The role of serotonergic neurons in dorsal raphe, median raphe and anterior hypothalamic pressor mechanisms

The role of serotonergic neurons in the dorsal raphe and median raphe in the pressor response to electrical stimulation of these areas, and the contribution of these neurons to the pressor response to serotonin (5-HT) in the anterior hypothalamus-preoptic area (AH/PO) have been studied by the use of local injections of 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin selective for 5-hydroxytryptamine (5-HT). When blood pressure was recorded in urethane-anesthetized rats, selective lesions of 5-HT-containing neurons in the dorsal raphe nucleus reduced by 60% the pressor response to electrical stimulation (50 Hz, 100-150 microA, 0.3 msec pulse duration) of this nucleus. On the other hand, selective lesion of 5-HT-containing neurons in the median raphe nucleus had no effect on the pressor response to electrical stimulation of this area. Injection of 5,7-dihydroxytryptamine into the anterior hypothalamus/preoptic area resulted in an increased pressor response to the injection of 5-HT (5 nmol) into the lesioned area 10 days later. Furthermore, the destruction of 5-HT-containing neurons in the dorsal raphe nucleus resulted in an enhanced pressor response to the injection of 5-HT (5 nmol) into the anterior hypothalamus/preoptic area, while the destruction of 5-HT-containing neurons in the median raphe nucleus had no effect on the pressor response to the injection of 5-HT (5 nmol) into the anterior hypothalamus/preoptic area. Therefore, it appears that 5-HT neurons in the dorsal raphe nucleus are important in the pressor response to electrical stimulation and are involved in a pressor mechanism in the anterior hypothalamus/preoptic area.(ABSTRACT TRUNCATED AT 250 WORDS)     

二氢埃托啡的条件性位置偏爱效应

目的··：研究二氢埃托啡（ＤＨＥ）在大鼠的精神依赖性潜力，并探讨ＤＨＥ偏爱效应的神经解剖基础。方法··：采用有倾向性程序的条件性位置偏爱实验模型，给药方法有皮下给药和核团内给药。结果··：ＤＨＥ在０．５ｎｇ·ｋｇ－１的微小剂量下，就能产生位置偏爱效应，随着剂量的增加，偏爱程度有所增强。微量ＤＨＥ分别注射到腹侧被盖区（ＶＴＡ）和伏隔核（ＮＡｃ）产生偏爱效应。结论··：ＤＨＥ的精神依赖性非常强大，ＶＴＡ－ＮＡｃ通路在ＤＨＥ偏爱效应中起重要作用。     

孕酮对大鼠吗啡位置偏爱效应及中枢单胺递质水平的影响

目的观察孕酮对于吗啡所致奖赏效应及脑内单胺类神经递质水平的影响。方法采用大鼠条件性位置偏爱(CPP)模型,高效液相色谱-电化学法测定大鼠伏隔核及腹侧被盖区内去甲肾上腺素(NE)、多巴胺(DA)和5羟色胺(5HT)的含量。结果吗啡(5mg·kg-1)可诱导大鼠产生稳定的CPP效应;孕酮(5、20mg·kg-1)本身不产生CPP效应,但能抑制吗啡的CPP效应。与对照组比较,吗啡CPP形成时,伏隔核内NE和DA的水平明显升高(P<0.01)。与吗啡组比较,合用5mg·kg-1或20mg·kg-1孕酮均可使伏隔核内DA水平下降(P<0.01,P<0.05);合用20mg·kg-1孕酮还可使伏隔核内的NE水平下降(P<0.01)。结论孕酮可有效抑制吗啡的CPP效应,其机制可能与降低伏隔核内DA及NE的水平有关。     

Alpha-1 Adrenergic Receptors are Localized on Presynaptic Elements in the Nucleus Accumbens and Regulate Mesolimbic Dopamine Transmission

