Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat

The neuropeptide neurotensin (NT) has been shown to modulate mesolimbic dopaminergic activity. Neurotensin injected into the VTA produces motor stimulation and release of dopamine in the nucleus accumbens. In contrast, when neurotensin is administered into the nucleus accumbens, it produces neuroleptic-like effects such as attenuation of the locomotor activity elicited by psychostimulants. In the present study, the hypothesis that neurotensin injected into the nucleus accumbens might modulate the psychostimulant and reinforcing actions of cocaine was tested. In experiment one, rats were trained to self-administer cocaine intravenously on an FR5 schedule of reinforcement. Following the establishment of baseline responding, rats were implanted with bilateral cannulae in the nucleus accumbens. One week later, rats were injected into the nucleus accumbens with various doses of neurotensin (4.2, 8.4 and 16.7 μg, total doses bilaterally) immediately prior to the self-administration session. No significant effects were found with any of the doses of neurotensin tested on the self-administration of cocaine. However, in experiment 2, neurotensin at doses of 4.2 and 16.7 μg injected into the nucleus accumbens significantly reduced the locomotor activation induced by an acute injection of cocaine (15 mg/kg i.p.) and a dose of 16.7 μg attenuated the locomotor activation induced by amphetamine (0.75 mg/kg i.p.). Thus, neurotensin in the nucleus accumbens appears to specifically modulate the acute locomotor activating properties of cocaine but not cocaine self-administration. Different mechanisms by which NT interacts with dopamine in the nucleus accumbens may provide a means of selectively altering psychostimulant motor actions without affecting psychostimulant reinforcement.     

海洛因成瘾大鼠伏隔核毁损术前后觅药行为及多巴胺神经递质的变化

目的研究海洛因成瘾大鼠毁损伏隔核前后觅药行为及多巴胺神经递质的变化。方法建立海洛因成瘾大鼠模型，毁损大鼠双侧伏隔核，利用条件性位置偏好实验测定成瘾前、后，术前、术后成瘾大鼠觅药行为的变化，利用高效液相方法测定边缘系统多巴胺神经递质的变化。结果毁损大鼠双侧伏隔核能够完全消除条件性地点偏好。成瘾大鼠边缘系统多巴胺含量较对照组明显增高。毁损前后大鼠边缘系统多巴胺含量无明显变化。结论伏隔核是调节强化作用的重要位置，长期使用海洛因可使大鼠边缘系统多巴胺含量明显增高，但毁损前后无明显变化，与条件性位置偏好表现不同步。     

Effect of ethanol on extracellular dopamine in nucleus accumbens: comparison between Lewis and Fischer 344 rat strains

The purpose of this study was to examine the differential effects of intraperitoneal ethanol on the mesoaccumbens dopamine (DA) system in Fischer 344 and Lewis rat strains, utilizing microdialysis in awake animals. At the lowest dose tested (0.5 g/kg), there were no changes in extracellular DA in the nucleus accumbens in either strain. There was a differential response to the intermediate dose of 1 g/kg ethanol, with an 84% increase in extracellular DA in the Fischer, but no change in Lewis rats. The highest dose administered (2 g/kg) did not induce significant increases in DA in either strain. These data demonstrate that the mesoaccumbens DA systems of Fischer and Lewis rat strains differ in their susceptibility to activation by ethanol, and suggest that the higher alcohol preference of Lewis rats is not associated with an enhanced DAergic response to acute experimental administration of ethanol.     

