Comparative studies of the ingestive behaviors produced by microinjections of muscimol into the midbrain raphe nuclei of the ventral tegmental area of the rat

Microinjection of the GABA-A agonist muscimol into the median (MR) or dorsal (DR) raphe nuclei or the ventral tegmental area (VTA) of non-deprived rats induced intense feeding and drinking in a dose-dependent and site-specific manner. Lower doses of muscimol were required to increase food intake, spillage and water intake with injections into the MR than with injections into the other two sites. These data demonstrate that the MR is a more sensitive site for the elicitation of ingestive behavior than either the DR or the VTA.     

Haloperidol increases DOPAC in the substantia nigra but not in the ventral tegmental area

Haloperidol (0.1 to 0.5 mg/kg) caused a dose related increase in DOPAC content both in the substantia nigra (pars compacta + pars reticulata) (by 27 to 134%) and in the caudate nucleus (by 127 to 252%). On the contrary even 5 mg/kg of haloperidol failed to modify DOPAC level in the ventral tegmental area. The results indicate that DA cells in ventral tegmental area differ from those in the substantia nigra not only on anatomical grounds but also on a functional point of view.     

食物成瘾及其神经环路调控机制

食物成瘾是指人们对某些特定食物（高度加工、可口、高热量的食物）的依赖性达到难以控制的程度,并表现出一系列成瘾样的行为学变化,具有强迫性、长期性和反复性的特点。食物成瘾可引起肥胖症,而且是大部分人不能维持减肥效果或坚持限制性饮食以保持健康体重的核心因素。深入理解食物成瘾及其神经生物学机制,将为干预食物成瘾以改善肥胖提供准确的靶点。食物成瘾的诊断标准是耶鲁大学食物成瘾量表,而食物成瘾的动物模型为小鼠食物自我管理模型。外侧下丘脑-腹侧被盖区-伏隔核神经环路、腹侧被盖区-前边缘皮质-伏隔核神经环路和外侧隔核-结节核神经环路是调控食物成瘾的关键神经环路机制。     

Effects of the opioid antagonist naltrexone on feeding induced by DAMGO in the ventral tegmental area and in the nucleus accumbens shell region in the rat

The nucleus accumbens shell region (sNAcc) and the ventral tegmental area (VTA) are two major nodes in the mesolimbic dopamine pathway, which mediates reward for various survival behaviors, including feeding. Opioids increase and maintain food intake when injected peripherally and centrally. Opioids in the VTA cause increased release of dopamine in the sNAcc, and when injected into either site, cause an increase in food intake. Animals in this study were double cannulated in the VTA and in the sNAcc and injected with various combinations of naltrexone (NTX) (2.5, 5, and 25 microg/side) and Tyr-d-Ala-Gly-(Me)Phe-Gly-ol (DAMGO) (0.1, 0.3, 1, 3, and 5 nmol/side) in both sites. DAMGO was found to dose dependently increase intake to an equal extent when injected into either site. DAMGO-induced increases in food intake when injected into the VTA were blocked to control levels with the highest dose of NTX injected bilaterally into the sNAcc; however, increases in intake when injected into the sNAcc were blocked only partially by the highest dose of NTX injected bilaterally into the VTA. These results indicate opioid-opioid communication between the two sites; however, the communication may be quite indirect, requiring other sites and transmitters to elicit a change in behavior.     

Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats

Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and micro opioid-stimulated sucrose feeding-when administered into several insulin-receptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75+/-5% of paired control). However, although the mu opioid DAMGO, [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) micro opioid-stimulated sucrose feeding: sucrose intake was 53+/-8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner.     

Central mechanisms of roles of taste in reward and eating

Taste is unique among sensory systems in its innate association with mechanisms of reward and aversion in addition to its recognition of quality, e.g., sucrose is sweet and preferable, and quinine is bitter and aversive. Taste information is sent to the reward system and feeding center via the prefrontal cortices such as the mediodorsal and ventrolateral prefrontal cortices in rodents and the orbitofrontal cortex in primates. The amygdala, which receives taste inputs, also influences reward and feeding. In terms of neuroactive substances, palatability is closely related to benzodiazepine derivatives and beta-endorphin, both of which facilitate consumption of food and fluid. The reward system contains the ventral tegmental area, nucleus accumbens and ventral pallidum and finally sends information to the lateral hypothalamic area, the feeding center. The dopaminergic system originating from the ventral tegmental area mediates the motivation to consume palatable food. The actual ingestive behavior is promoted by the orexigenic neuropeptides from the hypothalamus. Even palatable food can become aversive and avoided as a consequence of a postingestional unpleasant experience such as malaise. The neural mechanisms of this conditioned taste aversion will also be elucidated.     

