An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice / 神经科学通报·英文版

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

Resting-state functional connectivity alterations of ventral tegmental area in adult male smokers: a functional magnetic resonance imaging study / 中华行为医学与脑科学杂志

Objective:To investigate the alterations of resting-state functional connectivity (RSFC) in ventral tegmental area (VTA) and substantia nigra (SN) among male smokers, and its correlation with clinical characteristics of smoking.Methods:The resting-state functional magnetic resonance data of 131 subjects recruited from January 2014 to December 2018 were analyzed retrospectively, including 76 smokers (smoking group) and 55 non-smokers (control group). VTA/SN was selected as regions of interest (ROI), and then calculated RSFC between VTA/SN and the whole brain.Based on SPM12 software, independent sample t-test was conducted to compare the differences in RSFC between smoking group and control group.Based on SPSS 22.0 software, Pearson correlation analysis was used to investigate the relationships between the RSFC of brain regions with significant differences and Fagerstr?m test for nicotine dependence (FTND) score, pack-year of smokers. Results:Compared with control group, the results showed decreased RSFC between VTA and the brain regions related default mode network (DMN)(including posterior cingulate cortex, right anterior cuneiform lobe, bilateral superior temporal gyrus, right middle temporal gyrus and right inferior parietal lobule), and regions of limbic system(including right marginal lobe and right angular gyrus), right calcarine (MNI: x, y, z=24, -55, -14) and left insula(MNI: x, y, z=-35, -11, 9) in smoking group(GRF corrected, voxel level P<0.005, cluster level P<0.05). Taking SN as the seed, there was no significant difference between smoking group and control group ( P>0.05). RSFC of VTA-left superior temporal gyrus was positively correlated with pack-year( r=0.243, P=0.034) and FTND ( r=0.282, P=0.014). VTA-left insula RSFC was positively correlated with FTND ( r=0.316, P=0.006). Conclusion:The RSFC in the mesolimbic system and the VTA-DMN circuit exist abnormal changes in smokers.To some extent, it may explain the reward deficits and dysfunction of emotion regulation in smokers, which may provide clues for further understanding the mechanism of tobacco addiction.

Dopaminergic Neurons in the Ventral Tegmental-Prelimbic Pathway Promote the Emergence of Rats from Sevoflurane Anesthesia / 神经科学通报·英文版

Dopaminergic neurons in the ventral tegmental area (VTA) play an important role in cognition, emergence from anesthesia, reward, and aversion, and their projection to the cortex is a crucial part of the "bottom-up" ascending activating system. The prelimbic cortex (PrL) is one of the important projection regions of the VTA. However, the roles of dopaminergic neurons in the VTA and the VTADA-PrL pathway under sevoflurane anesthesia in rats remain unclear. In this study, we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist (Chloro-APB) into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats, while injection of a dopamine D1 receptor antagonist (SCH23390) deepened anesthesia. The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTADA-PrL pathway prolonged the induction time and shortened the emergence time of anesthesia. These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTADA-PrL pathway facilitates emergence from sevoflurane anesthesia.

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice / 神经科学通报·英文版

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Effect of acupuncture on pain-emotion related brain regions in patients with cervical spondylosis of cervical type: a fMRI study / 中国针灸

OBJECTIVE@#To observe the changes of functional connectivity of brain pain-emotion regulation region in patients with cervical spondylosis of cervical type by functional magnetic resonance imaging (fMRI).@*METHODS@#Thirty-two subjects were selected. Of them, 16 patients with cervical spondylosis of cervical type were divided into an observation group and 16 healthy subjects into a control group. The patients in the observation group were treated with acupuncture at Tianzhu (BL 10), Jingbailao (EX-HN 15), Jianzhongshu (SI 15) and @*RESULTS@#In the observation group, the VAS score was (1.94±1.12) after the treatment, which was lower than (5.62±1.20) before treatment (@*CONCLUSION@#Pain involves the formation and expression of "pain-emotion-cognition". Acupuncture can systematically regulate the brain functional connections between cognitive regions such as dorsal prefrontal lobe and anterior cingulate gyrus and emotional regions such as insula and VTA in patients with cervical spondylosis of cervical type, suggesting that acupuncture has a multi-dimensional and comprehensive regulation effect on pain.

