Effects of nucleus accumbens lesions in rats on spatial preference in an open field

Selective lesions placed in three different regions of the nucleus accumbens were performed to assess their effects on spatial preference in the rat. Histological verification allowed to establish three groups of lesioned animals: medial, intermediate and lateral. Sham operations involved all procedures except the passing of a current. All animals were tested once prior to operation and twice postoperatively. Sherman's directionality score (DS) was adopted. Positive values indicate right side preference and negative ones leftward bias. Statistical analysis revealed that rats used in this study showed a nonsignificant spontaneous right side preference in the open field (DS = +0.08). Medial and intermediate lesions increased the right side bias (DS = +0.37), whereas lateral lesioned animals reversed their preoperative rightward bias and showed a significant left side preference (DS = -0.48). These results suggest a participation of the nucleus accumbens in spatial preference and are considered to be due to the well known uneven distribution of the afferent and efferent fiber systems within the nucleus.     

Muscimol a GABA-agonist injected into the nucleus accumbens increases apomorphine stereotypy and decreases the motility

Muscimol, a highly potent GABA agonist was injected in the nucleus accumbens. Muscimol (10 and 100 ng) was found to facilitate the development of stereotyped licking and gnawing, but contrastingly to depress the locomotion induced by subcutaneously injected apomorphine (0.25 mg/ kg). The local injection of muscimol induces per se no stereotypy. These results indicate that GABA in the nucleus accumbens differentially influences behavior dependent on dopaminergic mechanisms.     

Asymmetry in the dopamine content in the nucleus accumbens and the motor preference in rats

A number of published studies reported a correlation between the paw preference in mice and asymmetry of tissue concentrations of dopamine (DA) and DA metabolites measured in the nucleus accumbens (NAcb) the DA concentration being higher in the nucleus ipsylateral to a preferred paw. This study aimed to investigate whether such asymmetry existed in rats. The paw preference was defined by reaching into a small horizontal tube for a food pellet. Tissue concentration of DA was measured by high-performance liquid chromatography with electrochemical detection. It was shown that the DA concentration in the left NAcb was significantly higher in "left-handed" rats than in "right-handed" animals. Within the group of "right-handers", the DA concentration was significantly higher in the right NAcb than in the left NAcb. The results confirm in part the experimental data obtained in mice and support the hypothesis that the paw preference is paralleled by elevated tissue DA in the ipsylateral NAcb of rodents.     

Modulation of dopamine-induced hypermotility following injection of various opioids into the nucleus accumbens

The aim of the present work was to obtain some data on the eventual role of nucleus accumbens in the antidopamine action of some opioids. Classical neuroleptics are known to inhibit the dopamine-elicited hypermotility when injecting them into the nucleus accumbens of rats pretreated with MAO inhibitors. In the present study the effects of some opioids have been examined in this model. The opioids examined were morphine, a mu-selective classical opiate, D-Ala2, Nle5-enkephalin sulphonic acid (ES), a delta selective opioid peptide and D-Met2, Pro5-enkephalinamide (EA), a non-selective opioid peptide. Haloperidol and chlorpromazine have been used for comparison. EA and morphine, especially the former, potently antagonized the dopamine-induced hyperactivity, similarly to haloperidol and chlorpromazine. ES exerted biphasic effect, the initial inhibition was followed by potentiation of the dopamine-elicited excitation. Thus the order of potency was: EA greater than haloperidol approximately equal to morphine greater than chlorpromazine greater than EA. The data indicate that the antidopamine action of opioids might be mediated, at least in part, by mu-receptors in the nucleus accumbens.     

Alimentary conditioned reflex behavior in the rat following injection of 6-hydroxydopamine into the caudate nucleus and nucleus accumbens

In Wistar rats with degenerated dopaminergic terminals of the caudate and accumbens nuclei (administration of 6-hydroxydopamine, 30 mcg, bilaterally), an alimentary conditioned reflex was elaborated in a T-maze. Degeneration of the caudate nucleus terminals disturbed the elaboration, while degeneration of N. accumbens terminals did not affect the learning.     

