Post-treatment of dextromethorphan on methamphetamine-induced drug-seeking and behavioral sensitization in rats

In our previous study, we first demonstrated a significant effect of dextromethorphan (DM) on morphine‐seeking behavior in morphine‐dependent rats, when DM was given during morphine withdrawal. Using the same conditioned place preference (CPP) paradigm modified for measuring drug‐seeking‐related behavior, we further investigated the possible effect of DM on methamphetamine (MA)‐seeking in MA‐dependent rats. Our data showed that DM could also effectively suppress the drug‐seeking behavior for MA, when administered during MA withdrawal. This suggests that DM may possess a pharmacological property to prevent drug‐seeking behavior for addictive drugs in general. To examine the action sites of DM in the brain, DM was microinjected into the VTA or the NAc, and tested for its effect on MA‐seeking during withdrawal. Both intra‐VTA and intra‐NAc injections of DM were able to block the MA‐seeking, suggesting that DM has a dual action sites. In our neurochemical results, intra‐NAc injection of DM showed a clear reduction of DA turnover rate at the NAc and the mPFC in response to MA challenge during withdrawal, which matched with the behavioral results. However, intra‐VTA injection of DM reduced the DA turnover rate at the mPFC but did not have effect on the DA turnover rate at the NAc. Although further investigations may be needed to verify the connection between our neurochemical and behavioral results, the present study highlights the therapeutic potential of DM in antidrug‐seeking behavior of MA and that the mechanism could be related to its effect on the mesolimbic and mesocortical dopaminergic pathways. Synapse 2012. © 2012 Wiley Periodicals, Inc.     

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine‐related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5‐day withdrawal period. In addition, c‐Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c‐Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. Synapse 67:553–567, 2013. © 2013 Wiley Periodicals, Inc.     

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.     

Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice

G protein-coupled receptor (GPCR) associated sorting protein 1 (GASP-1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP-1 has been shown to regulate dopamine (D₂) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP-1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP-1 knockout (KO) mice and have examined the consequences of the absence of GASP-1 on chronic cocaine treatments. GASP-1 KO and wild-type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self-administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self-administration. Acute and sensitized cocaine-locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self-administration was also observed in GASP-1-deficient mice, which was associated with pronounced down-regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP-1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP-1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP-1 stimulates recycling rather than receptor degradation.     

Methylphenidate dose–response behavioral and neurophysiological study of the ventral tegmental area and nucleus accumbens in adolescent rats

The psychostimulant methylphenidate (MPD) is the most common medication used in treating ADHD in children. Studies have shown an increasing prevalence among adolescents without ADHD to take MPD as a cognitive booster and recreational drug, even though it is a Schedule II drug and has a high potential for abuse. The objective of this study is to explore if there is an association between the animals’ behavioral and neurophysiological responses to acute and/or chronic methylphenidate exposure within the ventral tegmental area and the nucleus accumbens, and to compare how these two brain structures fire in response to methylphenidate. Freely moving adolescent rats implanted with semimicroelectrodes within the VTA and NAc were divided into three MPD dosing groups: 0.6, 2.5, and 10 mg/kg i.p., as well as a saline control group. The animals were divided into two groups based on their behavioral responses to chronic MPD, behavioral sensitization and tolerance, and the neuronal responses of the two groups were compared for each MPD dosing. Significant differences in the proportion of neuronal units in the VTA and NAc responding to MPD were observed at the 0.6 and 10.0 mg/kg MPD dosing groups. Moreover, the same doses of 0.6, 2.5, and 10.0 mg/kg MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. This specific study shows that the VTA and NAc neurons respond differently to the same doses of MPD. MPD has different neuronal and behavioral effects depending on the individual, the dosage of MPD, and the brain structure studied.     