Brainstem noradrenergic neurons innervate the mesocorticolimbic reward pathway both directly and indirectly, with norepinephrine facilitating dopamine (DA) neurotransmission via α1-adrenergic receptors (α1ARs). Although α1AR signaling in the prefrontal cortex (PFC) promotes mesolimbic transmission and drug-induced behaviors, the potential contribution of α1ARs in other parts of the pathway, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc), has not been investigated before. We found that local blockade of α1ARs in the medial NAc shell, but not the VTA, attenuates cocaine- and morphine-induced locomotion. To determine the neuronal substrates that could mediate these effects, we analyzed the cellular, subcellular, and subsynaptic localization of α1ARs and characterized the chemical phenotypes of α1AR-containing elements within the mesocorticolimbic system using single and double immunocytochemical methods at the electron microscopic (EM) level. We found that α1ARs are found mainly extra-synaptically in axons and axon terminals in the NAc and are enriched in glutamatergic and dopaminergic elements. α1ARs are also abundant in glutamatergic terminals in the PFC, and in GABA-positive terminals in the VTA. In line with these observations, microdialysis experiments revealed that local blockade of α1ARs attenuated the increase in extracellular DA in the medial NAc shell following administration of cocaine. These data indicate that local α1ARs control DA transmission in the medial NAc shell and behavioral responses to drugs of abuse.     

Extrasynaptic Glycine Receptors of Rodent Dorsal Raphe Serotonergic Neurons: A Sensitive Target for Ethanol

Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol''s actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory ‘phasic'' post-synaptic currents mediated primarily by synaptic GABA_A receptors (GABA_AR) and, to a lesser extent, by synaptic glycine receptors (GlyR). In addition to such phasic transmission mediated by the vesicular release of neurotransmitter, the activity of certain neurons may be governed by a ‘tonic'' conductance resulting from ambient GABA activating extrasynaptic GABA_ARs. However, for DR neurons extrasynaptic GABA_ARs exert only a limited influence. By contrast, we report that unusually the GlyR antagonist strychnine reveals a large tonic conductance mediated by extrasynaptic GlyRs, which dominates DR inhibition. In agreement, for DR neurons strychnine increases their input resistance, induces membrane depolarization, and consequently augments their excitability. Importantly, this glycinergic conductance is greatly enhanced in a strychnine-sensitive fashion, by behaviorally relevant ethanol concentrations, by drugs used for the treatment of alcohol withdrawal, and by taurine, an ingredient of certain ‘energy drinks'' often imbibed with ethanol. These findings identify extrasynaptic GlyRs as critical regulators of DR excitability and a novel molecular target for ethanol.     

脑源性生长因子参与疼痛-抑郁共病的研究进展

疼痛和抑郁症存在共病联系,两者之间可能存在共同的神经解剖机制及分子机制。近年来研究发现,中枢神经系统中的脑源性生长因子(brain-derived neurotrophic factor,BDNF)在疼痛-抑郁共病过程中发挥重要作用,BDNF也逐渐成为疼痛及抑郁症的研究热点及治疗靶点。该文就BDNF参与疼痛-抑郁共病的机制及外周血BDNF在疼痛、抑郁症的诊治中的意义做论述。     

Neuroanatomical substrates of the disruptive effect of olanzapine on rat maternal behavior as revealed by c-Fos immunoreactivity

Olanzapine is one of the most widely prescribed atypical antipsychotic drugs in the treatment of schizophrenia. Besides its well-known side effect on weight gain, it may also impair human parental behavior. In this study, we took a preclinical approach to examine the behavioral effects of olanzapine on rat maternal behavior and investigated the associated neural basis using the c-Fos immunohistochemistry. On postpartum days 6-8, Sprague-Dawley mother rats were given a single injection of sterile water or olanzapine (1.0, 3.0 or 5.0 mg/kg, sc). Maternal behavior was tested 2 h later, after which rats were sacrificed and brain tissues were collected. Ten brain regions that were either implicated in the action of antipsychotic drugs and/or in the regulation of maternal behavior were examined for c-Fos immunoreactivity. Acute olanzapine treatment dose-dependently disrupted various components of maternal behavior (e.g., pup retrieval, pup licking, nest building, crouching) and increased c-Fos immunoreactivity in the medial prefrontal cortex (mPFC), nucleus accumbens shell and core (NAs and NAc), dorsolateral striatum (DLSt), ventral lateral septum (LSv), central amygdala (CeA) and ventral tegmental area (VTA), important brain areas generally implicated in the incentive motivation and reward processing. In contrast, olanzapine treatment did not alter c-Fos in the medial preoptic nucleus (MPN), ventral bed nucleus of the stria terminalis (vBST) and medial amygdala (MeA), the core brain areas directly involved in the mediation of rat maternal behavior. These findings suggest that olanzapine disrupts rat maternal behavior primarily by suppressing incentive motivation and reward processing via its action on the mesocorticolimbic dopamine systems, other limbic and striatal areas, but not by disrupting the core processes involved in the mediation of maternal behavior in particular.     

