Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated. As a result of the lesion ( approximately 50% neuronal loss), the number of spontaneously active neurons was significantly reduced. Basal firing rate, burst firing and responsiveness to intravenously administered apomorphine remained unchanged. In contrast, the variation coefficient, a measure of interspike interval regularity, was significantly increased. Ibotenic acid (10 microg) lesion of the ipsilateral subthalamic nucleus in lesioned rats did not modify the electrophysiological parameters. However, prolonged levodopa treatment (100 mg/kg/day + benserazide 25 mg/kg/day, 14 days) reversed the irregularity observed in cells from lesioned rats, while it induced an irregular firing pattern in cells from intact rats. Our results using an experimental model of moderate Parkinson's disease indicate that surviving substantia nigra pars compacta dopaminergic neurons fire irregularly. In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them.     

Hemispheric asymmetries in spontaneous firing characteristics of substantia nigra pars reticulata neurons following a unilateral 6-hydroxydopamine lesion of the rat nigrostriatal pathway

Single unit activity of substantia nigra pars reticulata (SNR) neurons was recorded bilaterally in rats subjected to unilateral 6-hydroxydopamine lesions of the ascending mesostriatal dopaminergic pathway, resulting in an almost complete loss of dopaminergic neurons in the ipsilateral SN pars compacta. Firing rate and firing pattern of SNR neurons in lesioned rats were compared with respective data from sham-lesioned rats and naive controls. In lesioned rats, the mean firing rate of SNR neurons at the lesioned side was significantly reduced and there was an increase in the occurrence of bursting activity. In contrast, firing rate in the contralateral SNR was significantly increased without change in the frequency of bursting neurons. This asymmetrical change in spontaneous firing characteristics of SNR neurons following the lesion could be involved in the complex behavioral changes seen in this model of Parkinson's disease.     

Nigral reticulata neurons: potentiation of reponsiveness to amphetamine with long-term treatment

Single-unit activity was recorded in the substantia nigra pars reticulata of rats in response to intravenous challenge injections of d-amphetamine. The animals were pretreated with saline or 5.0 mg/kg d-amphetamine twice daily for 6 consecutive days. Whereas the large majority of saline controls (6 to 8) showed no consistent response to amphetamine at doses up to 2.0 mg/kg, amphetamine pretreated rats (7 of 10) responded with a progressive increase in firing rate. Both groups of animals responded to a subsequent injection of 5.0 mg/kg clozapine with a depression of firing rate. The remaining control rats were inhibited by amphetamine and this aberrant response was enhanced with long-term treatment. In this unusual cells, clozapine accelerated firing rate. Taken together, these results indicate that unlike dopaminergic neurons in the compacta region of the nigra, reticulata neurons increase their responsiveness to amphetamine with repeated administration.     

Effects of muscimol and picrotoxin on single unit activity of substantia nigra neurons

Intravenous administration of the GABA agonist, muscimol, caused dose-dependent increases in the unit activity of substantia nigra pars compacta (dopamine) neurons and an inhibition of nigral pars reticulata cells. The depressant effects of the drug upon reticulata neurons were reversible by subsequent administration of the GABA antagonists, picrotoxin and bicuculline HCl. However, the stimulatory effects of i.v. muscimol upon dopamine neurons were not abolished by these agents. Intravenous administration of picrotoxin alone caused only moderate increases in the activity of dopamine neurons (31% over baseline at 7.0 mg/kg), but markedly stimulated the firing of pars reticulata cells (154% over baseline at 7.0 mg/kg). In spite of the stimulation of dopamine neurons after i.v. muscimol, microiontophoresis of GABA and muscimol could inhibit the firing of both pars compacta and pars reticulata cells, although the reticulata neurons were much more sensitive to the inhibitory actions of these agents than the dopamine neurons. Considered together, these studies suggest that a population of neurons in the substantia nigra pars reticulata have the capacity to be more affected by a major GABA input to the nigra than the pars compacta dopamine neurons. The results further suggest that if the dopamine cells are regulated by GABAergic neurons of the striatonigral pathway, their regulation must be indirect and could involve a second inhibitory neuron within the nigra.     