大鼠局灶性脑缺血再灌注损伤后GAP-43及IGF-1促进神经元再生表达的实验研究

目的探讨Wistar大鼠脑缺血再灌注损伤后生长相关蛋白GAP-43抑制神经元凋亡和胰岛素样生长因子-I(IGF-1),促进神经元再生的可塑性表达机制。方法将80只成年健康雄性Wistar大鼠,分为GAP-43组和IGF-1组,每组各40只,并随机分为正常对照组、假手术组和缺血1h再灌注2h、6h、12h、24h、48h、3d、7d、14d组,每组4只(n=4)。应用线栓法制备大鼠脑缺血再灌注动物模型,并采用免疫组织化学方法检测GAP-43与IGF-1在神经元凋亡中的表达情况,并进行图像分析。结果GAP-43组:缺血再灌注2h,海马、皮质区及纹状体区神经元GAP-43呈基础表达,6~48h表达逐渐增高,7d达高峰,14d达最低,P<005。与假手术组比较有显著性差异,P<005。IGF-1组:正常对照组及假手术组在海马区、皮质区及纹状体区IGF-1阳性标记出芽细胞呈基础表达。缺血再灌2hIGF-1表达明显增高,24h达高峰,P<0.05。48h恒定表达。3~14d仍维持高值表达,P<0.05。结论GAP-43与IGF-1参与抑制并促进神经元轴突再生的表达。     

Condition-independent sensitization of locomotor stimulation and mesocortical dopamine release following chronic nicotine treatment in the rat

Chronic nicotine (NIC) pretreatment has been shown to enhance NIC-induced locomotor stimulation, an effect that seems critically dependent on activation of brain dopamine (DA) systems. In the present study the effects of chronic, intermittent NIC treatment were examined in the rat to establish whether such behavioral sensitization is associated with specific, regional changes in brain dopaminergic activity. Male rats received daily injections in their home cage with either saline (SAL) or NIC (0.5 mg/kg, s.c.) for 12 days. Twenty-four hours later, the locomotor activity of the animals subjected to NIC challenge as well as the functional responsiveness of the mesolimbocortical dopaminergic system were assessed. To this end, microdialysis experiments were performed in awake animals, measuring extracellular concentrations of DA and its metabolites in the prefrontal cortex (PFC) and the nucleus accumbens (NAC). Extracellular single cell recordings from DA neurons in the ventral tegmental area (VTA) were also performed in anesthetized animals. NIC (0.5 mg/kg, s.c.) increased all measured parameters of locomotor activity, with the exception of rearing, in SAL-pretreated animals; these effects were substantially enhanced after pretreatment with NIC. Nicotine (0.5 mg/kg, s.c.) increased DA release in both the PFC and the NAC in SAL-treated animals. Nicotine pretreatment significantly enhanced this effect in the PFC, whereas it did not affect the response in the NAC. Low doses of intravenously administered NIC dose-dependently increased burst activity, starting at 12 μg/kg in the SAL pretreated animals and at 6 μg/kg in the NIC-pretreated animals, and also dose-dependently increased firing rate in SAL as well as NIC-pretreated animals, although starting at a higher dose level, i.e., 25 μg/kg. These results demonstrate that behavioral sensitization after chronic NIC treatment is accompanied by an enhanced dopamine release specifically within the PFC. This phenomenon may be highly significant for the dependence-producing effects of NIC, particularly in association with major psychiatric disorder, such as schizophrenia. © 1996 Wiley-Liss, Inc.     

运动训练对大鼠脑缺血再灌注后神经修复及GAP-43和Neurocan表达的影响

目的 观察运动训练对大鼠脑缺血再灌注后不同时间神经修复及GAP-43与Neurocan表达的影响.方法 健康雄性Wistar大鼠72只,随机分成运动训练组、对照组、假手术组.采用线栓法制作一侧大脑中动脉闭塞(MCAO)模型,以神经功能缺损评分和Morris水迷宫试验进行神经功能评价,免疫组化法观察对脑缺血周围GAP-43与Neuorcan的表达.结果 与对照组比较,脑缺血再灌注后14d、21d,运动组的肢体运动及记忆功能明显恢复;缺血再灌注后7d,对照组缺血周围出现GAP-43阳性细胞,14d减少,21d、28d明显减少,运动组GAP-43表达在14d、21d、28d较对照组显著增加(P<0.05).Neurocan阳性细胞在对照组缺血再灌注7d出现,14d达高峰,21d、28d时下降;运动组Neurocan表达在缺血再灌注14d、21d、28d较对照组显著减少(P<0.05).结论 运动训练上调大鼠脑缺血区GAP-43表达与下调Neurocan表达,可能是其促进脑损伤区中枢神经修复的重要机制之一.     

The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats

Background

Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABA_B heteroreceptor (GABA_BR) is determined by its stability, and hence residence time, on the plasma membrane.

Aims

Here, we show that GABA_BR in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression.