Release of dopamine in the ventral tegmental area of rat

In this preliminary report we showed that 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolite of dopamine (DA), is present in the ventral tegmental area. This finding indicates that in the ventral tegmental area, which contains the cell bodies of dopaminergic neurons of the mesocortical and mesolimbic DA systems, DA may be released by a mechanism similar to that operating in the nerve endings. However, haloperidol, which increases DOPAC levels in the substantia nigra, failed to do so in the ventral tegmental area. The results support the contention that DA neurons in the ventral tegmental area have distinctive features from nigral DA neurones.     

Receptors in the Ventral Tegmental Area Mediating Nicotine-Induced Dopamine Release in the Nucleus Accumbens

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D₁: SCH 23390, D₂: eticlopride), and NMDA glutamatergic (MK 801) and GABA_B (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABA_B (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D₁ (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.     

The neuronal reactions of the cat motor cortex to electrical stimulation of the ventral tegmental area as a conditioned signal for the reflex of placing the forelimb on a support]

Electrical stimulation (50-100 pulses, 100-500 Hz) of the ventral tegmental area (VTA) in the vicinity of the n. interpeduncularis in the frontal plane AP2-AP4, L1-L2 caused a cat to grab food placed near its mouth. The conditioned forepaw placing reaction was elaborated using food reinforcement and VTA stimulation as a conditioned stimulus. The conditioned reflex, being once established, was repeatedly performed without extinction in the course of up to 250 trials without food reinforcement. Short (5-10 pulses) conditioned VTA stimulation evoked a prolonged (up to 1000 ms or longer) activation of neurons of the motor cortex and caused a substitution of the inhibitory phase of response to stimulation of the parietal cortex in poststimulus interval in 50-200 ms for the late secondary excitatory response.     

Reciprocal opioid-opioid interactions between the ventral tegmental area and nucleus accumbens regions in mediating mu agonist-induced feeding in rats

Feeding elicited by the mu-selective agonist, [D-Ala2, M-Phe4, Gly-ol5]-encephalin administered into the nucleus accumbens is blocked by accumbal pre-treatment with mu, delta1, delta2 and kappa, but not mu1 opioid antagonists. Correspondingly, mu-agonist-induced feeding elicited from the ventral tegmental area is blocked by ventral tegmental area pre-treatment with mu and kappa, but not delta opioid antagonists. A bi-directional opioid-opioid feeding interaction has been firmly established such that mu-agonist-induced feeding elicited from the ventral tegmental area is blocked by accumbal naltrexone, and that accumbal mu-agonist-induced feeding is blocked by naltrexone pre-treatment in the ventral tegmental area. To determine which opioid receptor subtypes mediate the regional bi-directional opioid-opioid feeding interactions between these two sites, the present study examined the dose-dependent ability of either general (naltrexone), mu (beta-funaltrexamine), kappa (nor-binaltorphamine) or delta (naltrindole) opioid antagonists administered into one site to block mu-agonist-induced feeding elicited from the other site. General, mu and kappa, but not delta opioid receptor antagonist pre-treatment in the ventral tegmental area dose-dependently reduced mu-agonist-induced feeding elicited from the nucleus accumbens. General, mu and delta, and to a lesser degree kappa, opioid receptor antagonist pre-treatment in the nucleus accumbens dose-dependently reduced mu-agonist-induced feeding elicited from the ventral tegmental area. Thus, multiple, but different opioid receptor subtypes are involved in mediating opioid-opioid feeding interactions between the nucleus accumbens and ventral tegmental area regions.     

Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter

Recent studies suggest that the mesoaccumbens dopamine system undergoes neurochemical alterations as a result of restricted feeding conditions with access to sugars. This effect appears to be similar to the neuroadaptation resulting from drugs of abuse and may underlay some pathological feeding behaviors. To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats. The restricted feeding regimen consisted of daily limited access to either a normally preferred sucrose solution (0.3 M) or a less preferred chow in a scheduled (i.e., contingent) fashion for 7 days. Restricted-fed rats with the contingent sucrose access lost less body weight, ate more total food, and drank more fluid than free-fed, contingent food, or noncontingent controls. In addition, these animals had selectively higher DAT binding in the nucleus accumbens and ventral tegmental area. This increase in protein binding also was accompanied by an increase in DAT mRNA levels in the ventral tegmental area. In contrast to the restricted-fed groups, no differential effect in DAT regulation was observed across free-fed groups. The observed alteration in behavior and DAT regulation suggest that neuroadaptation in the mesoaccumbens dopamine system develops in response to repeated feeding on palatable foods under dietary constraints. This supports the notion that similar cellular changes may be involved in restrictive eating disorders and bingeing.     

