or GAD65 mRNA levels in the striatum or nucleus accumbens (NAC). D2 receptor mRNA levels were, however, significantly higher in the dorsomedial striatum and in the core area of the NAC of the lesioned rats. Although the functional significance of increased D2 mRNA is unclear, these findings demonstrate that glutamate mPFC projections modulate gene expression in relatively regionally-localized subcortical neuronal populations.     

Amphetamine-induced c-fos mRNA expression is altered in rats with neonatal ventral hippocampal damage

To further characterize the mechanisms underlying enhanced dopamine-related behaviors expressed during adulthood in rats with neonatal excitotoxic ventral hippocampal (VH) damage, we studied the expression of c-fos mRNA in these rats after a single saline or amphetamine (AMPH) (10 mg/kg, i.p.) injection using in situ hybridization. The VH of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). At the age of 90 days, rats were challenged with AMPH or saline, and the expression of c-fos mRNA using an oligonucleotide probe was assessed 30, 90, and 180 min later. AMPH significantly increased c-fos mRNA expression in medial prefrontal cortex, piriform cortex, cingulate cortex, septal region, and dorsolateral and ventromedial striatum in control and lesioned rats. However, this response to AMPH was attenuated 30 min after AMPH injection in all of these regions in the lesioned as compared to the sham-operated rats. No significant changes were seen at other time points. These results indicate that the neonatal VH lesion alters time-dependent intracellular signal transduction mechanisms measured by AMPH-induced c-fos mRNA expression in cortical and subcortical brain regions. Changes in c-fos mRNA expression in this putative animal model of schizophrenia may have implications for long-term alterations in cellular pheno type because of altered regulation of certain target genes. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat.

To determine the influence of neurons of the ventral hippocampus on dopamine (DA) turnover in other limbic areas, spontaneous and amphetamine-induced locomotion as well as DA and its metabolites were assayed in nucleus accumbens, medial prefrontal cortex and anteromedial striatum, 14 and 28 days after bilateral ibotenic acid (IA) or sham lesions of the ventral hippocampus in the rat. Spontaneous locomotion was increased 28 days postoperatively, while D-amphetamine induced locomotion was augmented both 14 and 28 days postoperatively in IA lesioned animals. DA levels in the nucleus accumbens were decreased on the 14th, but increased on the 28th day after the lesion. Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the DOPAC/DA ratio in the medial prefrontal cortex (MPFC) were reduced 28 days postoperatively. Moreover, there was a significant negative correlation between the DOPAC/DA ratio in the MPFC and DA levels in the nucleus accumbens at this time point. These data indicate that a lesion of the ventral hippocampus can produce differential changes in cortical and limbic DA activity. Implications for an animal model of schizophrenia are considered.     

Medial prefrontal transection enhances social interaction. II: neurochemical studies

Medial prefrontal cortex (MPFC) transection enhances social interaction in an open arena test. Social interaction enhances dopaminergic activity in the nucleus accumbens (NAC). In the present set of experiments, microdialysis probes were implanted in the NAC, and glutamate, gamma-aminobutyric acid (GABA) and dopamine (DA) were measured during electrical stimulation of the MPFC, after coronal transection caudal to the MPFC and after a systemic injection of amphetamine in transected rats. Electrical stimulation of the MPFC caused a transient enhancement of glutamate release in the NAC, no change in GABA levels and a long lasting increase in DA levels. Medial prefrontal transection did not change basal glutamate or GABA levels in the NAC, but increased basal DA levels. Amphetamine administration decreased GABA levels in medial prefrontal transected rats, had no effect on glutamate and increased DA levels more than in controls. The experiments suggest that glutamatergic activity in the accumbens decreases dopamine release. Medial prefrontal transection reduces glutamatergic tone and enhances dopamine release, which probably decreases GABAergic activity in the NAC. Presumably, GABA inhibition in the NAC enhances social interaction.     

Central monoamine activity in genetically distinct strains of mice following a psychogenic stressor: effects of predator exposure

The effects of psychogenic stressors, rat exposure and fox urine odor, on central monoamine functioning was assessed in two inbred strains of mice, BALB/cByJ and C57BL/6ByJ, thought to be differentially reactive to stressors. These stressors markedly increased NE utilization, as reflected by MHPG accumulation, in the locus coeruleus, hippocampus, prefrontal cortex and central amygdala. Likewise, the 5-HT metabolite, 5-HIAA, was elevated in hippocampus, prefrontal cortex and central amygdala, and to some extent DOPAC accumulation was increased in the prefrontal cortex. In most brain regions, the neurochemical effects of the stressors were comparable in the two mouse strains. However, central amygdala 5-HIAA elevations as well as DOPAC increases in the prefrontal cortex elicited by fox odor were greater in C57BL/6ByJ than in BALB/cByJ mice. Although BALB/cByJ mice are more behaviorally reactive than C57BL/6ByJ mice, and also show greater corticosterone elevations in response to neurogenic and systemic stressors, it was previously shown that differential corticosterone changes were not elicited by a predator exposure. Taken together with earlier findings, it appears that despite greater behavioral reactivity/anxiety, the strain-specific neurochemical changes elicited may be situation-specific such that the profile apparent in response to neurogenic and systemic stressors may not be evident in response to predator-related threats.     

Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy.

BACKGROUND: There is growing evidence that the brain gamma-aminobutyric acid (GABA) system is involved in depression. Lowered plasma GABA levels were identified as a traitlike abnormality found in patients with remitted unipolar depression and in healthy first-degree relatives of patients with unipolar depression. Major depressive disorder has been associated with neuroimaging and neuropathological abnormalities in the prefrontal cortex by various types of evidence. As a result, the current study investigates whether GABA levels in the prefrontal cortex differ between unmedicated subjects with remitted major depressive disorder (rMDD) and healthy control subjects. METHODS: Sixteen rMDD subjects and 15 healthy control subjects underwent magnetic resonance spectroscopy. We used a 3 Tesla GE whole body scanner with a homogeneous resonator coil providing a homogenous radiofrequency field and capability of obtaining measurement from the prefrontal cortex. Gamma-aminobutyric acid levels were measured in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. RESULTS: There was no difference in GABA concentrations between rMDD subjects and healthy control subjects in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. Secondary analyses provided preliminary evidence for a negative relationship between the glutamate/glutamine (Glx)/GABA ratio and age of onset of major depression in the ventromedial prefrontal cortex. CONCLUSIONS: This result suggests that GABA levels in the prefrontal cortex, if found to be reduced in symptomatic depression, do not represent a persistent characteristic of major depression. Further research is needed to determine brain GABA levels in different brain regions, in different stages of depressive illness, and in different depressive subtypes.     

Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain

Serotonin (5-HT) plays a central role in the neurochemistry of the learned helplessness animal model of depression. Using quantitative autoradiography, we measured the density of 5-HT1A and 5-HT2A receptors and of 5-HT transport sites in medial prefrontal cortex, dorsal hippocampus, septum, hypothalamus, and amygdala in learned helpless rats, and in rats that were nonhelpless after inescapable stress, as well as in shuttlebox-tested and nonhandled controls. We found no changes in 5-HT1A receptor density among the groups in any region studied. In dorsal hippocampus, 5-HT2A receptor density was decreased in nonhelpless rats, while in amygdala 5-HT2A receptor density was decreased in both groups of stressed rats, whether helpless or nonhelpless. In the hypothalamus 5-HT2A receptor density, was decreased in helpless rats as compared to controls. In medial prefrontal cortex, the serotonin transport sites showed decreased density in helpless rats as compared to controls but not to nonhelpless rats. These findings further highlight the complexity of regional 5-HT effects in the learned helplessness animal model.     

Increased expression of glutamic acid decarboxylase mRNA in rat substantia nigra after an ibotenic acid lesion in the caudate-putamen

In situ hybridization histochemistry and RNA blots were used to study expression of glutamic acid decarboxylase (GAD) mRNA in rat caudate-nucleus and substantia nigra. In situ hybridization combined with computerized image analysis revealed that in the intact substantia nigra reticulata the cross-section area of GAD mRNA positive neurons were 25% larger in the dorsolateral part as compared with the ventromedial part. A unilateral ibotenic acid injection in caudate-putamen lesioned neurons, some of which project to the ipsilateral substantia nigra. An increased level of GAD mRNA was observed in substantia nigra ipsilateral to the lesion. Computerized image analysis of sections from in situ hybridization revealed an increase in the number of silver grains over GAD mRNA positive neurons in the dorsolateral substantia nigra reticulata ipsilateral to the lesion. However, no change was observed in the ventromedial part suggesting that GAD mRNA expression in this part of the nigra is less sensitive to inhibition by caudate-putamen afferents. In agreement with in situ experiments, RNA blots showed a 2-fold increased level of GAD mRNA in substantia nigra ipsilateral to the lesion. The increased GAD mRNA expression in the deafferented substantia nigra suggests a disinhibition of nigral GABA neurons, resulting in an increased utilization of GABA in these substantia nigra neurons.     

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs

We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase‐67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment‐naïve sham and neonatally VH‐lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down‐regulated in the striatum, GAD67 mRNA was down‐regulated in the prefrontal cortex and prodynorphin mRNA was up‐regulated in the striatum of the VH‐lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up‐regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug‐induced expression of any genes examined in this study.     

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.     