Materials & Methods

By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) to the control of GABA_BR membrane anchoring and cocaine induced-behavioral sensitization.

Results

Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABA_B1R and GABA_B2R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABA_BR was also decreased in NAc GAD₆₇⁺ neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABA_B1Rs exhibited perinuclear localization, a decrease in GABA_B1R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABA_B1R interaction.

Conclusion

These findings reveal a new mechanism by which pCaMKII-GABA_BR signaling can promote psychostimulant-induced behavioral sensitization.     

Glial cell line-derived neurotrophic factor-conjugated nanoparticles suppress acquisition of cocaine self-administration in rats

The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) may have therapeutic potential for preventing and treating cocaine addiction. Previously, we found that transplantation of a GDNF-expressing astrocyte cell line into the striatum and nucleus accumbens attenuates cocaine-seeking behavior in Sprague-Dawley rats. However, as a potential treatment for humans, cell transplantation presents several technical and ethical complications. Nanoparticulate systems are a safe and effective method for introducing exogenous compounds into the brain. Therefore, we examined the effect of GDNF-conjugated nanoparticles microinjected into the striatum and nucleus accumbens on cocaine self-administration in rats. GDNF-conjugated nanoparticles blocked the acquisition of cocaine self-administration compared to control treatments. Furthermore, a cocaine dose response demonstrated that decreased lever response in rats that received GDNF-conjugated nanoparticles persisted after substitution with different cocaine doses. This effect is not due to a non-specific disruption of locomotor or operant behavior, as seen following a water operant task. The current study is one of the first demonstrations that drug-conjugated nanoparticles may be effective in treating brain disorders. These findings suggest that GDNF-conjugated nanoparticles may serve as a novel potential treatment for drug addiction.     

Stimulation of ventral tegmental area and nucleus accumbens reduce receptive fields for hypothalamic biting reflex in cats

Stimulation of the ventral tegmental area (VTA) and nucleus accumbens (NA) suppressed attack behavior elicited by hypothalamic stimulation. Because the nondirected somatic motor and autonomic components of attack were not affected by VTA or NA stimulation, and previous work had demonstrated the importance of sensory guidance in attack, the mechanism for suppression was postulated to be on the sensory component of the attack reaction. We investigated the effects of VTA and NA stimulation on the biting reflex, one of the sensory-controlled components of hypothalamically elicited attack behavior. The receptive field for biting was measured during hypothalamic stimulation with and without concurrent VTA and NA stimulation. At stimulation parameters that inhibited attack, the extent of the receptive field was reduced. Thus, VTA and NA may produce inhibition of attack by acting on the sensory component of the response mechanism. We suggest that reduction of receptive fields is a mechanism by which behavioral inhibition is mediated in the central nervous system.     

Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area

In situ hybridization was combined with Fluoro-Gold retrograde labeling to determine if cells projecting from the forebrain to the ventral tegmental area (VTA) express D₁ receptor mRNA. Cell counts were made in the prefrontal cortex, shell of the nucleus accumbens, and ventral pallidum to estimate the percentage of neurons projecting to the VTA that express D₁ receptor mRNA. Retrogradely labeled cells were observed in the infralimbic and prelimbic regions of the prefrontal cortex, and up to 37% of the retrogradely labeled cells expressed D₁ receptor mRNA. Double-labeled cells constituted up to 89% of retrogradely labeled neurons in the rostral shell and up to 68% in the caudal shell of the nucleus accumbens. The number of retrogradely labeled cells in the ventral pallidum that were double-labeled ranged from 13% in the rostral to less than 10% in the caudal portions. These data provide anatomical support for a role of D₁ receptors in the reciprocal innervation between the forebrain and VTA. Synapse 25:205–214, 1997. © 1997 Wiley-Liss, Inc.     