Myorelaxant effect of baclofen injected to the nucleus accumbens septi

Summary The GABAergic modulation in the nucleus accumbens septi (NAS) of muscle tone was investigated in rats using behavioral tests. The GABA_B receptor agonist baclofen dose-dependently decreased muscle tone in the wiremesh and bar holding tests both after local injection into the NAS (1.0 and 2.5 g), and after intraperitoneal administration in a dose of 20 mg/kg. In the Wirth's test haloperidol (5 mg/kg i.p.), produced catalepsy, whereas baclofen (20 mg/kg, i.p.) significantly deteriorated rats' performance. Intraaccumbens microinjections of muscimol, midazolam, nicardipine, as well as peripheral injections of haloperidol and midazolam failed to modify muscle tone in the wire-mesh test. These findings argue against the involvement of GABA_A receptors, benzodiazepine receptors, as well as dopaminergic- and calcium channel-related mechanisms in the effect of baclofen. Hence, the muscle relaxant effect of baclofen seems to be also mediated through GABA_B receptor sites within the NAS.     

高频电刺激伏隔核对大鼠可卡因自身给药行为的影响

目的通过高频电刺激大鼠双侧伏隔核(nucleus accumbens,NAc),研究其对可卡因诱导的大鼠自身给药行为的影响,为临床治疗药物成瘾提供新的思路。方法16只大鼠随机分为假刺激组和刺激组,每组8只,二组均进行15天可卡因固定比率自身给药训练,自第16天起,行熄灭训练直到其触鼻反应率小于15%稳定阶段的触鼻反应率,复燃阶段两组大鼠均腹腔注射20mg/kg的可卡因点燃,刺激组大鼠在整个复燃阶段给予持续伏隔核高频电刺激,假刺激组不施加刺激。大鼠的熄灭阶段和点燃复吸阶段交替进行三次。结果刺激组大鼠在三次复吸期内的触鼻频率与自身给药训练第15天触鼻频率相比明显减少(P<0.01),而假刺激组无明显统计学差异(P>0.05);刺激组大鼠在三次复吸期内触鼻频率与假刺激组相比明显减少(P<0.01)。结论腹腔注射可卡因(20mg/Kg)可引起戒断大鼠的复燃,在这一过程中给予持续伏隔核高频电刺激可抑制大鼠的复燃现象。     

Effects of psychological stress on monoamine systems in subregions of the frontal cortex and nucleus accumbens of the rat

We investigated the effects of two types of psychological stress, novelty stress and psychological stress using the communication box, on dopamine and serotonin systems in subregions of the frontal cortex and nucleus accumbens of rats. Placement of rats into a compartment of the communication box (novelty stress) increased both dopamine and serotonin metabolism in medial precentral, anterior cingulate, and prelimbic subregions of the frontal cortex as evaluated by the levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid for dopamine, and 5-hydroxyindoleacetic acid for serotonin. In contrast, novelty stress had no effect on these monoamine systems in infralimbic and sulcal subregions of the frontal cortex. In the nucleus accumbens, novelty stress increased both dopamine and serotonin metabolism in the shell, but decreased dopamine metabolism in the core. On the other hand, psychological stress using the communication box augmented dopamine metabolism in the anterior cingulate and prelimbic subregions. This stress, however, failed to affect the dopamine system in the medial precentral, infralimbic and sulcal subregions. In the nucleus accumbens, the stress selectively decreased dopamine metabolism in the shell but showed no effect in the core. The serotonin system showed little change due to the stress. These results demonstrate that psychological stress causes distinct changes in both the dopamine and serotonin systems in the frontal cortex and the nucleus accumbens. These changes vary with the subregions of these areas, suggesting that the region-specific responsiveness to psychological stress reflects the functional differences among these subregions. In addition, our results also suggest that changes in brain monoamine systems induced by psychological stress are quite different from those induced by physical stress.     

Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats

The extracellular changes of amino acids (glutamate, taurine and GABA) in the nucleus accumbens of freely moving rats were estimated using the microdialysis technique following acute and chronic ethanol injections (1, 2, and 3 g/kg body weight). Compared to baseline values, taurine increased by 154% ± 73%, 142% ± 40% and 162% ± 75% 20 min after the acute injection of, respectively, 1, 2, and 3 g/kg body weight ethanol, while 40 min after ethanol injection, taurine had increased by 124% ± 36%, 146% ± 54% and 168% ± 98%. No changes in either glutamate or GABA were detected at any time points assayed. In the rats which had received chronic ethanol administration prior to a further acute ethanol injection (1, 2, and 3 g/kg body weight), taurine increased by 138% ± 73%, 144% ± 39% and 180% ± 85% 20 min after the ethanol injection at 40 min post ethanol injection taurine had increased by 134% ± 44%, 160% ± 56% and 158% ± 45%, compared to the basal baseline value. No significant changes were observed in either glutamate or GABA microdialysate content in these chronic studies. The biological role played by taurine after acute ethanol injection in the nucleus accumbens remains unclear but may be associated with a yet, undefined mechanism, in reducing the cytotoxicity of ethanol.     

NMDA receptors in the nucleus accumbens modulate intravenous cocaine but not heroin self-administration in the rat

The role of endogenous glutamate neurotransmission within the nucleus accumbens in the modulation of intravenous (i.v.) cocaine and heroin self-administration in rats was analyzed. APV (2-amino-5-phosphonovaleric acid), a blocker of glutamate receptors of the N-methyl-D-aspartate (NMDA) type, was microinfused within the nucleus accumbens of the ventral striatum of rats trained to lever press for i.v. cocaine or heroin self-administration. APV, at the dose of 1.5 and 3.0 micrograms/side, reduced the rewarding value of cocaine while it left heroin self-administration unaffected. These results suggest that integrity of NMDA receptor function within the nucleus accumbens may be of importance for the maintenance of i.v. cocaine, but not heroin self-administration in rats.     

伏隔核DBS对大鼠海洛因强化作用的影响

目的观察脑深部电刺激伏隔核核心部对大鼠海洛因强化作用的影响。方法用固定比率程序建立大鼠海洛因自身给药模型,随机分为刺激组(6只)和假刺激组(6只),训练累进比率程序达稳定状态后,两组大鼠行双侧伏隔核核心部微电极植入。刺激组大鼠每日给予高频电刺激1h(频率130Hz,电流150μA,波宽100μs),连续10d。刺激结束后两组大鼠进行累进比率程序测试。两组大鼠在刺激前、后分别测试自发活动;累进比率程序测试结束后进行Morris水迷宫实验。结果在累进比率程序测试中,刺激组大鼠的有效鼻触数(211.17±98.31)和注射次数(10.83±1.72)均明显少于假刺激组的有效鼻触数(356.17±66.25)及注射次数(13.50±1.05),且具有统计学差异(P<0.05);两组大鼠在总活动度和水迷宫中的表现均无统计学差异(P>0.05)。结论脑深部电刺激大鼠伏隔核核心部可以明显减低海洛因的强化作用,降低大鼠获取海洛因的动机,且不会影响其活动度及学习记忆能力。     

脑深部电刺激伏核对自身给药大鼠海洛因觅药行为的影响

目的观察脑深部电刺激(deep brain stimulation,DBS)伏核对大鼠海洛因自身给药觅药行为的影响。方法用固定比率程序建立大鼠海洛因自身给药复吸模型。将18只大鼠随机分成对照组、假刺激组和DBS组,假刺激组及DBS组大鼠行双侧伏核核心部微电极植入术。DBS组大鼠在消退期每天给予高频电刺激1h(刺激参数:方波,频率130 Hz,电流150μA,波宽100μs),共7d。消退后采用条件性线索和小剂量海洛因诱导引燃大鼠海洛因觅药行为。结果在条件性线索诱导的复吸测评中,DBS组大鼠有效鼻触数(8.00±5.33)明显少于对照组(36.50±9.16)和假手术组(34.00±7.93),具统计学意义(P<0.01);在小剂量海洛因诱导的复吸测评中,DBS组大鼠有效鼻触数(11.17±7.78)明显少于对照组(29.67±5.24)和假手术组(28.00±11.92),具统计学意义(P<0.01);DBS组、对照组和假手术组大鼠在总活动度和每阶段活动度上的差异均无统计学意义(P>0.01)。结论DBS高频电刺激伏核可减少海洛因自身给药大鼠条件性线索和小剂量海洛因诱导的觅药行为,且不会影响其活动度。     