Alpha-MSH injected into the substantia nigra or intraventricularly alters behavior and the striatal dopaminergic activity

Rats were injected with 1 μg of alpha-melanocyte stimulating hormone (α-MSH) into the third ventricle and locally in the ventral tegmental area and in different regions of the substantia nigra. The modifications produced on grooming behavior and locomotion as well as on the dopamine content of the nucleus accumbens and the caudate putamen, were studied. Both intraventricular peptide administration and microinjections into the ventral tegmental area induced excessive grooming and a significant increase of the locomotor activity. The dopamine content of the nucleus accumbens and caudate putamen was markedly reduced. Injections of the peptide into the substantia nigra pars compacta failed to induce excessive grooming but did provoke a slight increase in locomotor activity and a smaller change in caudate dopamine content than that observed by injections in the ventral tegmental area or in the third ventricle. Dopamine levels in the nucleus accumbens were not changed. Finally, the injections of α-MSH into the lateral substantia nigra did not produce either biochemical or behavioral changes.The results suggests that α-MSH can modify, directly or indirectly, the striatal dopaminergic activity and that the behavioral alterations observed such as excessive grooming, could be mediated by the activation of the dopamine cells from the ventral tegmental area, that in turn may provoke a significative release of dopamine at the caudate putamen nucleus as well as in nucleus accumbens.     

Orphanin FQ/Nociceptin Modulation of Mesolimbic Dopamine Transmission Determined by Microdialysis

Orphanin FQ has been reported to suppress extracellular dopamine levels in the nucleus accumbens after intracerebroventricular administration. This study sought to provide evidence for an intra-ventral tegmental site of action for this effect using a dual-probe microdialysis experimental design. Orphanin FQ was applied to the ventral tegmental area of anesthetized rats by reverse dialysis while extracellular dopamine was sampled with a second dialysis probe in the nucleus accumbens. Orphanin FQ at a probe concentration of 1 mM (but not at 0.1 mM) significantly reduced nucleus accumbens dialysate dopamine levels. The receptor-inactive analogue, des-Phe1-orphanin FQ (1 mM), produced a small but significant increase in nucleus accumbens dialysate dopamine levels. Simultaneous measurement of ventral tegmental area dialysate amino acid content revealed significant increases in both GABA and glutamate during infusion of orphanin FQ (1 mM). To determine if increased GABA overflow mediates the action of orphanin FQ on mesolimbic neurons, orphanin FQ (10 nmol) was microinjected directly into the ventral tegmental area in the presence or absence of the GABA(A) receptor antagonist, bicuculline (1 nmol). Bicuculline transiently blocked the suppressive action of orphanin FQ on accumbens dialysate dopamine levels. These data indicate that orphanin FQ decreases dopamine transmission in the nucleus accumbens by inhibiting dopamine neuronal activity in the ventral tegmental area through a mechanism that may involve an increased overflow of GABA.     

Central integration of cardiovascular and drinking responses elicited by central administration of angiotensin II: divergence of regulation by the ventral tegmental area and nucleus accumbens

Previous studies had implicated the involvement of the ventral tegmental area and its dopamine projections to the nucleus accumbens in goal-directed behavior. This study investigated whether or not the GABAergic inputs to the ventral tegmental area and, in turn, dopaminergic input to the nucleus accumbens from the ventral tegmental area modify drinking and cardiovascular responses elicited by central administration of angiotensin II. Injections of 25 ng of angiotensin II into a lateral cerebral ventricle of the rat elicited water intakes averaging 7-8 mL in 15 min with latencies usually less than 3 min. Pretreatment of the nucleus accumbens with spiperone, a dopamine antagonist, or the ventral tegmental area with gamma-amino butyric acid (GABA) produced dose-dependent reductions in water intake and number of laps taken while increasing the latency to drink. The spiperone injection did not alter the pressor response. On the other hand, the GABA injections attenuated the pressor responses to central angiotensin II administration. These findings suggest that GABA input to the ventral tegmental area modifies both the cardiovascular and drinking responses elicited following central administration of angiotensin II. However, the dopamine projections to the nucleus accumbens appear to be involved only in the drinking responses elicited by central injections of angiotensin II. Divergence for the coordination of the skeletal motor behavioral component and the cardiovascular component elicited by central administration of angiotensin II must occur before the involvement of these dopamine pathways.     