Stimulation of food intake following opioid microinjection into the nucleus accumbens septi in rats

The involvement of opioid peptides in the regulation of food intake has been postulated. However, it is not known how they are involved in this regulation and which brain region is responsible for the mediation of their effects. We studied the effect of a microinjection of opioid agonists and antagonists into the nucleus accumbens septi (NAS) on the food intake in rats, as this area is known to be important for motivation. Male Wistar rats were implanted stereotaxically with guide cannulae. Rats were not allowed food prior to drug treatment and solutions (1 microliter) were microinjected bilaterally. Food intake was measured throughout a 2 hr period after the drug injection. Infusions into the NAS of 2, 5 and 10 nmol of morphine, D-ala2, D-Leu5-enkephalin (DADLE), and beta-endorphin (beta E), or of 5 and 10 nmol of alpha-neoendorphin (ANEO) induced a dose-dependent increase in the food intake. Dynorphin (DYN) also increased the food intake, but only at a 10 nmol dose. The new, highly selective delta agonist D-Pen2,5-enkephalin (DPDPE) induced a dose-dependent increase in the food intake. Naloxone in doses of 2 and 10 nmol antagonized the increased food intake induced by morphine, beta E, ANEO and DYN in a dose-dependent manner, but only partly antagonized the effect of DADLE on the food intake. The selective mu-receptor antagonist beta-funaltrexamine (beta-FNA), in a dose of 5 nmol completely blocked the increase in the food intake induced by morphine but not by DADLE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-endorphin-(10-16) antagonizes behavioral responses elicited by melatonin following injection into the nucleus accumbens of rats

The behavioral changes induced by low doses of melatonin bilaterally injected into the nucleus accumbens of rats (decrease of locomotor activity and rearing and increase of grooming and sniffing behavior) were not affected by local pretreatment with beta-endorphin, but could be completely antagonized by alpha-type and gamma-type endorphins. Structure activity relationship studies revealed that the peptide beta-endorphin-(10-16) contains the essential information in this respect. The lowest effective dose of this peptide was 10 pg. The peptide, in contrast to gamma-type endorphins, did not interfere with the decrease of locomotor activity and rearing induced by injection of low doses of apomorphine into the nucleus accumbens. It is concluded that the described action of beta-endorphin-(10-16) resembles that of serotonin and various antidepressant drugs.     

CRF receptors in the nucleus accumbens modulate partner preference in prairie voles

Recent evidence suggests a role for corticotropin-releasing factor (CRF) in the regulation of pair bonding in prairie voles. We have previously shown that monogamous and non-monogamous vole species have dramatically different distributions of CRF receptor type 1 (CRF(1)) and CRF receptor type 2 (CRF(2)) in the brain and that CRF(1) and CRF(2) receptor densities in the nucleus accumbens (NAcc) are correlated with social organization. Monogamous prairie and pine voles have significantly lower levels of CRF receptor type 1 (CRF(1)), and significantly higher levels of type 2 (CRF(2)) binding, in NAcc than non-monogamous meadow and montane voles. Here, we report that microinjections of CRF directly into the NAcc accelerate partner preference formation in male prairie voles. Control injections of CSF into NAcc, and CRF into caudate-putamen, did not facilitate partner preference. Likewise, CRF injections into NAcc of non-monogamous meadow voles also did not facilitate partner preference. In prairie voles, this CRF facilitation effect was blocked by co-injection of either CRF(1) or CRF(2) receptor antagonists into NAcc. Immunocytochemical staining for CRF and Urocortin-1 (Ucn-1), two endogenous ligands for CRF(1) and CRF(2) receptors in the brain, revealed that CRF, but not Ucn-1, immunoreactive fibers were present in NAcc. This supports the hypothesis that local CRF release into NAcc could activate CRF(1) or CRF(2) receptors in the region. Taken together, our results reveal a novel role for accumbal CRF systems in social behavior.     

Influence of cholecystokinin on the synaptosomal dopamine uptake in the nucleus accumbens of rats

The influence of the sulfated cholecystokinin octapeptide (CCK-8S) on the synaptosomal high-affinity [³H]dopamine (DA) uptake was investigated in the medial and lateral part of nucleus accumbens in rats. CCK-8S induced a concentration-dependent biphasic inhibition of [³H]-DA uptake in both subregions. After preincubation of CCK-8S with the synaptosomes the inhibitory effect was completely abolished. Kinetic analysis of the uptake influence suggests an uncompetitive inhibition by CCK-8S; this means that CCK-8S attacks only the DA-uptake carrier complex by inhibitory manner. The possible regulatory relevance of this mechanism is discussed.     

Effect of serotonergic agonists in the nucleus accumbens on d-amphetamine-stimulated locomotion.