High frequency stimulation of the STN influences the activity of dopamine neurons in the rat

The effect of high frequency stimulation (HFS) of the subthalamic nucleus (STN) on the spontaneous activity of substantia nigra pars compacta (SNc) dopaminergic neurons was investigated in normal rats and in rats with globus pallidus (GP) lesions. In normal rats, the spontaneous activity of SNc neurons did not significantly differ from that of rats with GP lesions (4.2+/-2.2 versus 4.4+/-2.6 spikes/s). STN-HFS induced an increase of firing rate in the majority of tested cells in normal (76%) and GP-lesioned rats (73%) with an after-effect of 34.4+/-3.4 and 33.2+/-3.1 s, respectively. These results demonstrate that STN-HFS influences the activity of the SNc dopaminergic neurons by increasing their firing rate and that this increase of activity is independent of the globus pallidus.     

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

Subpopulations of mesencephalic dopaminergic neurons express different levels of tyrosine hydroxylase messenger RNA.

Subpopulations of mesencephalic dopamine containing neurons possess different electrophysiological, pharmacological, biochemical, and anatomical properties. In order to determine whether such differences are related to the regulation of tyrosine hydroxylase, the rate limiting enzyme in the synthesis of catecholamines, the regional distribution of tyrosine hydroxylase messenger RNA in these neurons was examined using in situ hybridization histochemistry. In the mouse, labelling for tyrosine hydroxylase messenger RNA associated with individual neurons was significantly less in the lateral substantia nigra pars compacta than in the medial substantia nigra pars compacta and the ventral tegmental area. A similar pattern of labelling was observed in the rat. Labelling for tyrosine hydroxylase messenger RNA was significantly less in the lateral substantia nigra pars compacta than in medial pars compacta (a densely cellular region), the area dorsal to the medial substantia nigra pars compacta (a less cell dense region), and the ventral tegmental area. Differences in levels of labelling for messenger RNA in mesencephalic dopamine neurons were not related to differences in cell size as measured in sections processed for tyrosine hydroxylase immunohistochemistry. The results suggest that tyrosine hydroxylase messenger RNA is differentially regulated in subpopulations of mesencephalic dopamine neurons, supporting the view that these neurons are physiologically distinct.     

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N-methyl-D-aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non-dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinson's disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non-competitive NMDA antagonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (±)-CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine-depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4–7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)-HA-966 (30 mg/kg i.v.) also effectively attenuated SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non-dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1-mediated effects on substantia nigra firing rates in reserpine and 6-OHDA-treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra. Synapse 30:18–29, 1998. Published 1998 Wiley-Liss, Inc.     

蛋白酶体抑制剂诱导大鼠黑质变性伴包涵体形成

目的 观察蛋白酶体抑制剂Lactacystin诱导大鼠黑质变性伴包涵体形成及运动行为学的改变,探讨蛋白酶体功能下降在帕金森病(PDl发病机制中的作用. 方法 24只SD大鼠采用随机数字表法分为kactacystin实验组和生理盐水组.每组12只,Lactacystin实验组将蛋白酶体抑制剂Lactacystin立体定向注射人大鼠左侧黑质致密部(SNc).生理盐水组注射等体积生理盐水;观察大鼠自主行为和阿朴吗啡(APO)诱导的旋转行为的改变;Nissl染色法观察SNc病理改变;免疫组化法观察SNc及纹状体酪氨酸羟化酶(TH)和SNc中α-共核蛋白的表达;透射电镜观察SNc超微结构的改变. 结果 Lactacystin实验组大鼠给药7 d后出现自发性活动减少、动作缓慢、震颤、且症状逐步加重.APO可诱导出向健侧的旋转运动;Nissl染色发现Lactacystin实验组左侧SNc神经元数量减少,尼氏体结构松散;免疫组化结果表明21 d后Lactacystin实验组左侧SNc出现变性,TH免疫阳性神经元数量减少,α-共核蛋白表达增强,纹状体内TH免疫阳性纤维数量减少;电镜观察到蛋白质聚集形成的包涵体. 结论 Lactacystin单侧SNc注射可以诱导大鼠黑质变性伴包涵体形成及大鼠行为改变.蛋白酶体功能下降可能在PD发病机制中起重要作用.     

Low doses of gamma-hydroxybutyric acid stimulate the firing rate of dopaminergic neurons in unanesthetized rats.