Reinforcement omission effects in rats with bilateral lesions in the substantia nigra pars compacta and ventral tegmental area

Reinforcement omission effects (ROEs) are characterized by higher response rates after reinforcement omission than after reinforcement delivery. This pattern of behavior is interpreted in terms of motivational and attentional processes. Recent studies from our laboratory have shown that the amygdala, nucleus accumbens, and medial prefrontal cortex are involved in ROE modulation. Also, the literature has demonstrated a role of other areas such as substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) in processes related to surprising events, such as prediction error and presentation or omission of an event (exteroceptive stimulus and reinforcement). Since these structures send projections to areas related to ROE modulation such as the amygdala, nucleus accumbens, and prefrontal cortex, the objective of the present study was to determine whether the SNc and VTA also integrate the circuit involved in ROE modulation. Rats were trained on a fixed-interval 12 s with limited-hold 6 s signaled schedule of reinforcement (Pre-lesion training). After acquisition of stable performance, the rats received bilateral neurotoxic lesions of the SNc (Experiment 1) and VTA (Experiment 2). Following postoperative recovery, the rats were submitted to two refresher sessions (Post-lesion training). Subsequently, the training was changed from a 100 to a 50% schedule of reinforcement (Post-lesion testing). In both experiments, the results showed that there was no difference in performance between sham rats and rats with bilateral lesions of the SNc or the VTA.

Mechanism of dopaminergic neurotransmission on morphine addiction and stress depression / 中国药理学通报

Morphine addiction causes the disturbance in the dopaminergic transmission. The activity of dopaminergic neurons in patients with stress depression is reduced. These studies indicate a strong correlation between morphine addiction and stress depression, which involvement of one or more common neurobiological mechanisms. The dysfunction of dopaminergic neurotransmission from the ventral tegmental area(VTA) to the nucleus accumbens (NAc), prefrontal cortex (mPFC), amygdala (Amy), hippocampus (Hip), and striatum (ST) plays an important role in regulating morphine addiction and stress depression. This article summarizes the mechanism of the dopaminergic transmission regulating morphine addiction and stress depression.

Neural circuit mechanisms in mesolimbic reward system underlying opioid addiction / 中国药理学通报

Opioid addiction has high incidence and does great harm to individuals and society. The mesolimbic reward system plays an important role in opioid addiction. Previous studies have focused on functional adaptations in specific brain regions of the mesolimbic reward system, but the neuronal interactions in mesolimbic reward system underlying opioid addiction remain unknown. The paper reviews the neural circuit mechanisms in mesolimbic reward system involved in opioid addiction, in order to provide a broader vision for understanding the mechanisms of opioid addiction.

Correlation between bilateral lesion of anterior ventral tegmental area and depression-like behavior in rats / 西安交通大学学报(医学版)

Objective: To explore the correlation between bilateral anterior ventral tegmental area (aVTA) and depression-like behavior in rats. Methods The subjects in the study were aVTA-lesioned rats which were prepared by microinjecting 6-OHDA into their aVTA nucleus. Four weeks after the operation, all the rats were examined by behavior tests, including open-field test, sucrose preference test, and forced swimming test. We recorded and calculated the number of squares crossed, rearings, sucrose preference, immobility time. Immunohistochemistry method was used to observe the change of TH-positive neurons' number in bilateral aVTA and SNc of the 6-OHDA lesioned rats. Meanwhile, we analyzed and compared the changes of DA, 5-HT, NE levels in themPFC, LHb, STr and VHPC in the two groups of rats by high performance liquid chromatography with electrochemical detection (HPLC-ED). Results ① Bilateral aVTA lesions in the rats significantly decreased the number of squares crossed and rearings and sucrose preference, increased immobility time when compared with the sham-operated rats (P<0.001). ② In the lesioned rats, the aVTA of the bilateral injected side showed partial loss of TH-ir neurons when compared with the sham-operated rats, and the bilateral SNc in aVTA lesioned rats had a coherence of changing trend, showed a certain decrease (P<0.001). ③ Compared with sham-operated rats, bilateral aVTA 6-OHDA lesioned rats' 5-HT levels in the mPFC, STr, LHB and VHPC significantly decreased. Likewise, 6-OHDA lesioned rats' NA levels in the mPFC, striatum, and habenula vHPC significantly decreased, too(P<0.001). However, bilateral aVTA 6-OHDA lesioned rats' DA levels only in the striatum showed significantly decreased when compared to the sham-operated rats (P<0.001). Conclusion Bilateral aVTA is involved in depression-like behavior. DA neurons of the VTA and the changes of monoamine neurotransmitters of the limbic and limbic-related areas may be involved in the development of depression.

Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats

Objective: To investigate the effect of crocin carotenoid on BNDF and CREB gene expression in the brain ventral tegmental area (VTA) and the serum level of BDNF in morphine-treated rats compared to control. Methods: In this study, 40 male Wistar rats (200-250 g) were used in 5 experimental groups: 1) non morphine treat rats (control); 2) non morphine-treated rats with 25 mg/kg crocin carotenoid (i.p., for 21 d); 3) morphine treated rats (10 mg/kg twice a day, s.c., 21 d); 4 and 5) morphine-treated rats with 12.5 and 25 mg/kg crocin carotenoid, respectively. By the end of research, BDNF and CREB expression was determined by real-time-PCR method. ELISA analysis was also applied for assessing the serum BDNF level. Results: The data indicated that morphine treatment could cause a significant decrease in BDNF and CREB gene expression (P<0.01 and P<0.001, respectively) in brain VTA as well as serum level of BDNF (P<0.01) in comparison to control group. Treatment with 25 mg/kg crocin carotenoid caused a significant enhancement in BDNF and CREF gene expression (P<0.01 and P<0.05, respectively) and serum level of BDNF (P<0.01) in morphine-treated rats in comparison to morphine-treated group. Conclusions: Regarding to obtained results, crocin carotenoid can inhibit unfavorable effects of morphine on the neural system to some extent through enhancing BDNF and CREB gene expression in brain VTA and serum level of BDNF.

Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats

Objective: To investigate the effect of crocin carotenoid on BNDF and CREB gene expression in the brain ventral tegmental area (VTA) and the serum level of BDNF in morphine-treated rats compared to control. Methods: In this study, 40 male Wistar rats (200-250 g) were used in 5 experimental groups: 1) non morphine treat rats (control); 2) non morphine-treated rats with 25 mg/kg crocin carotenoid (i.p., for 21 d); 3) morphine treated rats (10 mg/kg twice a day, s.c., 21 d); 4 and 5) morphine-treated rats with 12.5 and 25 mg/kg crocin carotenoid, respectively. By the end of research, BDNF and CREB expression was determined by real-time-PCR method. ELISA analysis was also applied for assessing the serum BDNF level. Results: The data indicated that morphine treatment could cause a significant decrease in BDNF and CREB gene expression (P<0.01 and P<0.001, respectively) in brain VTA as well as serum level of BDNF (P<0.01) in comparison to control group. Treatment with 25 mg/kg crocin carotenoid caused a significant enhancement in BDNF and CREF gene expression (P<0.01 and P<0.05, respectively) and serum level of BDNF (P<0.01) in morphine-treated rats in comparison to morphine-treated group. Conclusions: Regarding to obtained results, crocin carotenoid can inhibit unfavorable effects of morphine on the neural system to some extent through enhancing BDNF and CREB gene expression in brain VTA and serum level of BDNF.

Volume Gain of Brainstem on Medication-Overuse Headache Using Voxel-Based Morphometry / 中华医学杂志(英文版)

<p><b>Background</b>Histopathology identified the anatomical and molecular abnormalities of brainstem nuclei in migraine patients. However, the exact whole brainstem structural changes in vivo have not yet been identified in medication-overuse headache (MOH) transformed from migraine. The aim of this study was to investigate the regional volume changes over the whole brainstem in the MOH patients using voxel-based morphometry (VBM) in vivo.</p><p><b>Methods</b>High-resolution three-dimensional structural images were obtained using a 3.0-Tesla magnetic resonance system from 36 MOH patients and 32 normal controls (NCs) who were consecutively recruited from the International Headache Center, Chinese People's Liberation Army General Hospital, from March 2013 to June 2016. VBM was used to assess the brainstem structural alteration in the MOH patients, and voxel-wise correlation was performed to evaluate the relationship with the clinical characteristics.</p><p><b>Results</b>The brainstem region with increased volume located in the left ventrolateral periaqueductal gray (MNI coordinate: -1, -33, -8), ventral tegmental area (MNI coordinate: 0, -22, -12), bilateral substantia nigra (MNI coordinate: -8, -16, -12, 9, -16, -12), and trigeminal root entry zone (MNI coordinate: -19, -29, -31; 19, -32, -29) in MOH patients compared with NCs. The headache visual analog scale score was positively related with the left rostral ventromedial medulla (RVM) (MNI coordinate: -1, -37, -56; cluster size: 20; r = 0.602) in the MOH patients.</p><p><b>Conclusions</b>The regional volume gain of brainstem could underlie the neuromechanism of impaired ascending and descending pathway in the MOH patients, and the left RVM volume alteration could imply the impaired tolerance of nociceptive pain input and could be used to assess the headache disability in the MOH patients.</p>

