Involvement of lateral habenula-dorsal raphe neurons in the differential regulation of striatal and nigral serotonergic transmission cats

The importance of the lateral habenula-dorsal raphe pathway in the control of in vivo [3H]serotonin release in the cat basal ganglia was examined using the push-pull cannula technique and an isotopic method for the estimation of [3H]serotonin continuously formed from [3H]tryptophan. [3H]Serotonin was measured in both caudate nuclei and substantiae nigra and, in some cases, in the dorsal raphe. Electrical stimulation of the lateral habenula decreased [3H]serotonin release in all structures studied. Blockade of the GABA inhibitory pathway to the lateral habenula by the local application of picrotoxin reduced [3H]serotonin release in both substantiae nigra and increased release of the 3H-amine in the dorsal raphe but was without effect on [3H]serotonin release in either caudate nucleus. This inhibition of nigral [3H]serotonin release was antagonized by simultaneous application of picrotoxin to the dorsal raphe. Substance P delivery to the dorsal raphe produced the same effects on [3H]serotonin release as described for picrotoxin application to the lateral habenula except that inhibition of nigral [3H]serotonin release was not prevented by local co-administration of picrotoxin. These results suggest that the lateral habenula can control serotonergic transmission in the basal ganglia and that this regulation may be different for those serotonergic neurons innervating the caudate nucleus versus those projecting to the substantia nigra.     

Efferent connections of the striatum and the nucleus accumbens in the lizard Gekko gecko

The efferent connections of the striatum and the nucleus accumbens of the lizard Gekko gecko were studied with the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). These structures were found to have segregated output systems. The striatum shows a major projection to the globus pallidus. Striatal fibers which are more caudally directed run through the lateral forebrain bundle and can be traced as far caudally as the pars reticularis of the substantia nigra where they exhibit many varicosities. Along its course, the lateral forebrain bundle issues fibers with varicosities to the anterior and posterior entopeduncular nuclei. The major recipient structure of the nucleus accumbens is the ventral pallidum. The nucleus accumbens, in addition, projects to the portion of the lateral hypothalamus in the path of the medial forebrain bundle and to the ventral tegmental area, which is its most caudal target. Subsequently, the same technique was used in an attempt to study the efferents of the globus pallidus and the ventral pallidum, the major recipient structures of the striatum and the nucleus accumbens. The globus pallidus was found to project to the rostral part of the suprapeduncular nucleus in the ventral thalamus and, in addition, may distribute fibers to the same structures as does the striatum. The ventral pallidum distributes fibers to the ventromedial thalamic nucleus. It probably also projects diffusely to the hypothalamus, the habenula, and the mesencephalic tegmentum.     

Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat

Neurons in the lateral habenula (LHb) of rats have efferent projections that terminate in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA), where cell bodies of dopamine-containing neurons are located. In order to study the influence of the habenula on dopaminergic activity, single-cell electrophysiological techniques were used to record unit discharge of dopamine-containing neurons in the SNC and VTA during electrical stimulation of the LHb or adjacent structures. Dopamine-containing neurons in the SNC and VTA were identified by their characteristic spike duration (greater than 2 msec), discharge rate (2-8 spikes/sec), and irregular firing pattern. Analysis of peristimulus time histograms showed that 85% of SNC cells and 91% of VTA neurons were inhibited after single pulse stimulation (0.25 mA, 0.1 msec) of the LHb. The mean time between stimulation and onset of inhibition was 11 msec (range, 2-22 msec) and mean duration of maximal suppression was 76 msec (range, 20-250 msec). Stimulation of structures adjacent to the LHb (hippocampus, lateral thalamus, medial dorsal thalamus, medial habenula) had little or no effect. Destruction of the fasciculus retroflexus, the fiber pathway that contains most habenular efferents, blocked the stimulation effects on dopamine-containing neurons. Destruction of the stria medullaris, which contains most habenular afferents, did not alter the inhibitory effect of habenular stimulation. Injection of a cytotoxin, kainic acid, in the LHb 1 week before recording sessions blocked the inhibitory consequences of habenular stimulation. These experiments show that activation of neuronal perikarya in the LHb causes orthodromic inhibition of dopamine-containing neurons in SNC and VTA via the fasciculus retroflexus.     