In unanesthetized rats the intravenous (i.v.) administration of gamma-hydroxybutyric acid (GHB) at the doses of 50-400 mg/kg produced a dose-related stimulation (10-56%) of the firing rate of dopaminergic (DA) neurons in the pars compacta of the substantia nigra. Doses of 1000 and 1500 mg/kg inhibited the firing rate almost completely. In unanesthetized rats the intraperitoneal injection of GHB at the dose of 750 mg/kg produced a brief initial stimulation (23%) followed by a modest reduction in the firing rate (29%). On the other hand, in chloral hydrate-anesthetized rats the i.v. administration of GHB at cumulative doses of up to 200 mg/kg failed to modify the firing rate of DA neurons, while a cumulative dose of 400 mg/kg suppressed neuronal firing. The results indicate that sub-anesthetic doses of GHB stimulate the firing rate of DA neurons in unanesthetized rats.     

Dose-dependent biphasic alterations in the spontaneous activity of neurons in the rat neostriatum produced by D-amphetamine and methylphenidate

A dose-response analysis was performed on D-amphetamine- and methylphenidate-induced changes in neuronal activity in the neostriatum of immobilized, phenidate-induced changes in neuronal activity in the neostriatum of immobilized, locally anesthetized rats. Whereas a marked depression of firing rate characterized the response to intraperitoneal injections of 2.5 mg/kg D-amphetamine or 10 mg/kg methylphenidate, increasing the dose (5.0--7.5 mg/kg D-amphetamine and 20--25 mg/kg methylphenidate) shifted this response pattern to a prolonged increase in activity. Both stimulant-induced increases and decreases in neostriatal activity are reversed by 2.0 mg/kg haloperidol. In contrast to the response of neostriatal neurons, the firing rate in the substantia nigra pars compacta was inhibited by both stimulants, even at doses that increased the activity of neurons in the neostriatum. The possible mechanisms underlying these drug-induced changes in firing rate are discussed along with the behavioral implications of a stimulant-induced dose-dependent shift in neostriatal unit activity.     

Activation by nicotine of striatal neurons receiving excitatory input from the substantia nigra via dopamine release

An electrophysiological study was performed to elucidate the role of nicotinic receptors in the striatal neurons in chloral hydrate-anesthetized rats. The effects of microiontophoretic application of nicotine and other drugs were examined on the caudate nucleus (CN) neurons activated monosynaptically by stimulation of the substantia nigra pars compacta (SN). Application of nicotine facilitated spontaneous firing. The nicotine-induced firing of the CN neurons was inhibited by concomitant application of domperidone or hexamethonium. These findings suggested that nicotine enhances dopamine release from the SN-derived dopaminergic nerve terminals by activating the neurons via D2 receptors.     

Dopaminergic mechanisms in subthalamic nucleus of rat: analysis using horseradish peroxidase and microiontophoresis

Afferent connections to the subthalamic nucleus (STN) were studied by microiontophoretically injecting horseradish peroxidase (HRP) into the STN and studying its retrograde transport. Remotely labelled neurons were frequently observed in both the globus pallidus and the pars compacta region of substantia nigra. In addition, individually labelled neurons were occasionally found in other brain regions. The sensitivity of neurons in the STN to dopamine (DA) was studied by applying DA to neurons in the STN by microiontophoresis. Three patterns of response to DA were observed. The most frequent response, observed in 46% of the STN neurons studied, was a decrease in the discharge frequency. In 15% of the neurons there was an increased frequency of firing. Eleven percent of the neurons exhibited a mixed response consisting of an initial depression of discharge rate followed by a delayed increase. The responses of STN neurons to DA were not antagonized by iontophoretically applied haloperidol. In neurons whose firing frequency was decreased by DA, the iontophoretic application of apomorphine and norepinephrine also decreased discharge rate. The observations of HRP-labelled neurons in the pars compacta region of substantia nigra following injection of HRP into the STN together with the DA responsiveness of STN neurons suggest the possibility of a dopaminergic nigro-subthalamic pathway.     

Spreading of slow cortical rhythms to the basal ganglia output nuclei in rats with nigrostriatal lesions

A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.     