Research on effect of midbrain VTA dopaminergic neurons in general anesthesia / 重庆医学

Objective To investigate the effect of dopaminergic neurons of midbrain ventral tegmental area(VTA) in general anesthesia.Methods Forty adult healthy male SD rats were randomly divided into lesion group (n=20) and control group (n=20).The lesion group was given the bilateral infusion of specific dopaminergic neuron injury agent 6-OHDA in midbrain lateral VTA,while the control group received the same volume of normal saline at the same areas.The time of loss of righting reflex (LORR)loss and recovery of righting reflex(RORR)at postoperative 2 week were observed in each group.Results Compared with the control group,the LORR time in the lesion group was shortened and the RORR time was significantly prolonged under propofol-induced anesthesia (P＜0.05).However,the LORR time under the isoflurane anesthesia had no statistically significant difference between the two groups(P＞0.05),while the RORR time in the lesion group was increased(P＜0.05).Conclusion Dopaminergic neurons in midbrain VTA might play different roles in the induction and recovery of different general anesthetics.

Protective effect of Mrh-aFGF on the neurons in ventral tegmental area of rats with Parkinson’ s disease / 局解手术学杂志

Objepctive To explore the protective effect of modified recombinant human aFGF ( Mrh-aFGF) on the neurons in ventral tegmental area of rats with Parkinson’ s disease ( PD) . Methods The 54 SD rats were ramdomly divided into the control group,the model group and the treatment group,and there were 18 rats in each group. PD rats of the model group and the treatment group were induced by in-jecting 6-OHDA into the left substantia nigra compacta ( SNC) and ventral tegmental area ( VTA) to build the PD model. Rats in the treat-ment group were given Mrh-aFGF injection after lateral ventricle injection,and the behavioral changes of the rats were detected after apomor-phine injection. The morphologic features and pathological changes of neurons in the ventral tegmental area were observed by Nissl’ s staining and electronic microscope. Results Compared to the right VTA of PD rats,the number of neurons in left side ( the injured side) decreased significantly in the model group(P<0. 05). In the treatment group,the structure of left (the injured side) VTA was markedly improved and the number of neurons was increased one week,two weeks and four weeks after operation compared with the model group (P<0. 05). The neurons in the VTA of the model group were found to have karyopyknosis,endoplasmic reticulum,degranulation,mitochondria swelling,cristae disappear,pre-synaptic and post-synaptic membranes swelling,and synaptic cleft disappear. In the treatment group,the ultrastructure of the neurons in the VTA,such as nuclei,mitochondria,synaptic structure,kept well compared to the model group. Conclusion Mrh-aFGF could protect the neurons in the ventral tegmental area from the loss and improve the ultrastructure of the neurons of PD rats.

How Leptin Controls the Drive to Eat

A complex set of brain based systems modulate feeding to maintain constant body weight. The adipose derived-hormone, leptin, plays a crucial role in this control by acting on diverse leptin receptor (LepRb)-expressing neurons in the hypothalamus and brainstem to modify behavior and metabolism. In addition to controlling energy expenditure and satiety, leptin controls motivation and the reward value of food by regulating two interconnected systems: hypocretin (HCRT) neurons and the mesolimbic dopamine (MLDA) system. Modest/acute decreases in leptin levels, as associated with mild caloric restriction, increase MLDA activity and overall food-seeking behavior; in contrast, severe starvation or complete leptin deficiency blunt MLDA activity, along with motivation and associated behaviors. Lateral hypothalamic (LHA) LepRb neurons project to dopamine (DA) neurons in the ventral tegmental area, where neurotensin (NT) release augments MLDA function; these LepRb(NT) cells also innervate HCRT neurons to control Hcrt expression and inhibit HCRT neurons. Ablation of LepRb in these cells abrogates the control of HCRT cells by leptin and decreases activity and MLDA function. We propose that this neural pathway regulates the MLDA, activity, and motivation in response to leptin and nutritional status.