不同频率电刺激VTA对吗啡成瘾大鼠ACbSh的放电活动的影响

目的:观察电刺激大鼠腹侧被盖区(VTA)对吗啡成瘾大鼠伏隔核壳部(ACbSh)神经元的影响,为应用脑深部电刺激技术治疗阿片类药物成瘾提供实验依据。方法:采用单管玻璃微电极细胞外记录法,观察不同频率电刺激VTA对吗啡成瘾大鼠ACbSh神经元放电的影响。结果:低频(50Hz)电刺激VTA,吗啡组ACbSh神经元主要表现为无反应(47.83%);高频(135Hz)电刺激VTA,吗啡组多数ACbSh神经元表现为抑制性作用(50.00%)。结论:高频电刺激VTA有可能作为新方法用于治疗阿片类药物成瘾。     

Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin

Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D₁-class DA receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF81297","term_id":"1156277425","term_text":"SKF81297"}}SKF81297 induced pMeCP2 widely; however, coadministration of the D₂-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.     

Cortico-Basal Ganglia Reward Network: Microcircuitry

Many of the brain''s reward systems converge on the nucleus accumbens, a region richly innervated by excitatory, inhibitory, and modulatory afferents representing the circuitry necessary for selecting adaptive motivated behaviors. The ventral subiculum of the hippocampus provides contextual and spatial information, the basolateral amygdala conveys affective influence, and the prefrontal cortex provides an integrative impact on goal-directed behavior. The balance of these afferents is under the modulatory influence of dopamine neurons in the ventral tegmental area. This midbrain region receives its own complex mix of excitatory and inhibitory inputs, some of which have only recently been identified. Such afferent regulation positions the dopamine system to bias goal-directed behavior based on internal drives and environmental contingencies. Conditions that result in reward promote phasic dopamine release, which serves to maintain ongoing behavior by selectively potentiating ventral subicular drive to the accumbens. Behaviors that fail to produce an expected reward decrease dopamine transmission, which favors prefrontal cortical-driven switching to new behavioral strategies. As such, the limbic reward system is designed to optimize action plans for maximizing reward outcomes. This system can be commandeered by drugs of abuse or psychiatric disorders, resulting in inappropriate behaviors that sustain failed reward strategies. A fuller appreciation of the circuitry interconnecting the nucleus accumbens and ventral tegmental area should serve to advance discovery of new treatment options for these conditions.     

Impact of maternal separation on neural cell adhesion molecules expression in dopaminergic brain regions of juvenile, adolescent and adult rats

Stressful experiences in the early stages of life can influence brain development and maturation, and they can also increase the risk for some psychiatric disorders; however, the specific mechanisms of this effect are still poorly understood. Neural cell adhesion molecules (NCAM 120, 140, 180 kDa) are known to play an important role in normal brain development and synaptic plasticity. Therefore, we decided to investigate whether maternal separation (MS) in rats, a paradigm which models an early life stress, has any impact on the expression of NCAM proteins in the juvenile, adolescent and adult brains of both male and female rats. Specifically, we focused our efforts on the brain regions associated with dopaminergic neurotransmission. In juvenile rats, MS decreased the levels of NCAM-140 in the substantia nigra (SN) of females and NCAM-180 in the ventral tegmental area of males. During adolescence, a reduction in NCAM-180 levels in the SN and medial prefrontal cortex (mPFC) of MS females was revealed. Finally, in adulthood, a decrease in NCAM-180 expression was observed in the mPFC of MS males. The results that we obtained indicate that early life stress can affect maturation and NCAM-driven plasticity in dopaminergic brain areas at different stages of ontogenesis and with a sex-specific manner.     