Serotonergic projections from the raphe nuclei are thought to modulate locomotor activity in the rat, and serotonin injection into the nucleus accumbens attenuates the hypermotility elicited by amphetamine. The purpose of the present study was to characterize the effects of various classes of serotonergic agonists administered into the nucleus accumbens on d-amphetamine-stimulated locomotor activity in order to determine which serotonin receptor subtypes are involved. Administration of the nonselective 5-HT agonist quipazine, the 5-HT-1 agonist mCPP, the 5-HT-1a agonist 8-OH-DPAT, the 5-HT-1b agonist CGS-12066B, and the 5HT-1c/2 agonist DOI did not inhibit d-amphetamine-stimulated locomotor activity. Pronounced lateral head weaving was noted after 8-OH-DPAT administration. The combination of the 5-HT-1a agonist 8-OH-DPAT and the 5-HT-1b agonist CGS-12066B, however, did inhibit d-amphetamine-stimulated locomotor activity. In contrast, the 5-HT-3 agonist 1-phenylbiguanide enhanced the locomotor effect of d-amphetamine. This effect was partially reversed by the 5-HT-3 antagonist MDL-7222. These studies suggest that serotonin has complex and multiple effects on the regulation of locomotor activity within the nucleus accumbens.     

Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats

The effects induced by nociceptin on morphine-induced release of dopamine (DA), 3,4-dihydroxyphenilacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and nucleus caudate were studied in rats by microdialysis with electrochemical detection. Nociceptin administered intracerebroventricularly (i.c.v.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate. Morphine administered intraperitoneally (i.p.) (2, 5, and 10 mg/kg) increased DA and metabolites release more in the shell of the nucleus accumbens than in the nucleus caudate. When nociceptin (5 or 10 nmol) was administered 15 min before morphine (5 or 10 mg/kg), it significantly reduced morphine-induced DA and metabolites release in the shell of the nucleus accumbens, whereas only a slight, nonsignificant reduction was observed in the nucleus caudate. Our data indicate that nociceptin may regulate the stimulating action associated with morphine-induced DA release more in the nucleus accumbens than in the nucleus caudate, and are consistent with recent observations that nociceptin reversed ethanol- and morphine-induced conditioned place preference. Therefore, the nociceptin-induced reduction of DA release stimulated by morphine in the nucleus accumbens, and the results obtained with nociceptin in the conditioned place preference procedure suggest a role for nociceptin in the modulation of the behavioral and neurochemical effects of abuse drugs.     

Effect of the serotoninergic substrate of the nucleus accumbens on the latent inhibition

Latent inhibition (LI) is a reduction in the rate of acquisition of a conditioned response that results from repeated preexposure of an animal to a conditioned stimulus (CS). The present experiment was conducted to assess the effect of bilateral lesions of 5-OT terminals of the nucleus accumbens on LI in a conditioned passive avoidance response paradigm. The lesions were produced by administration of 5,7-DHT and resulted in disruption of LI. Sham-operated animals displayed the delay of conditioning (LI) in comparison with the non-preexposed controls. Disruption of the LI was prevented by systemic injection of haloperidol. Involvement of 5-HT substrate of the nucleus accumbens and its interaction with dopaminergic system in the process of the LI development is discussed.     

Specificity of nucleus accumbens to activities related to cholecystokinins in rats

Cholecystokinin octapeptide (CCK-8) or cholecystokinin tetrapeptide (CCK-4) were bilaterally injected into the areas where dopamine (DA) terminals and receptors have been detected; nucleus accumbens (NA), nucleus caudatus (NC), medial profrontal cortex (MPC), or prefrontal cortex (PC). The amount injected to each animal varied from 0 (control), 1 to 500 ng of CCK-8 and 0 (saline control), 0.5 to 2.5 micrograms of CCK-4 in NA in a volume of 1 microliter. The other areas received 500 ng CCK-8, 2.5 micrograms CCK-4 and proper control injections. The effects were observed in an open-field apparatus by measuring locomotor and rearing responses, the latency to move out of a specified area where the animal was first placed, and the amount of excretory bolus during a 5 min period following injections. When injected into NA, CCK-8 decreased locomotion and rearing at doses of 2.5 ng or more in a dose-related manner whereas CCK-4 increased locomotion and rearing at 1 microgram or more. The effects on latency and defecation were not detected. When the peptides were injected into NC, MPC or PC no effects were detectable. It appears that the effects of CCK-8 and CCK-4 on the exploratory responses are site-specific at NA where CCK-8 and DA are found to coexist in same neurons. CCK-4, a metabolite of CCK-8, could exert a negative feedback to moderate the effect of CCK-8.     

Inhibition of affective aggression and dominance in rats after thyrotropin-releasing hormone (TRH) microinjection into the nucleus accumbens

The effect of 10 micrograms TRH injected bilaterally into the nucleus accumbens septi on two models of affective aggression and on dominance in a water-competition task was investigated in pairs of male Wistar rats. TRH significantly suppressed affective shock-induced and apomorphine-induced fighting. It also decreased dominance when administered to dominant rats while no effect was noted upon injection into subordinate animals. The peptide influenced neither water consumption in thirsty rats nor the pain threshold in a hot plate test.     

Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS‐CC mice

Previous studies on changes in murine brain gene expression associated with the selection for ethanol preference have used F₂ intercross or heterogeneous stock (HS) founders, derived from standard laboratory strains. However, these populations represent only a small proportion of the genetic variance available in Mus musculus. To investigate a wider range of genetic diversity, we selected mice for ethanol preference using an HS derived from the eight strains of the collaborative cross. These HS mice were selectively bred (four generations) for high and low ethanol preference. The nucleus accumbens shell of naive S₄ mice was interrogated using RNA sequencing (RNA‐Seq). Gene networks were constructed using the weighted gene coexpression network analysis assessing both coexpression and cosplicing. Selection targeted one of the network coexpression modules (greenyellow) that was significantly enriched in genes associated with receptor signaling activity including Chrna7, Grin2a, Htr2a and Oprd1. Connectivity in the module as measured by changes in the hub nodes was significantly reduced in the low preference line. Of particular interest was the observation that selection had marked effects on a large number of cell adhesion molecules, including cadherins and protocadherins. In addition, the coexpression data showed that selection had marked effects on long non‐coding RNA hub nodes. Analysis of the cosplicing network data showed a significant effect of selection on a large cluster of Ras GTPase‐binding genes including Cdkl5, Cyfip1, Ndrg1, Sod1 and Stxbp5. These data in part support the earlier observation that preference is linked to Ras/Mapk pathways.     

伏隔核壳部巴氯芬灌注阻断吗啡成瘾小鼠条件位置性偏爱记忆再巩固

氨基丁酸B型受体(GABAB受体)是治疗药物成瘾的潜在靶点,伏隔核壳部(nucleus accumbens shell, AcbSh)是成瘾环路的关键节点,但AcbSh GABA_B受体与记忆再巩固的关系尚不清楚。本文旨在探讨AcbSh微量灌注GABA_B受体激动剂巴氯芬(baclofen, BLF)对吗啡奖赏记忆再巩固及复吸行为的影响。建立吗啡条件位置性偏爱(conditioned place preference, CPP)小鼠模型,采用吗啡奖赏记忆提取激活实验,对比观察环境线索激活吗啡奖赏记忆后,双侧AcbSh灌注BLF对吗啡CPP、吗啡激发CPP重建以及自主活动量的影响。结果表明,吗啡奖赏记忆激活后,Acb Sh单次注入0.06nmol/0.2μL/侧或0.12nmol/0.2μL/侧BLF显著抑制吗啡CPP,且吗啡激发不能重建CPP,而0.01nmol/0.2μL/侧BLF灌注不能抑制吗啡CPP。激活后注入生理盐水及未激活组BLF灌注均未抑制CPP。无论是否激活吗啡奖赏记忆,BLF注入AcbSh都不影响小鼠自主活动。以上结果提示,AcbSh GABA_B受体参与了吗啡CPP的记忆再巩固。记忆激活后激动AcbSh GABA_B受体可通过阻断吗啡CPP的记忆再巩固,消除奖赏记忆,抑制复吸行为。     

高频电刺激伏隔核对可卡因成瘾大鼠自身给药行为学的影响

目的:研究可卡因诱导的大鼠自身给药行为,为临床治疗药物成瘾提供新的思路.方法:24只雄性大鼠随机分为对照组,假手术组和DBS高频电刺激组,每组8只.3组大鼠全部行右侧颈静脉长期置管术,假手术组和刺激组同时进行双侧伏隔核电极植入术,术后第7天起进行每天2小时的自身给药训练,训练程序为固定比率的FRI程序(即大鼠触碰鼻触一次可获得药物注射一次).每次注射后20s内为不应期,当大鼠连续3天触鼻频率最高值与最低值的差值小于均数标准差的1/4后,FRI模式下的大鼠自身给药训练成功.模型建立成功以后对DBS刺激组进行高频电刺激.结果:刺激组大鼠在高频电刺激15天触鼻频率与自身给药动练第15天触鼻频率相比明显减少(P＜0.01),而对照组和假手术组无明显统计学差异(P＞0.05);剌激组大鼠触鼻频率与假刺激组和对照组相比明显减少(P＜0.01).结论:脑深部高频电刺激可抑制可卡因成瘾大鼠对可卡因的依赖.     

Effect of epiphysectomy on the temporal dynamics of apomorphine stereotypy in rats

Pinealectomized rats did not differ from pseudooperated animals in the time of onset, degree and duration of apomorphine-induced stereotypy. However, pinealectomy normalized stereotypy during repeated apomorphine injections to young (7-8 weeks), but not old (26-28 weeks) rats, slowing down minute fluctuations of stereotyped motions.