Effects of crus cerebri lesions and repeated amphetamine treatment on the activity of nigral dopaminergic neurons

Previous research suggests that the firing rate of dopamine (DA) neurons in the substantia nigra pars compacta (SNC) may be altered by repeated DA agonist treatment. Because changes in the frequency of DA activity could reflect the firing patterns (e.g., bursting) of the neurons sampled, this study examined both the firing rate and pattern of SNC DA neurons after long-term amphetamine (AMPH) treatment (5 mg/kg d-AMPH s.c. twice daily for 6 days). To assess the contribution of postsynaptic feedback from the forebrain, unilateral electrolytic lesions were made to the crus cerebri (CC), containing the striatonigral pathway, prior to AMPH treatment. Single-unit activity of presumed SNC DA neurons was recorded in adult male rats under urethane anesthesia. Spontaneous firing rate was reduced by AMPH treatment, relative to saline vehicle, but was unaffected by CC or sham lesions. Neurons categorized as bursting had faster rates of activity than nonbursting cells. AMPH treatment reduced the number of bursts seen in intact rats but increased bursting in lesioned rats. These results suggest that changes in DA firing rate previously found after chronic AMPH may reflect altered patterns of activity. In addition, the effects of long-term AMPH on the firing patterns of DA neurons appear to be mediated by fibers in the CC.     

Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease

We carried out an investigation to identify neuromelanin-containing noradrenergic and dopaminergic neurons in the locus ceruleus and substantia nigra pars compacta of healthy volunteers and patients with Parkinson's disease using a newly developed magnetic resonance imaging technique that can demonstrate neuromelanin-related contrast. The high-resolution neuromelanin images obtained by a 3-T scanner revealed high signal areas in the brain stem and these corresponded well with the location of the locus ceruleus and substantia nigra pars compacta in gross specimens. In Parkinson's disease patients, the signal intensity in the locus ceruleus and substantia nigra pars compacta was greatly reduced, suggesting depletion of neuromelanin-containing neurons. We conclude that neuromelanin magnetic resonance imaging can be used for direct visualization of the locus ceruleus and substantia nigra pars compacta, and may help in detecting pathological changes in Parkinson's disease and related disorders.     

Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats

Subthalamic nucleus lesion altered the statistical properties of the firing patterns of globus pallidus and substantia nigra pars reticulata neurons recorded in urethane anesthetized rats by increasing the proportion of cells in both structures that fired with a very highly regular pattern (from 25%to 50%). In all cases, the most regularly firing neurons fired at a higher mean rate than did more slowly firing neurons. In contrast, globus pallidus lesion shifted the pattern of substantia nigra neurons towards more irregular firing and induced a bursty pattern in two neurons.     

D1 dopamine receptor stimulation inhibits firing activity of midbrain dopamine neurons in reserpine treated rats: An effect eliminated after hemitransection of diencephalon

It has been reported that systemic administration of the D₁ dopamine (DA) receptor agonist SKF 38393 inhibits the firing rate of substantia nigra pars compacta (SNC, A9) DA neurons after repeated reserpine treatment in locally anesthetized rats, although SKF 38393 induces little effect on the firing of midbrain DA neurons in normal rats. The present study found that local pressure microejection of SKF 38393 (10⁻² M, 20–100 nl) to SNC or substantia nigra pars reticulata (SNR) failed to influence the firing of SNC DA neurons in reserpinized rats (reserpine 1 mg/kg × 6 days, s.c.); subsequent intravenous (i.v.) injection of SKF 38393 (4 mg/kg), however, inhibited their firing and the inhibition was reversed by the D₁ receptor antagonist SCH 23390. Similarly, systemic administration of SKF 38393 (4 mg/kg, i.v.) inhibited the firing of ventral tegmental area (VTA, A10) DA cells in reserpinized rats, while local microejection of SKF 38393 (10⁻² M, 30–60 nl) did not affect their firing. Furthermore, the inhibitory effect of systemic SKF 38393 on firing rate of either SNC or VTA DA neurons in reserpinized rats was eliminated after hemitransection of diencephalon. These results suggest that repeated reserpine treatment renders midbrain DA neurons responsive to D₁ receptor stimulation and that D₁ receptor agonist-induced inhibition of midbrain DA cell firing in reserpinized rats may require the involvement of long-loop feedback pathways. © 1996 Wiley-Liss, Inc.     

选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

目的腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用。然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT_(1A)受体的作用仍不清楚。本研究观察了6-羟基多巴胺(6- hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT_(1A)受体拮抗剂WAY-100635后神经元活动的改变。方法采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动。结果6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变。体循环给予WAY-100635 (0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率。结论黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT_(1A)受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT_(1A)受体功能失调。     

选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

目的 腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用.然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT1A受体的作用仍不清楚.本研究观察了6-羟基多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT1A受体拮抗剂WAY-100635后神经元活动的改变.方法 采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动.结果 6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变.体循环给予WAY-100635(0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率.结论 黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT1A受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT1A受体功能失调.