Comparison of the effects of bupropion and nicotine on locomotor activation and dopamine release in vivo

Bupropion is an atypical anti-depressant that is approved for smoking cessation. In addition to inhibiting dopamine reuptake, bupropion has been reported to block nicotinic acetylcholine receptors in vitro, and this action might contribute to its efficacy for smoking cessation. In this study we investigated if nicotinic receptor-mediated responses in vivo are decreased in the presence of a behaviorally effective dose of bupropion. In separate experiments we measured locomotor activation and dopamine overflow in the nucleus accumbens core, using in vivo microdialysis in freely moving rats. Bupropion (30 mg/kg i.p.) increased locomotor activity, which remained elevated for up to 2 h. Nicotine (0.4 mg/kg s.c.) also increased locomotor activity but for a shorter duration. When given 20 min after bupropion, hyperlocomotion was significantly enhanced, compared to the response to either nicotine or bupropion alone, consistent with the effects of the two drugs being additive. Systemic administration of bupropion (30 mg/kg i.p.) also elicited a significant increase in dopamine overflow (113+/-16% above basal levels). Nicotine (3 mM; delivered into the nucleus accumbens core via the microdialysis probe) increased dopamine overflow by 126 +/- 35%. Nicotine delivered during the response to bupropion resulted in enhanced dopamine overflow of 294 +/- 50%, also consistent with the actions of the two drugs being additive. This study suggests that behaviorally effective concentrations of bupropion in the rat do not diminish the effects of nicotine by blocking nicotinic receptors.     

The importance of serotonergic mechanisms for the induction of hyperactivity by amphetamine and its antagonism by intra-accumbens (3,4-dihydroxy-phenylamino)-2-imidazoline (DPI).

The present studies analyzed the role of serotonergic mechanisms in the action of two agents having purportedly different actions on the dopamine mechanisms of the rat nucleus accumbens. amphetamine and (3,4-dihydroxy-phenylamino)-2-imidazoline (DPI). Amphetamine, given by the intraperitoneal or intra-accumbens route, caused locomotor hyperactivity. This was shown to be specific for dopamine since it was antagonized by the dopamine antagonist, fluphenazine, but not by the α- and β-adrenolytics, piperoxan and propranolol, or the cholinolytic, atropine. Intra-accumbens DPI antagonized the amphetamine hyperactivity and this effect was not mimicked by the α-agonist, clonidine. The importance of serotonin for the actions of both amphetamine and DPI was established. Thus, intra-accumbens serotonin reduced amphetamine hyperactivity whilst lesions of the medial raphé nucleus, which depleted mesolimbic serotonin, enhanced the same response. Further, the inhibitory effects of DPI against amphetamine were antagonized by the serotonergic antagonists, methysergide and cypro-heptadine, but not by piperoxan, propranolol or atropine. Also, lesions of the medial raphé nucleus markedly reduced the inhibitory effect of DPI. Finally, threshold doses of intra-accumbens DPI and serotonin synergized to reduce amphetamine hyperactivity.     

Effects of ketanserin on neuronal responses to serotonin in the prefrontal cortex, lateral geniculate and dorsal raphe nucleus

The ability of the putative serotonin2 (5-HT2) antagonist ketanserin, to alter serotonin (5-HT)-induced responses in cell firing was examined in the prefrontal cortex, the lateral geniculate nucleus and the dorsal raphe nucleus of the rat by microiontophoretic extracellular single unit recording techniques. In the prefrontal cortex, ketanserin failed to antagonize the inhibitory effects of 5-HT recorded in cerveau isolé or preparations anesthetized with chloral hydrate (pure excitatory responses to 5-HT were not observed in either of these preparations). Paradoxically, the inhibitory response produced by 5-HT (but not gamma-aminobutyric acid, tryptamine or norepinephrine) was potentiated, even in cells where ketanserin alone did not alter spontaneous firing rates. The systemic administration of ketanserin (5 mg/kg, i.p.) had effects similar to those observed in the microiontophoretic experiments in the prefrontal cortex. In the dorsal raphe nucleus of animals anesthetized with chloral hydrate, ketanserin neither attenuated nor potentiated the inhibition of serotonergic neurons by 5-HT. In the lateral geniculate nucleus, as in the prefrontal cortex, ketanserin potentiated rather than attenuated, the inhibitory effect of 5-HT. Ketanserin was found to attenuate the excitatory responses produced by norepinephrine, an alpha 1-adrenoceptor-mediated response, in the lateral geniculate nucleus. The observed potentiation by ketanserin of inhibitory responses to 5-HT but not those of gamma-aminobutyric acid, tryptamine or norepinephrine, recorded in the prefrontal cortex, may be consistent with the proposed interaction between ketanserin and a specific 5-HT2 binding site.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of morphine treatment on the NCAM and its signaling in the MLDS of rats