Cholecystokinin-induced release of dopamine in the nucleus accumbens of the spontaneously hypertensive rat

Changes in dopamine neurotransmission in the nucleus accumbens of the spontaneously hypertensive rat (SHR) may be involved in the pathogenesis of hypertension. This investigation tested the hypothesis that the sulfated octapeptide cholecystokinin (CCK8S) induced release of dopamine is greater in the SHR than in its normotensive control, the Wistar-Kyoto rat (WKY). Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were sampled using microdialysis in the caudal half of the nucleus accumbens of 10-week-old anesthetized SHRs and WKYs. Samples were collected in the following order: 3 baseline, 3 CCK8S (10 μmol/l), and 3 postdrug samples. The samples were then analyzed using high pressure liquid chromatography with electrochemical detection. CCK8S increased dopamine and DOPAC levels in both the SHR and WKY with a larger increase in basal dopamine in the SHR (greater than 200%). Perfusion of the nucleus accumbens with 1 μmol/l of CCK8S or the nonsulfated form of CCK8 (CCK8US, 10 μmol/l) produced no significant increase in the release of dopamine in the SHR. These results indicate that CCK8S-induced release of dopamine in the nucleus accumbens is greater in the SHR. Changes in CCK8S neurotransmission/receptor function may be responsible for the alterations in dopaminergic function of the SHR and the pathogenesis of hypertension.     

Role of the nucleus accumbens in social memory in rats

Recognition of a juvenile conspecific by an adult male rat is known to be reflected by reduced anogenital investigation (A.G.I.) of this young individual by the adult, when the two animals are reexposed to each other after some short delay. As the delay is increased, the reduction in A.G.I. is reduced. This measure of social memory can be modulated by several drugs, among others cholinomimetic agents. In this study, the effects of direct manipulation of the nucleus accumbens were studied. Local administration of (3,4-dihydroxyphenylimino)-2-imidazoline (DPI: 0.1-1.5 micrograms) decreased investigatory behaviour at the second exposure after a long interexposure-interval, while ergometrine (0.1 micrograms) counteracted this reduction by DPI. These findings suggest a role for the nucleus accumbens in social recognition, in particular for the so-called DAi receptors which are stimulated and inhibited by DPI and ergometrine respectively.     

Electrophysiological evidence of modulatory interaction between dopamine and cholecystokinin in the nucleus accumbens

Dopamine has been shown to modulate responses of accumbens neurones to excitatory inputs from the amygdala. The demonstration that cholecystokinin (CCK) co-exists and appears to be co-released with dopamine in the accumbens suggests that the modulatory action of dopamine in the accumbens may in turn be modified by CCK. This possibility was investigated in the present study. Single unit recordings were obtained in the medial and caudal accumbens of urethane-anaesthetized rats. These neurones were strongly excited by amygdala stimulation, and concurrent stimulation of the ventral tegmental area (VTA) at 10 Hz attenuated the responses, presumably due to dopamine release. Iontophoretic application of proglumide (PRG) at 30 nA enhanced the attenuating effect of VTA stimulation on the excitatory response to amygdala stimulation. Exogenous dopamine produced a similar attenuation in response and the attenuation was in turn suppressed by concurrent iontophoresis of sulphated CCK fragments applied at a current titrated not to produce significant effect on the spontaneous activity of the neurone nor its response to amygdala stimulation. These results demonstrate that exogenous and endogenous CCK can modify the postsynaptic action of dopamine in the nucleus accumbens in addition to modulating its release shown in other studies, and further suggests that CCK is likely an endogenous functional antagonist of dopamine, serving a comodulatory role in regulating synaptic transmission in the ventral striatum.     