The habenula as an evolutionary conserved link between basal ganglia,limbic, and sensory systems—A phylogenetic comparison based on anuran amphibians

Based on anatomical and functional data, the habenula—a phylogenetically old brain structure present in all vertebrates—takes part in the integration of limbic, sensory, and basal ganglia information to guide effective response strategies appropriate to environmental conditions. In the present study, we investigated the connections of the habenular nuclei of the oriental fire-bellied toad, Bombina orientalis, and compared them with published data from lampreys, chondrichthyes, teleosts, reptiles, birds, and mammals. During phylogenetic development, the primordial habenula circuitry underwent various evolutionary adaptations and in the tetrapod line, the circuit complexity increased. The habenula circuitry of anuran amphibians, decedents of the first land-living tetrapods, seem to exhibit a mix of ancient as well as modern features. The anuran medial and lateral habenula homologs receive differential input from the septum, nucleus of the diagonal band of Broca, preoptic area, hypothalamus, rostral pallium, nucleus accumbens, ventral pallidum, and bed nucleus of the stria terminalis. Additional input arises from a border region in the ventral prethalamus, here discussed as a putative homolog of the entopeduncular nucleus of rodents. The habenular subnuclei also differentially innervate the interpeduncular nucleus, raphe nuclei, substantia nigra pars compacta and ventral tegmental area homologs, superficial mamillary area, laterodorsal tegmental nucleus, locus coeruleus, inferior and superior colliculus homologs, hypothalamus, preoptic area, septum, nucleus of the diagonal band of Broca, and main olfactory bulb. It seems likely that the main connectivity between the habenula and the basal ganglia, limbic, and sensory systems was already present in the common tetrapod ancestor.     

Increase in accumbal dopaminergic transmission correlates with response cost not reward of hypothalamic stimulation

Rats were trained to lever-press for intracranial self-stimulation (ICSS) of the lateral hypothalamus on either a fixed ratio (FR) 1 or 10 schedule. Their brains were removed after a 20 min session and tissue punches taken from the nucleus accumbens, olfactory tubercle, anterior striatum, or central striatum. These punches were assayed for content of dopamine (DA) and the major DA metabolite DOPAC. Compared with implanted controls, only the FR10 group showed significantly elevated DOPAC/DA ratios. These elevations were statistically significant in nucleus accumbens and central striatum and near significance in anterior striatum. They occurred to similar degrees in each hemisphere. In contrast, we found that stimulation of the ventral tegmental area of anesthetized rats asymmetrically increased the DOPAC/DA ratio, being most prominent in the ipsilateral accumbens. Because the FR10 group made only 58% of the responses of the FR1 group and received only 6% of the stimulations of the FR1 group, yet unlike the FR1 group showed a significant increase in the DOPAC/DA ratio, we suggest that the DA release was primarily influenced by the schedule, not the stimulation or the reward of the stimulation. These results were interpreted in terms of a model in which hypothalamic ICSS reward is largely dependent on non-dopaminergic mechanisms, with accumbal DA transmission being strongly dependent on the costs versus benefits of ongoing behavior.     

The role of dopamine in intracranial self-stimulation of the ventral tegmental area

The role of dopaminergic (DA) neurons in brain stimulation reward produced by electrical stimulation of the ventral tegmental area (VTA) was investigated in the rat. In the first experiment, extensive 6-hydroxydopamine lesions of the ascending fibers of the mesotelencephalic DA projections resulted in significant changes in intracranial self-stimulation (ICS) rate-current intensity functions when the lesion was ipsilateral to the stimulating electrode. Similar contralateral lesions had no effect on these functions, thus ruling out lesion-induced performance deficits as being responsible for the decreases in ICS rates across the wide range of current intensities that occurred after the ipsilateral lesions. In the second experiment, ICS obtained from electrodes in the VTA resulted in significant increases in the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, nucleus accumbens, and olfactory tubercle ipsilateral to the stimulating electrode. The ratios of DOPAC and HVA to DA, considered to be indices of DA utilization, were also increased in these brain regions ipsilateral to the electrode. No changes were observed in the contralateral striatum, nucleus accumbens, and olfactory tubercle. Similar increases were observed in stimulated "yoked" animals that received brain stimulation at identical rates and currents but did not lever-press for this stimulation. The third experiment examined the effects of lever-pressing for food on an FR8 schedule of reinforcement on DA utilization in the striatum, nucleus accumbens, and olfactory tubercle. Despite high rates of responding, no effects were observed on DOPAC:DA or HVA:DA ratios in these brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of post-trial reinforcing vs. subreinforcing stimulation of the substantia nigra on passive avoidance learning