海洛因成瘾模型建立及中脑腹侧被盖区Bax的表达

目的探索海洛因对中脑腹侧被盖区细胞Bax表达的影响。方法肌肉注射海洛因,建立成瘾大鼠模型,用免疫组化方法检测中脑腹侧被盖区细胞Bax的表达。结果连续给大鼠注射海洛因7d后,大鼠出现明显的戒断症状;中脑腹侧被盖区细胞Bax表达阳性细胞比对照组明显增多,与对照组相比差异有显著性（P〈0.01）。结论海洛因具有诱导Bax基因表达、损伤脑组织细胞的作用。     

LOCALIZATION OF GABAERGIC, CHOLINERGIC AND AMINERGIC STRUCTURES IN THE MESOLIMBIC SYSTEM

Abstract— The localization of cholinergic, GABAergic and aminergic structures in the 'mesolimbic' system has been discussed from studies on the topographical distribution of choline acetyltransferase, glutamate decarboxylase and aromatic amino acid decarboxylase in normal rat brain and in brains hemitransected at the level of globus pallidus. The structures analysed included nucleus accumbens, olfactory tubercle, septum, medial forebrain bundle, striatum, substantia nigra, ventral tegmental area and nucleus interpeduncularis.
Choline acetyltranferase was highly concentrated in the nucleus interpeduncularis, but it did also exhibit considerable activity in the nucleus accumbens, the olfactory tubercle and the striatum. The activities did not change after hemitransection. Aromatic amino acid decarboxylase was highly concentrated in the ventral tegmental area, but high activities were also found in the striatum, the nucleus accumbens, the olfactory tubercle and the pars compacta of the substantia nigra. The activity decreased in all areas rostral to the hemitransection. Glutamate decarboxylase was highly concentrated in the dopamine innervated regions, moreso in the limbic structures than in the striatum. Much higher activity was found in the substantia nigra than in the ventral tegmental area. After hemitransection the activity in the substantia nigra was decreased whereas in the ventral tegmental area it was unchanged. Our results thus suggest that dopaminergic cells in the ventral tegmental area do not receive GABAergic fibres from the terminal regions of the ascending dopaminergic fibres. In addition, we found a very high concentration of glutamate decarboxylase in a region traversed by the rostral medial forebrain bundle. Here the activity was mainly confined to the paniculate fraction, probably the synaptosomes. This fraction also displayed a very active high affinity uptake of y-aminobutyric acid.     

Increases in dopamine metabolism are not a general feature of intracranial self-stimulation

Rats with electrodes implanted in the ventral tegmentum and posterior hypothalamus were trained to press a lever to obtain electrical stimulation through the electrodes. Stimulation in animals with ventral tegmental electrodes led to an increased concentration of homovanillic acid and dihydroxyphenylacetic acid in the forebrain of the animals. Stimulation in the posterior hypothalamus did not result in such raised concentrations in spite of the fact that the behaviour from the two sites was indistinguishable. Responding in the posterior hypothalamus was reduced by doses of neuroleptic drug similar to those reported to reduce responding in the ventral tegmental area.     

Effect of Excitotoxin Lesions in the Medial Prefrontal Cortex on Cortical and Subcortical Catecholamine Turnover in the Rat

Catecholamine turnover in brain areas innervated by dopaminergic neurons was examined 2, 6, and 12 days after bilateral, N-methyl-D-aspartate lesions confined to the rat medial prefrontal cortex. The lesion produced a significant regional increase in the concentration of 3,4-dihydroxyphenylethylamine (DA, dopamine) in both the medial prefrontal cortex and the ventral tegmental area. DA concentrations were increased in the nucleus accumbens on day 6 (128% of control), in the ventral tegmental area on day 2 (130% of control), and in the medial prefrontal cortex on days 2 (145% of control) and 6 (127% of control). The only significant changes in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) (197% of control), and in the ratio DOPAC/DA (163% of control) were found in the medial prefrontal cortex on day 6 post-lesion. All parameters had returned to control levels by day 12. DA depletion after the administration of alpha-methyl-p-tyrosine (AMPT) was not significantly different between excitotoxin-lesioned and sham animals on day 6 in all brain regions. Noradrenaline (NA) and 3,4-dihydroxyphenylethyleneglycol concentrations and their ratios, and the depletion of noradrenaline after AMPT were also determined, and the lesion resulted in a significant regional increase in NA in both the nucleus accumbens and the ventral tegmental area. An elevation of NA (147% of control) in the nucleus accumbens was found on day 12. Since the excitotoxin lesion destroys corticofugal efferents from medial prefrontal cortex to the nucleus accumbens, the anterior corpus striatum and the ventral tegmental area, our results provide no evidence for a role of these cortical projections in the regulation of subcortical DA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Topical organization of the neuronal projections of the substantia nigra and ventral field of the tectum mesencephali onto the head of the caudate nucleus in the cat brain

The investigation performed on cats by means of retrograde axonal transport of horseradish peroxidase and luminophores has presented the data demonstrating spatial organization of separate part projections of the nigral complex and the tegmental ventral field to various segments of the caudate nucleus head. Terminal fields from neurons of various parts of the substantia nigra and the tegmental ventral field are demonstrated to overlap in segments of the caudate nucleus. Experiments with double fluorescent labelling demonstrate divergence of axons of the nigral neurons.     

Different Effects of Opiate Withdrawal on Dopamine Turnover,Uptake, and Release in the Striatum and Nucleus Accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.