Caudate-putamen and nucleus accumbens extracellular acetylcholine responses to methamphetamine binges

Exposure of experimental animals to an escalating dose, multiple binge pattern of methamphetamine administration results in the progressive emergence of a unique behavioral profile, which includes a significant decrease in the duration of the stereotypy phase as well as a profound increase and qualitative change in the locomotor activation. This behavioral profile is associated with a selective decrease in the caudate-putamen but not nucleus accumbens extracellular dopamine response. Since the acetylcholine interneurons in these regions are partly under the control of the mesostriatal and mesoaccumbens dopamine inputs, changes in the activation of these interneurons should parallel the regionally differential dopamine responses during multiple binge treatment. Therefore, we characterized the caudate-putamen and nucleus accumbens extracellular acetylcholine responses to escalating-dose, multiple binge methamphetamine administration. An acute methamphetamine binge decreased acetylcholine levels in caudate-putamen, but had no effect on levels in nucleus accumbens. Furthermore, corresponding to the selective decrease in the dopamine response, the caudate-putamen but not nucleus accumbens extracellular acetylcholine response exhibited tolerance with repeated binge exposures; i.e. the decrease in acetylcholine associated with the acute methamphetamine binge was attenuated with multiple binge exposure. These results are consistent with our hypothesis and suggest that the regionally differential acetylcholine responses reflect one functional consequence of the escalating-dose, multiple binge stimulant treatment.     

Anticonvulsant effects of ipsilateral but not contralateral microinjections of the dopamine D2 agonist LY 171555 into the nucleus accumbens of amygdala-kindled rats

Recent radioligand binding studies demonstrated an increase in the density of dopamine D₂ receptors in the nucleus accumbens ipsilateral to the stimulating electrode in amygdala- or hippocampal-kindled rats. In the present study we examined the anticonvulsant effect of dopamine agonists by unilateral microinjections into the nucleus accumbens in rats kindled from the right basolateral amygdaloid nucleus. Microinjections of the D₂ agonist LY 171555 into the ipsilateral nucleus accumbens 15 min prior to the kindling stimulation in fully kindled rats decreased significantly kindling parameters such as seizure severity, seizure duration and afterdischarge duration, whereas the D₁ agonist SKF 38393 had no anticonvulsant effects. After ipsilateral microinjection of 40 pmol LY 171555, focal and generalized kindled seizures were totally blocked in almost 50% of the rats. The anticonvulsant effect of LY 171555 could be completely antagonised by systemic administration of the D₂ antagonist sulpiride. Microinjection of the D₁ or D₂ agonist into the nucleus accumbens contralateral to the stimulating electrode had no anticonvulsant effects. In accordance with other reports our data indicate a possible topographic limitation of D₂ receptor mediated anticonvulsant effects to specific regions of the basal ganglia.     

单双侧脑深部电刺激伏核对大鼠海洛因觅药行为的影响

目的 观察单侧和双侧脑深部电刺激(DBS)伏核核心部对条件性线索和小剂量海洛因诱导大鼠海洛因觅药行为的影响,探讨DBS治疗药物成瘾的单双侧靶点选取问题. 方法 采用固定比率程序(FR1)建立大鼠海洛因静脉自身给药模型.模型稳定后,将大鼠按照随机数字表法分成对照组、假手术组、左侧DBS组、右侧DBS组和双侧DBS组(每组6只).各DBS组大鼠行单侧或双侧伏核核心部微电极植入术,术后休息5d,在环境消退期对各DBS组大鼠每天电刺激1h(参数:方波,频率130 Hz,电流强度150 μA,波宽100 μs),持续7d.通过比较各组大鼠的有效鼻触数来反映各组大鼠海洛因觅药行为的差异. 结果 在条件性线索和小剂量海洛因诱导的复吸测评中,各组大鼠有效鼻触反应数之间的差异具有统计学意义(P＜0.05);右侧DBS组和双侧DBS组大鼠有效鼻触反应数分别与对照组、假手术组和左侧DBS组相比差异具有统计学意义(P＜0.05);且右侧DBS组大鼠与双侧DBS组有效鼻触反应数之间的差异无统计学意义(P＞0.05). 结论 高频电刺激右侧或双侧伏核核心部均能明显抑制条件性线索和小剂量海洛因诱导的大鼠觅药行为;且右侧DBS可获得与双侧DBS相近的疗效.     