Knockdown of tropomyosin‐related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress‐induced cross‐sensitization to amphetamine in rats

The nucleus accumbens (NAc) is a critical brain region for the rewarding effects of drugs of abuse. Brain‐derived neurotrophic factor (BDNF) can facilitate stress‐ and drug‐induced neuroadaptation in the mesocorticolimbic system. BDNF‐containing projections to the NAc originate from the ventral tegmental area (VTA) and the prefrontal cortex, and BDNF release activates tropomyosin‐related kinase B (TrkB). In this study, we examined the necessity for BDNF‐TrkB signaling in the NAc shell during social defeat stress‐induced cross‐sensitization to amphetamine. Adeno‐associated virus expressing short hairpin RNA directed against TrkB (AAV‐shTrkB) was infused bilaterally into the NAc shell to knock down TrkB, whereas AAV‐GFP (green fluorescent protein) was used as the control virus. Rats were exposed to intermittent social defeat stress or handling procedures; amphetamine challenge was given at 10 days after the last defeat and locomotor activity was measured. Stressed rats that received the control virus showed cross‐sensitization to amphetamine compared with the handled rats. In contrast, NAc TrkB knockdown prevented social defeat stress‐induced cross‐sensitization. TrkB knockdown in the NAc was found to reduce the level of phospho‐extracellular signal‐regulated kinase 1 in this region. NAc TrkB knockdown also prevented stress‐induced elevation of BDNF and the glutamate receptor type 1 (GluA1) subunit of AMPA receptor in the VTA, as well as ΔFosB expression in the NAc. These findings indicated that BDNF‐TrkB signaling in the NAc shell was required for social defeat stress‐induced cross‐sensitization. NAc TrkB‐BDNF signaling also appeared to be involved in the regulation of GluA1 in the VTA, as well as in the NAc ΔFosB accumulation that could trigger cross‐sensitization after social defeat stress.     

大鼠脑缺血再灌注损伤后GAP-43及IGF-1在神经系统中的表达

目的探讨大鼠脑缺血再灌注损伤后生长相关蛋白-43（GAP-43）和胰岛素样生长因子-1（IGF-1）的表达。方法成年健康雄性Wistar大鼠72只，随机分为GAP-43组36只和IGF-1组36只，每组再分为假手术组和缺血1h再灌注2h、6h、12h、24h、48h、3d、7d、14d组，每组4只（n=4）。应用线栓法制备大鼠脑缺血再灌注动物模型，免疫组织化学方法检测GAP-43与IGF-1在神经元中的表达。结果GAP-43组：缺血再灌注2h，皮质区、海马及纹状体区神经元GAP-43呈基础表达，6h后表达逐渐增高，7d达高峰，14d开始降低，较假手术组高（P〈0．05）。IGF-1组：缺血再灌2h IGF-1表达明显增高，24h达高峰，48h恒定表达，14d仍维持高表达，较假手术组高（P〈0．05）。结论GAP-43和IGF-1可能参与促进神经元轴突的再生。     

Distribution of B-50(GAP-43) mRNA and protein in the normal adult human spinal cord

B-50(GAP-43) is a phosphoprotein mainly found in the nervous system which plays a major role in neurite growth during development and regeneration as well as in synaptic remodelling. In the mature intact central nervous system, intense B-50 immunoreactivity (B-50-IR) can still be detected in regions which maintain residual capacity for structural re-organization. B-50 expression has been studied extensively in laboratory animals; however, its distribution and regulation in the human spinal cord is largely unknown. As a first step to analyze lesion-induced structural alterations, we investigated the distribution of B-50 protein and mRNA in the normal adult human spinal cord and dorsal root ganglia. Intense B-50-IR was localized to the superficial laminae of the dorsal horn at all segmental levels, the intermediolateral nucleus at thoracic levels and Onuf’s nucleus at sacral levels. Scattered neurons, particularly in the ventral horn of lumbar and sacral segmental levels (and occasionally also in Clarke’s nucleus) displayed intense B-50-IR in close apposition to the perikaryal and proximal dendritic surfaces. Nonradioactive in situ hybridization indicated that B-50 mRNA could also be detected in neurons of the ventral horn and also in the intermediolateral nucleus. The distribution of B-50 mRNA and protein in the normal human spinal cord shows a marked similarity to that reported in experimental animals, including the selective labelling of Onuf’s nucleus. However, the strong B-50-IR on the surface of some large anterior horn motor neurons has not been observed in other mammals. This finding might reflect a particular state of readiness for synaptic plasticity. Received: 4 August 1997 / Accepted: 27 October 1997     

Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D₁ family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18–22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D₁ ligand [³H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D₁ binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D₁ binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D₁ receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use. Synapse 28:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Dopamine-rich transplants in rats with 6-OHDA lesions of the ventral tegmental area. I. Effects on spontaneous and drug-induced locomotor activity