Prolonged exposure to opiates induces a constellation of neuroadaptations, especially in the mesolimbic dopamine system (MLDS), which leads to alteration in the function of motivational circuitry. The neural cell adhesion molecule (NCAM) mediates cell–cell interactions and plays an important role in processes associated with neural plasticity. Moreover, it has been shown that NCAM were related to risk of alcoholism in human populations. Here, coimmunoprecipitation and western blotting were used to investigate whether morphine treatment induced alteration of the expression of NCAM or its signaling level in MLDS. The rats receiving escalating dose of morphine treatment were divided into three groups: morphine 1d, 3d and 5d group, which were injected subcutaneously with morphine hydrochloride for 1?day, 3 days and 5 days, respectively. Twelve?hours after the last injection, animals were sacrificed and the tissues of ventral tegmental area (VTA), prefrontal cortex (PFC) and nucleus accumbens (NAc) were punched out to examine the expression of NCAM or its signaling level. The results showed that morphine treatment had no significant effect on the expression of NCAM, but downregulated the phosphorylation of NCAM-associated focal adhesion kinase (FAK) in the VTA and PFC of rats. In the NAc of rats, however, the expression of NCAM and its signaling were not altered significantly by morphine treatment. These results indicated that the downregulation of NCAM signaling in the VTA and PFC might be involved in the formation of morphine addiction.     

Coincident signaling in mesolimbic structures underlying alcohol reinforcement

The medium spiny neurons (MSNs) of the nucleus accumbens function in a critical regard to examine and integrate information in the processing of rewarding behaviors. These neurons are aberrantly affected by drugs of abuse, including alcohol. However, ethanol is unlike any other common drug of abuse, due to its pleiotropic actions on intracellular and intercellular signaling processes. Intracellular biochemical pathways appear to critically contribute to long-term changes in the level of synaptic activation of these neurons, which have been implicated in ethanol dependence. Additionally, these neurons also display a fascinating pattern of up/down activity, which appears to be, at least in part, regulated by convergent activation of dopaminergic and glutamatergic (NMDA) inputs. Thus, dopaminergic and NMDA receptor-mediated synaptic transmission onto these neurons may constitute a critical site of ethanol action in mesolimbic structures. For instance, dopaminergic inputs alter the ability of ethanol to regulate NMDA receptor-mediated synaptic transmission onto accumbal MSNs. Prior activation of D1-signaling cascade through the cAMP-regulated phosphoprotein-32kD (DARPP-32) and protein phosphatase-1 (PP-1) pathway significantly attenuates ethanol inhibition of NMDA receptor function. Therefore, the interaction of D1-signaling and NMDA receptor signaling may alter NMDA receptor-dependent long-term synaptic plasticity, contributing to the development of ethanol-induced neuroadaptation of the reward pathway.     

Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain

1. The regulation of 5-hydroxytryptamine (5-HT) release by excitatory amino acid (EAA) receptors was examined by use of microdialysis in the CNS of freely behaving rats. Extracellular 5-HT was measured in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), nucleus accumbens, hypothalamus, frontal cortex, dorsal and ventral hippocampus.
2. Local infusion of kainate produced increases in extracellular 5-HT in the DRN and MRN. Kainate infusion into forebrain sites had a less potent effect.
3. In further studies of the DRN and nucleus accumbens, kainate-induced increases in extracellular 5-HT were blocked by the EAA receptor antagonists, kynurenate and 6,7-dinitroquinoxaline-2,3-dione (DNQX).
4. The effect of infusing kainate into the DRN or nucleus accumbens was attenuated or abolished by tetrodotoxin (TTX), suggesting that the increase in extracellular 5-HT is dependent on 5-HT neuronal activity. In contrast, ibotenate-induced lesion of intrinsic neurones did not attenuate the effect of infusing kainate into the nucleus accumbens. Thus, the effect of kainate in the nucleus accumbens does not depend on intrinsic neurones.
5. Infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate (AMPA) into the DRN and nucleus accumbens induced nonsignificant changes in extracellular 5-HT. Cyclothiazide and diazoxide, which attenuate receptor desensitization, greatly enhanced the effect of AMPA on 5-HT in the DRN, but not in the nucleus accumbens.
6. In conclusion, AMPA/kainate receptors regulate 5-HT in the raphe and in forebrain sites.

     

M_5受体参与激活吗啡奖赏大鼠腹侧背盖区nNOS表达

目的　研究不同毒蕈碱受体亚型 (M4,M5)对吗啡诱发大鼠奖赏效应的影响 ,同时观察腹侧背盖区 (ventraltegmentalarea ,VTA)神经型一氧化氮合酶 (nNOS)表达的变化。方法　实验通过侧脑室置管给药 ,采用反义寡核苷酸技术 ,免疫组织化学技术和条件位置偏爱 (conditionedplacepreference,CPP)程序 ,研究M4,M5反义寡脱氧核苷酸干预下吗啡的奖赏行为 ,以及VTA内nNOS表达情况。结果　吗啡 (5mg·kg-1)皮下注射 ,可以建立起稳定的大鼠对伴吗啡环境的位置偏爱 ,同时VTA内nNOS阳性神经元表达也显著增加。而M5反义寡脱氧核苷酸 (M5 AS) (2nmol)侧脑室预注射则可阻断吗啡诱发CPP的形成 ,同时也显著减少VTA内nNOS表达。在吗啡诱发的CPP形成后 ,侧脑室单次注射M5 AS(2nmol)也可以逆转大鼠对伴吗啡环境的位置偏爱 ,同时也明显减少VTA内nNOS表达。相比之下 ,M4反义寡脱氧核苷酸 (M4 AS)对吗啡诱发的CPP形成以及VTA内nNOS表达的影响均不明显。实验前后所有大鼠的运动活性并未发生显著改变 ,可排除运动活性对实验的影响。结论　M5毒蕈碱受体在大鼠吗啡诱发的条件位置偏爱形成过程中起重要作用 ;M5毒蕈碱受体可能是通过激活大鼠VTA内nNOS的表达 ,参与调控吗啡奖赏效应的。     

Effects of unilatral‐ and bilateral inhibition of rostral ventral tegmental area and central nucleus of amygdala on morphine‐induced place conditioning in male Wistar rat

The rostral ventral tegmental area (VTAR) and central nucleus of amygdala (CeA) are considered the main regions for induction of psychological dependence on abused drugs, such as morphine. The main aim of this study was to investigate the transient inhibition of each right and left side as well as both sides of the VTAR and the CeA by lidocaine (2%) on morphine reward properties using the conditioned place preference (CPP) method. Male Wistar rats (250±20 g) 7 days after recovery from surgery and cannulation were conditioned to morphine (7.5 mg/kg) in CPP apparatus. Five minutes before morphine injection in conditioning phase, lidocaine was administered either uni‐ or bilaterally into the VTAR (0.25 μL/site) or CeA (0.5 μL/site). The results revealed that lidocaine administration into the left side, but not the right side of the VTAR and the CeA reduced morphine CPP significantly. The reduction was potentiated when lidocaine was injected into both sides of the VTAR and the CeA. The number of compartment crossings was reduced when lidocaine was injected into both sides of the VTAR and the CeA as well as the left side. Rearing was reduced when lidocaine was injected into the right, but not the left side of the VTAR. Sniffing and rearing increased when animals received lidocaine in the right side and reduced in the group that received lidocaine in the left side of the CeA. It was concluded that the right and the left side of VTAR and the CeA play different roles in morphine‐induced activity and reward.