The effects of electrical hippocampal kindling of seizures on amino acids and kynurenic acid concentrations in brain structures

Our study demonstrated that the development of seizures during the electrically induced kindling of seizures is associated with significant changes in the concentration of kynurenic acid (KYNA) and its precursor, tryptophan (TRP). The primary finding of our study was an increase in KYNA levels and the KYNA/TRP ratio (a theoretical index of activity of the kynurenine pathway) in the amygdala and hippocampus of kindled animals. We also found decreases in the concentration of tryptophan in the hippocampus and prefrontal cortex. Changes in the concentration of KYNA and TRP in the amygdala were accompanied by a significant decrease in γ-Aminobutryic Acid (GABA) levels and an increase in the glutamate/GABA ratio. Moreover, we found a significant negative correlation between the local concentrations of KYNA and glutamate in the amygdala of kindled rats. However, there were no changes in the local concentrations of the following amino acids: glutamate, aspartate, glutamine, glycine, taurine and alanine. In conclusion, these new results suggest a modulatory influence of KYNA on the process of epileptogenesis, characterized by a negative relationship between the KYNA and glutamate systems in the amygdala.     

精神分裂症患者前额叶的GABA及谷氨酸浓度异常——活体1H-MRS研究

背景:精神分裂症的病因及病理机制不明,传统的多巴胺(Dopamine,DA)假说不能完全解释其病理学及治疗学.谷氨酸(glutamate,Glu)及γ-氨基丁酸(γ-aminobutyric acid,GABA)假说认为精神分裂症患者脑内的Glu或GABA浓度异常.磁共振波谱(magnetic resonance spectroscopy,MRS)技术发现精神分裂症谷氨酸类物质水平在前额叶腹内侧(ventromedial prefrontal cortex,vmPFC)(包括前扣带回)(anterior cingulate cortex,ACC)升高.目的:探讨谷氨酸系统(谷氨酸及γ-氨基丁酸)在精神分裂症原因学及病理机制中的作用.方法:24例未服药精神分裂症患者及24例性别、年龄及教育程度相配的健康志愿者入组,应用西门子MRI 3T采集被试的磁共振波谱(magnetic resonance spectroscopy,MRS)数据,感兴趣区包括左侧前额叶背外侧(left dorsolateral prefrontal cortex,lDLPFC)、前额叶腹内侧(ventromedial prefrontal cortex,vmPFC)及前扣带回(anterior cingulate cortex,ACC),运用LCModel软件分析了感兴趣区的γ-氨基丁酸(γ-aminobutyric acid,GABA)、谷氨酸(glutamate,Glu)、谷氨酰胺(glutamine,Gln)、氮乙酰天冬氨酸(N-acetylaspartate,NAA)及氮乙酰天冬氨酸谷氨酸(N-acetylaspartylglutamate,NAAG)等物质浓度.同时应用阳性与阴性症状量表(positive and negative Syndrome scale,PANSS)及临床总体印象量表(Clinical Global Impression Scale,CGI)评估患者的精神症状和疾病严重程度.结果:精神分裂症组和健康对照组前扣带回的GABA浓度分别为1.90(Q1=1.55,Q3=2.09)及2.16(Q1=1.87,Q3=2.59)、Glu浓度分别为6.07(2.48)及6.54(1.99)、Gln浓度分别为0.36(Q1=0.00,Q3=0.74)及0.29(Q1=0.00,Q3=0.59),GABA浓度的组间差异有统计学意义(Z=-2.95,p=0.003),GABA/(NAA+NAAG)的组间差异有统计学意义(t=-2.72,p=0.012),而Glu及Gln的组间差异均无统计学意义.精神分裂症患者组的年龄与前扣带回的GABA浓度呈负相关(R=-0.494,p=0.014),与GABA/(NAA+NAAG)呈负相关(R=-0.473,p=0.020),但对照组无此相关性.经过FDR方法校正后,未发现临床症状与各代谢产物浓度无显著相关性.结论:精神分裂症患者前额叶腹内侧的谷氨酸类物质浓度异常,而前扣带回的GABA浓度降低,支持精神分裂症脑内谷氨酸-GABA异常假说.精神分裂症患者前扣带回的GABA随年龄增长加速减退.临床症状与前扣带回的代谢物浓度可能相关.     

Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle

Our previous experiments demonstrated that systemic depletion of serotonin (5-hydroxytryptamine, 5-HT), similar to levels reported in patients with emotional disorders, enhanced glutamateric activity in the lateral nucleus of the amygdala (LA) and potentiated fear behaviors. However, the effects of isolated depletion of 5-HT in the LA, and the molecular mechanisms underlying enhanced glutamatergic activity are unknown. In the present study, we tested the hypothesis that depletion of 5-HT in the LA induces increased fear behavior, and concomitantly enhances glutamate receptor (GluR) expression. Bilateral infusions of 5,7-dihydroxytryptamine (4 μg per side) into the LA produced a regional reduction of serotonergic fibers, resulting in decreased 5-HT concentrations. The induction of low 5-HT in the LA elevated fear-potentiated startle, with a parallel increase in GluR1 mRNA and GluR1 protein expression. These findings suggest that low 5-HT concentrations in the LA may facilitate fear behavior through enhanced GluR-mediated mechanisms. Moreover, our data support a relationship between 5-HT and glutamate in psychopathologies.