STAUBLI, U. AND J. P. HUSTON. Effects of post-trial reinforcing vs. subreinforcing stimulation of the substantianigra on passive avoidance learning. BRAIN RES. BULL. 3(5) 519–524, 1978.—Experiments were designed to investigate the role of post-trial reinforcing and subreinforcing stimulation of the substantia nigra on memory processing. Thirty sec post-trial reinforcing stimulation (0.2 sec on/1.8 sec off) impaired learning of response suppression in a step-down task compared to control animals as well as to animals stimulated at subthreshold current level (i.e., at 25% of the current level shown to maintain optimal self-stimulation in previously performed self-stimulation sessions). In a second small-box passive avoidance experiment, i.e., the alcove-avoidance task, opposite results were attained: Subreinforcing stimulation attenuated learning whereas neither suprathreshold stimulated animals nor control animals showed impairment of learning. The conclusions drawn from these results are as follows: Post-trial stimulation of the substantia nigra interferes with memory processing. This attenuation of learning is obviously task-dependent and can additionally be influenced by the quality of the stimulation, i.e., whether it is reinforcing or not. Possible explanations to account for these task-dependent and quality of stimulation-dependent effects of post-trial substantia nigra stimulation are discussed.     

Morphine treatment during juvenile isolation increases social activity and opioid peptides release in the adult rat

The consequences of juvenile isolation and morphine treatment on general activity, social activity and endogenous opioid release during a social interaction test were investigated in the adult rat. Rats were either isolated or socially housed during weeks 4 and 5 of age and treated daily during this isolation period subcutaneously with either saline or morphine. Directly after a social interaction test at 10 weeks of age, rats were injected with [3H]-diprenorphine and subsequently prepared for in vivo autoradiography. The autoradiographic technique was used to visualise neuroanatomical changes in opioid receptor occupancy, probably reflecting changes in opioid peptide release, as a result of social activity. Juvenile isolation increased general activity during the social interaction test, an effect which was accompanied by a reduction of opioid receptor occupancy in many brain areas, suggesting an increased opioid peptide release as a consequence of socially-induced general activity. Morphine treatment in isolated rats caused an increase in adult social activity and enhanced opioid peptide release in some cortical regions and the ventral tegmental area as compared to saline treated rats. Both social activity and opioid receptor occupancy were unaffected by morphine treatment in non-isolated rats. The present study underscores the role of opioid systems in adult social behaviors as a consequence of juvenile isolation. The results suggest a relationship between social activity and opioid peptide release during social contact. Increased social activity seems to be accompanied by elevated opioid peptide release in distinct brain areas after morphine treatment during juvenile isolation.     

Descending projections of the basal forebrain in the rat demonstrated by the anterograde neural tracer Phaseolus vulgaris leucoagglutinin (PHA-L)

Descending pathways from the mediobasal forebrain were studied in the rat by injecting anterograde axonal tracer Phaseolus vulgaris leucoagglutinin into the substantia innominata and diagonal band of Broca. From both areas, positive fibers which varied in density were observed in the mediodorsal and ventral parts of the ventroposterior and ventromedial thalamic nuclei, the lateral habenula, the stria medullaris, the lateral hypothalamus and the ventral tegmental area. This descending complex appeared predominantly course through the medial forebrain bundle from which positive fibers ramified into the fasciculus thalamicus to distribute in the thalamic nuclei. A minor descending pathway through the stria medullaris was also noted which terminated in the lateral habenula and the mediodorsal thalamic nucleus. An obvious difference in terminal distribution in the medial habenula, mediodorsal thalamic nucleus and pons could be observed following substantia innominata or diagonal band injection.     