In order to investigate the relative contribution of dopaminergic projections to the nucleus accumbens and prefrontal cortex in the regulation of spontaneous and drug-induced locomotor activity, separate groups of rats were prepared with 6-OHDA lesions of the ventral tegmental area alone, or additional grafts of dopamine-rich tissue reinnervating either the nucleus accumbens or medial prefrontal cortex. A fourth unoperated group served as normal controls. The lesions induced no change in spontaneous, daytime activity, but increased overnight activity. The lesioned rats were also hyperactive to apomorphine, while the activational effects of amphetamine were blocked. Grafts of dopamine-rich tissue, whether into the prefrontal cortex or nucleus accumbens, resulted in a significant normalization of both drug responses towards control levels. Neither graft influenced overnight hyperactivity, whereas spontaneous daytime activity was increased above both control and lesion levels by the accumbens grafts alone. The results are interpreted as suggesting that dopaminergic projections to prefrontal cortex and nucleus accumbens are similarly rather than antagonistically involved in the regulation of drug-induced locomotor activation.     

环维黄杨星D对高血压大鼠脑缺血GAP-43 mRNA表达与细胞损伤的影响

目的观察中药单体环维黄杨星D(CVB-D)对易卒中型肾血管性高血压大鼠(RHRSP)脑缺血再灌注不同时间脑组织生长相关蛋白-43(GAP-43)mRNA表达与细胞超微结构损伤的影响。方法采用环形银夹使SD大鼠的双侧肾动脉狭窄,制成RHRSP,再用线栓法制成一侧大脑中动脉闭塞(MCAO)模型。用原位杂交等方法观察CVB-D对脑缺血2h后复流1d、7d、14d、30d不同时间点大鼠脑组织GAP-43mRNA表达、水含量、梗死面积百分率、行为学评分及细胞超微结构的干预作用。结果脑缺血2h复流后1d缺血区周围及海马可见GAP-43mRNA表达,7d明显增多至高峰,14d开始下降,30d时则明显减少,CVB-D治疗组在上述区域各时间点较对照组显著增加。脑缺血再灌注7d后,治疗组较对照组大鼠脑水含量及梗死面积显著降低,受损脑组织神经元和血管壁的超微结构亦明显改善。结论CVB-D对RHRSP缺血性脑细胞损伤有一定保护作用,其促进轴突的再生可能与上调脑组织GAP-43mRNA表达有关。     

Electrophysiological responses of neurones in the nucleus accumbens to hippocampal stimulation and the attenuation of the excitatory responses by the mesolimbic dopaminergic system

Extracellular single unit recordings were obtained from neurones in the nucleus accumbens of urethane anaesthetized rats. Single pulse stimulation (300-800 microA, 0.15 ms, 0.5-1.5 Hz) of the ventral subiculum of the hippocampus strongly excited silent and spontaneously active (3-6 spikes/s) medial accumbens neurones. The majority of neurones excited by hippocampal stimulation were quiescent and identified only by the elicited action potentials. Neurones on the dorso-medial border of the nucleus accumbens and adjacent lateral septum, with a faster spontaneous discharge rate (8-12 spikes/s), were inhibited by hippocampal stimulation. In the ventral border of the accumbens and the olfactory tubercle, hippocampal stimulation also inhibited the fast-firing (greater than 20 spikes/s) neurones. When trains of 10 conditioning pulses (300-800 microA, 0.15 ms, 10 Hz) were delivered to the ventral tegmental area (VTA) 100 ms before each single-pulse stimulation of the hippocampus, the excitatory responses of the silent and spontaneously active accumbens neurones were attenuated. The possibility of this relatively prolonged attenuation effect being dopamine-mediated was supported by several lines of evidence. Dopamine, applied iontophoretically, reduced markedly the excitatory response of accumbens neurones to hippocampal stimulation. Iontophoretically applied dopamine mimicked the attenuating effect produced by VTA conditioning stimulation in the same neurone. The attenuating effects of VTA conditioning stimulation on the activation of accumbens neurones by hippocampal stimulation was reduced by: (1) administration of 6-hydroxydopamine to the VTA 2 days and 7-9 days prior to the recording session, (2) the intraperitoneal injection of haloperidol 1 h before the recording session, and (3) the iontophoretic application of trifluoperazine to accumbens neurones. These observations support the hypothesis that the attenuating effects of the mesolimbic dopamine system on limbic inputs to the nucleus accumbens may have a role in limbic-motor integration.