Iontophoresis of amphetamine in the neostriatum and nucleus accumbens of awake, unrestrained rats

When administered systemically to ambulant animals, amphetamine (AMPH) has both excitatory and inhibitory effects on single-unit activity in the neostriatum and nucleus accumbens. To determine the extent to which these results reflect a direct action of the drug, AMPH was applied iontophoretically to neostriatal and accumbal neurons under naturally occurring behavioral conditions. AMPH dose-dependently (5–40 nA) inhibited the vast majority of spontaneously active units. The inhibition, which was evident at low ejection currents (5–10 nA), had relatively short onset (4–12 s) and offset (6–24 s) latencies, and was positively correlated with basal firing rate. Even stronger dose-dependent inhibitory responses were recorded when neurons having no or a very low rate of spontaneous activity were tonically activated by continuous, low-current applications of glutamate (Glu). Systemic injection of either SCH-23390 (0.1 mg/kg) or haloperidol (0.2 mg/kg), relatively selective D₁ and D₂ receptor antagonists, respectively, blocked the AMPH-induced inhibition. Prolonged AMPH iontophoresis (2–3 min; 5–30 nA) inhibited both spontaneous impulse activity and Glu-induced excitations, resulting in a complete blockade of the Glu response at relatively high AMPH ejection currents (≥20 nA). Taken together, these results suggest that although dopamine is largely responsible for the inhibitory effects of iontophoretic AMPH, dopamine alone cannot account for the complex response of neostriatal and accumbal neurons to systemic AMPH administration.     

Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity.     

Kainic acid decreases hippocampal neuronal number and increases dopamine receptor binding in the nucleus accumbens: an animal model of schizophrenia

Intracerebroventricular (i.c.v.) administration of kainic acid (KA) produces graded neuronal loss in the hippocampus and other regions of the medial temporal lobe. Many of these brain regions send excitatory projections to the nucleus accumbens, a dopaminergic brain area implicated in psychotomimetic and antipsychotic drug action. In the present study, neurochemical function in the nucleus accumbens and anterior caudate-putamen was examined one week after i.c.v. administration of 1.5, 4.5, or 6.6 nmol of KA. As expected, i.c.v. KA produced dose-dependent neuronal loss in the dorsal and ventral hippocampus. Extrahippocampal neuronal loss was also observed in the thalamus and piriform cortex in some of the KA-treated rats. While ambient levels of dopamine turnover and excitatory amino acids in the nucleus accumbens were unaltered by KA, administration of the highest KA dose elevated [³H]spiperone binding exclusively in the accumbens. Finally, behavioral hyperactivity was observed in KA-treated rats over a five-week period following i.c.v. administration. The pattern of neuronal loss, receptor upregulation, and behavioral hyperactivity found after i.c.v. KA administration may provide a useful animal model of the limbic neuropathology and neurochemical dysfunction associated with schizophrenia.     

Microinjection of CART peptide 55-102 into the nucleus accumbens blocks amphetamine-induced locomotion

The role played by the biologically active CART 55-102 peptide in NAcc AMPH induced locomotion was investigated. When microinjected alone into this site, none of the doses of CART 55-102 tested (0.1, 0.4, 1.0 or 2.5 microg/0.5 microl/side) produced effects on locomotion during a two-h test. However, when co-injected with AMPH (2.5 microg/0.5 microl/side) into the NAcc, moderately high (2.5 microg/side) and middle to high (0.4-2.5 microg/side) doses of CART 55-102 significantly attenuated the effects of AMPH on locomotion and rearing, respectively. These results indicate that CART peptides can exert an antagonistic effect on the generation of locomotion by AMPH in the NAcc.