Asymmetry in functional connectivity of the human habenula revealed by high‐resolution cardiac‐gated resting state imaging

The habenula is a hub for cognitive and emotional signals that are relayed to the aminergic centers in the midbrain and, thus, plays an important role in goal‐oriented behaviors. Although it is well described in rodents and non‐human primates, the habenula functional network remains relatively uncharacterized in humans, partly because of the methodological challenges associated with the functional magnetic resonance imaging of small structures in the brain. Using high‐resolution cardiac‐gated resting state imaging in healthy humans and precisely identifying each participants' habenula, we show that the habenula is functionally coupled with the insula, parahippocampus, thalamus, periaqueductal grey, pons, striatum and substantia nigra/ventral tegmental area complex. Furthermore, by separately examining and comparing the functional maps from the left and right habenula, we provide the first evidence of an asymmetry in the functional connectivity of the habenula in humans. Hum Brain Mapp 37:2602–2615, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc .     

Dorsal raphe, substantia nigra and locus coeruleus: Interconnections with each other and the neostriatum

Using a retrograde axonal transport method, direct projections to the neostriatum were demonstrated from the dorsal raphe nucleus, a large area of the ventral midbrain tegmentum (including the ventral tegmental area of Tsai, the substantia nigra pars compacta, reticulata and suboculomotoria), and the tegmentum ventral to the caudal red nucleus. A direct projection was also found from the mediodorsal part of the substantia nigra to the rostral part of the dorsal raphe nucleus. Projections from the entopeduncular nucleus (pallidum) and the lateral hypothalamic area to the lateral habenular nucleus, and from the latter to the dorsal raphe nucleus were also found. This habenular projection arises primarily from large neurons in the medial part of the lateral habenula and also from another group of small cells immediately adjacent to the medial habenular nucleus. A non-reciprocal connection of the dorsal raphe nucleus to the locus coeruleus was also found. On the basis of these results and the data available in the literature on the possible neurotransmitters used by these various structures, it is suggested that the dorsal raphe nucleus may play an important role in brain stem modulation of neostriatal function.     

Suppression of cell firing in the substantia nigra by caudate nucleus stimulation

Cats anesthetized with barbiturates show a unique 8–12/sec continuous rhythmic activity in the subthalamic nucleus and ventral tegmental region which may be correlated with the “barbiturate tremor.” Pallidal stimulation inhibits subthalamic nucleus slow-wave and single-unit activity, while nigral stimulation produces a phasic discharge in subthalamic neurons. In contrast to pallidal stimulation, caudate stimulation does not inhibit the firing of subthalamic nucleus cells. In view of this and the action of the substantia nigra upon the subthalamic nucleus, we studied the effects of caudate activation upon extracellularly recorded single unit responses in the nigra of barbiturate-anesthetized cats. Fifty-one units were analyzed. Of these, 24 were localized to the tegmentum just above the substantia nigra, 25 in the nigra, and two in the cerebral peduncle. The predominant effect of single caudate stimuli was suppression of firing of nigral (95%) or tegmental (58%) cells for either 70 or 140 msec, or more. These effects were seen in both medial and lateral portions of the nigra, and at rostral and caudal levels of the nucleus. No short-latency spikes were seen in nigral cells following caudate stimulation, and only a few in units localized to the tegmentum. In the barbiturate anesthetized cat, caudate stimulation leads to a suppression of firing of cells throughout the substantia nigra.     

Measuring threshold of reinforcing brain stimulation by the method of constant stimuli

A new method for measuring threshold of reinforcing electrical brain stimulation is described and results of a parametric study using this method are presented. Two groups of rats were trained under a concurrent FR-CRF (fixed ratio-continuous reinforcement) schedule of reinforcement provided by electrical stimulation of the lateral hypothalamus. The invariant intermittent FR schedule of reinforcement was used to maintain a baseline of behavior while a superimposed concurrent CRF schedule was used to measure reinforcement magnitude by varying the intensity of the CRF stimulus between zero and a maximum. Increasing and decreasing stimulus intensity on the CRF schedule leads to a gradual disappearance, respectively reappearance, of post-reinforcement pauses (PRPs) on the concurrent FR schedule, providing a criterion for changeover in schedule control, and thus, for threshold of reinforcement. To illustrate the measurement of threshold according to psychophysical requirements of the Method of Constant Stimuli, different CRF intensities were given in a randomized order. In one group of animals FR and CRF stimuli were given through the same electrode. Another group received FR and CRF stimuli through separate electrodes implanted in different hemispheres of the brain. For both groups the duration of the PRP was used as the dependent variable. The data of both groups showed a high negative correlation between the intensity of the CRF stimulus and the duration of the PRP, which is consistent with the results of experiments in which a Method of Limits procedure was used. On the basis of this relationship between CRF current intensity and PRP duration a threshold for reinforcing brain stimulation was calculated.     