Progress on brain-derived neurotrophic factor participating in pain-depression comorbidity / 中国药理学通报

The comorbidity of pain and depression is common. Both disorders might share common neuroanatomical and molecu-lar mechanisms. Recent studies have found that the brain-de-rived neurotrophic factor( BDNF) ,which plays an important role in the process of pain-depression comorbidity, has gradually be-come a hot topic and target of treatment. The article mainly sum-marizes the mechanism underlying comorbid pain and depres-sion,as well as the significance of blood BDNF in diagnosis and treatment of pain and depression.

Effects of neuroactive peptide urocortin 2 on VTA neuron′s spontaneous discharge and DA-ergic neurotransmission in morphine addiction / 中国药理学通报

Aim To investigate the inhibitory effects of urocortin2 (UCN2) on ventral tegmental area (VTA) nervous activity of morphine addiction rats and the mechanism. Methods Morphine addiction rats and the microiontophoresis method were used to observe the effects of UCN2 on VTA neuron′s spontaneous dis-charge changing rule, as well as the inhibitory effects of UCN2 on DA neuron′s cluster spontaneous dis-charge, to identify UCN2 and DA on the same VTA neuron. Morever, the inhibitor of corticotropin-regula-ting factor′s receptor ( CRF-2 R ) and the blocker of protein kinase A ( PKA ) , AST-2 B and H89 , were used to investigate the effects of UCN2 on VTA neuron′s of morphine addiction rats. Results UCN2 could inhibit the firing rate 82% (31/38) of the tested VTA neuron ( P<0. 01 ) , the discharge frequency changed from (20. 89 ± 2. 86) Hz to (13. 66 ± 3. 93) Hz (P<0. 01). Further, the inhibitor of PKA, AST-2B and H89 could ablolish the inhibitory effects of UCN2 . Morever, the excitatory firing of VTA neurons was at-tenuated by addition of UCN2 , while AST application could inhibit the UCN2′s inhibitory effects. Conclu-sion UCN2 could regulate the effects of VTA via PKA pathway and may thereby contribute to the improvement of drug addiction.

Procesamiento central del dolor neuropático: una aproximación integrativa / Central processing of neuropathic pain: an integrative approach

The term pain matrix refers to the structures and pathways in the central nervous system that play a role in pain processing and integration. For the last several years, our group has been studying the mechanisms that are involved in the establishment of long-term pain. Our research focus has been the study of the different nuclei and corticolimbic pathways that are involved in the affective-cognitive component of pain. In addition, we have also explored painful processes and memory. The pain matrix is constituted by the ventral tegmental area (VTA), anterior cingulate cortex (ACC), and insular cortex, among others. VTA is a predominantly dopaminergic area and has projections to ACC and the insular cortex. Stimulation of this region can reduce nociception, whereas its lesion has the opposite effect. In the ACC, it has been studied how excitatory aminoacids, such as glutamate, increase nociception while inhibitory ones decrease it. Moreover, this cortex is associated with mechanisms of pain memory. In this sense, we have seen that blocking cholinergic receptors diminishes the acquisition of pain-related memories. Nociceptive stimuli increase the expression of inhibitory muscarinic M2 receptors. In relation with insular cortex, the focus of study has been on the dopaminergic system. We have found that blocking dopaminergic D2 receptors significantly reduces neuropathic nociception. In response to an inflammatory process there is a decrease in the extracellular levels of dopamine and in the expression of mRNA for excitatory dopamine D1 receptors, while there is an increase in mRNA expression for inhibitory D2 receptors. Despite current progress in this research area, more studies are needed in order to integrate the relationship among the different neurotransmission systems. This will contribute to the proposal of novel therapeutic alternatives to the conventional treatments for pain.