The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta

Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responses to aversive stimuli. We now designate the region containing them as the “mesopontine rostromedial tegmental nucleus” (RMTg) and report herein on its neuroanatomy. Dense μ‐opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial, and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic‐lateral hypothalamic continuum, and midline‐intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe, and locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures. J. Comp. Neurol. 513:566–596, 2009. © 2009 Wiley‐Liss, Inc.     

Electrolytic lesions of the habenula attenuate brain stimulation reward

The present experiment used electrolytic lesions in combination with curve-shift scaling to study the functional relation between the habenula and four different brain sites that support operant responding for brain stimulation reward. Rats were implanted with a monopolar stimulation electrode aimed at the lateral hypothalamus, ventral tegmental area, dorsal raphe or median raphe nuclei, and a lesioning electrode in the ipsilateral habenula. Operant nose poking resulted in self-administration of trains of electrical pulses to one of the above stimulation sites. Reward thresholds were derived from response-number curves and defined as the pulse number necessary for half-maximal responding. Rats were tested daily at each of three current intensities that were chosen from individual number-current trade-off functions and that yielded baseline reward thresholds of approximately 10, 20 and 40 pulses/train. Testing resumed 24h after lesioning the habenula (100 muA anodal current, 20-25s) and continued for 3-4 weeks. A total of 19 rats completed the experiment. In five of these, habenular lesions clearly reduced the rewarding effectiveness of the stimulation; reward thresholds increased by approximately 30-245% (0.12-0.54 log10 units). Generally, lesion effects were observed at low and medium current intensities, developed gradually and did not recover. Histological analysis revealed that in two rats the stimulation electrode was located in the posterior lateral hypothalamus, two in the anterior ventral tegmental area and one in the area of the dorsal raphe. These results strongly suggest that the habenula constitutes an important component of the neural circuitry important for brain stimulation reward.     

Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat

Orphanin FQ (OFQ) is the endogenous agonist of the opioid receptor-like receptor (ORL-1). It and its precursor, prepro-OFQ, exhibit structural features suggestive of the opioid peptides. A cDNA encoding the OFQ precursor sequence in the rat recently has been cloned, and the authors recently generated a polyclonal antibody directed against the OFQ peptide. In the present study, the authors used in situ hybridization and immunohistochemistry to examine the distribution of OFQ peptide and mRNA in the central nervous system of the adult rat. OFQ immunoreactivity and prepro-OFQ mRNA expression correlated virtually in all brain areas studied. In the forebrain, OFQ peptide and mRNA were prominent in the neocortex endopiriform nucleus, claustrum, lateral septum, ventral forebrain, hypothalamus, mammillary bodies, central and medial nuclei of the amygdala, hippocampal formation, paratenial and reticular nuclei of the thalamus, medial habenula, and zona incerta. No OFQ was observed in the pineal or pituitary glands. In the brainstem, OFQ was prominent in the ventral tegmental area, substantia nigra, nucleus of the posterior commissure, central gray, nucleus of Darkschewitsch, peripeduncular nucleus, interpeduncular nucleus, tegmental nuclei, locus coeruleus, raphe complex, lateral parabrachial nucleus, inferior olivary complex, vestibular nuclear complex, prepositus hypoglossus, solitary nucleus, nucleus ambiguous, caudal spinal trigeminal nucleus, and reticular formation. In the spinal cord, OFQ was observed throughout the dorsal and ventral horns. The wide distribution of this peptide provides support for its role in a multitude of functions, including not only nociception but also motor and balance control, special sensory processing, and various autonomic and physiologic processes.     