El término "matriz del dolor" se refiriere a todas las estructuras y vías del Sistema Nervioso Central relacionadas con la integración del dolor. Nuestro grupo estudia desde hace varios años los principales mecanismos involucrados en el desarrollo del dolor a largo plazo. Nos hemos enfocado en el estudio de diferentes núcleos y vías cortico-límbicas que están relacionadas con la parte afectiva-cognitiva, así como en la memoria de los procesos dolorosos. Dentro de estos núcleos se encuentra el área tegmental ventral (ATV), la corteza anterior del cíngulo (CAC) y la corteza insular. El ATV es una estructura principalmente dopaminérgica con proyecciones a la CAC y a la corteza insular. Como se verá más adelante, estimular este núcleo disminuye la nocicepción, mientras que el lesionarlo, la aumenta. En la CAC se ha estudiado cómo aminoácidos excitadores como el glutamato aumentan la nocicepción y cómo, por el contrario, los aminoácidos inhibitorios como la taurina, la disminuyen. Además esta corteza está relacionada con mecanismos de memoria dolorosa. Hemos visto que el bloqueo de receptores colinérgicos disminuye la adquisición de la memoria relacionada al dolor. Además, un estímulo nociceptivo aumenta la expresión de los receptores muscarínicos inhibitorios M2. En el caso de la corteza insular, se ha estudiado principalmente el papel del sistema dopaminérgico. Hemos encontrado que el bloqueo de receptores dopaminérgicos D2 disminuye de manera significativa la nocicepción neuropática. Encontramos también que los niveles extracelulares de dopamina en esta región disminuyen a consecuencia de un proceso inflamatorio, además de que disminuye la expresión del RNAm de los receptores excitadores D1 y aumenta la de los receptores inhibidores D2. A pesar del avance que se ha obtenido en esta área de investigación, se necesitan más estudios para integrar la relación entre los diferentes sistemas de neurotransmisión y poder proponer alternativas a los tratamientos convencionales para las diferentes patologías que cursan con una experiencia dolorosa.

Transcriptional Mechanisms of Drug Addiction

Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (DeltaFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFkappaB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

Effects of nicotine exposure and ethanol-preferring behavior on mRNA expression of some nAChR subunits in the rat VTA / 中华行为医学与脑科学杂志

ObjectiveTo investigate the effects of nicotine exposure and ethanol-preferring behavior on mRNA expression of some nAChR subunits in the rat ventral tegmental area(VTA) and to explore possible mechanisms of dependence on tobacco and alcohol.Methods39 male Wistar rats,35-day-old,were randomly divided into an experimental group (group N,n=20) and a control group (group C,n=19).Rats in group N were treated with nicotine ( 1.0 mg · kg -1 · d -1 ) by subcutaneous injection while in group C with saline both for 10 days,after which 6 rats (respectively group NE,n =6,group CE,n =6 )were drawn randomly from each group and killed by cutting off the head.mRNA was extracted from the VTA tissue,and the expression of nAChR subunits,including α4,α5,α7 and β2,were examined by Real Time-PCR.Other rats both in groups N and C ( respectively group NA,n=14,group CA,n=13) were induced for 69 days to establish two-bottle free choice alcohol-preferring behavior model by Samson sucrose fading program from 60-day-old on.The same indexes mentioned above were detected by the same methods in the VTA tissue.Results① The factor analysis showed that both the two factors,nicotine and alcohol-preferring behavior,showed regulating effects on the expression of nAChR subunits α4 and α5 ( respectively F was 6.13,5.407,5.186,7.132,P ＜ 0.05 ),and the factor,alcohol-preferring behavior,on subunit β2 (F =5.896,P＜0.05) ; the two factors exhibited strong interaction on the expression of subunit α7 (F=13.894,P＜0.001 ),and some interaction on subunits α5 and β2 (respectively F was 6.149,4.222,P＜0.05 ).② The mRNA expression of nAChR subunits α4,α5,α7,and β2 were significantly up-regulated by different degrees in group NA compared to group CA ( respectively Fwas 7.941,13.517,17.438,9.272,respectively P ＜ 0.05,P ＜ 0.05,P ＜ 0.01,P ＜ 0.01 ),the expression level of subunits α4,α5,α7 and β2 were significantly higher in different degrees in group NA than in group NE( respectively F was 5.293,8.500,6.149,4.837,P ＜0.05) ; while subunit α7 was significantly down-regulated in group CA compared to group CE (F =12.750,P ＜0.01 ).ConclusionNicotine and ethanol co-affect on the nAChR subtype comprised of subunits α4,α5,α7 and β2.