Involvement of GABA neurons in allylnitrile-induced dyskinesia

Nitriles are a class of compounds with potential relevance to human health. Allylnitrile, one of nitriles, induces persistent behavioral abnormalities in mice. To explore what type of neuronal system is involved in these behavioral abnormalities, five neuronal markers, gamma-aminobutyric acid (GABA), tyrosine hydroxylase, serotonin, the serotonin transporter and choline acetyltransferase were immunohistochemically examined within various brain structures in allylnitrile and vehicle-treated mice. Allylnitrile induced changes in the immunolabelling of GABA in the medial habenula, interpeduncular nucleus, substantia nigra, dorsal raphe nucleus and median raphe nucleus; the amount of immunolabelling decreased in all of these brain structures except the medial habenula at 2 days postdosing, and increased in all of these structures at 14 days postdosing. Allylnitrile also induced changes in the amount of immunolabelling of tyrosine hydroxylase in the arcuate nucleus, substantia nigra pars compacta, locus coeruleus and caudoventrolateral reticular nucleus at either 2 or 14 days postdosing, depending on the structures. No immunohistochemical change was seen for serotonin, serotonin transporter and choline acetyltransferase. The present results suggest that the GABAergic systems through the medial habenula-interpeduncular nucleus-ascending raphe nuclei relay and through the substantia nigra may be involved in allylnitrile-induced behavioral abnormalities.     

经颅重复性低频磁刺激后大鼠苍白球及黑质HMW MAP-2表达的变化

观察经颅重复性低频磁刺激 (rTMS)对大鼠基底节输出结构高分子量微管相关蛋白 (HMWMAP 2 )阳性标记变化的影响。采用磁刺激器给予大鼠头部 1Hz,10 0mT的重复性刺激 ,然后用免疫组织化学ABC法检测苍白球外侧部 (GPe)、腹侧苍白球 (VGP)及黑质 (SN)等部位HMWMAP 2的免疫阳性产物。较之对照组动物 ,rTMS后苍白球外侧部和腹侧苍白球HMWMAP 2免疫反应物未见减少 ,且染色明显增强 ,阳性标记的纤维增粗 ;黑质特别是黑质网状部 (SNR)亦可见到染色明显增强的HMWMAP 2免疫标记出现。rTMS能够使基底节输出结构中HMWMAP 2的表达发生变化 ,推测可能通过树突重塑而致突触传递的变化等而发挥其临床治疗作用。     

Simultaneous Recording of Spontaneous Activities and Nociceptive Responses from Neurons in the Pars Compacta of Substantia Nigra and in the Lateral Habenula

Using simultaneous extracellular single-unit recording in the pars compacta of the substantia nigra and in the lateral habenula of rats, 45 pairs of neurons responding to peripheral nociceptive stimulation were recorded. In 41 of these pairs, nigral dopaminergic neurons were inhibited by peripheral nociceptive stimulation, while lateral habenula neurons were excited. Moreover, in 14 pairs, when sweeps were triggered randomly by spontaneous spikes from lateral habenula neurons the spontaneous firing rate of the dopaminergic neurons during the first 250 ms after the sweep was much lower than rates after this time period. In this case, the sweep was often triggered by burst-firing of lateral habenula neurons. Our results indicate a cross-correlation between the spontaneous activities of these two nuclei, suggesting that the excitation of lateral habenula neurons induced by peripheral nociceptive stimulation might be directly responsible for inhibition of nigral dopaminergic neurons.     

Ethanol-induced Changes in Proenkephalin mRNA Expression in the Rat Nigrostriatal Pathway

Endogenous opioid systems have been suggested to play a key role in ethanol reinforcement mechanisms and alcohol-drinking behavior. Ethanol induces differential alterations in opioid peptide expression in brain areas of the reward circuits, which may be linked to the reinforcing effects of ethanol. In addition, ethanol-induced alterations in opioidergic nigrostriatal transmission could be involved in brain sensitivity to ethanol and play a role in addictive processes. The aim of this work was to study the effects of acute ethanol administration on proenkephalin (proenk) mRNA expression in the rat substantia nigra and caudate–putamen (CP) for up to 24 h post treatment. Male Wistar rats received ethanol (2.5 g/kg) or distilled water by intragastric administration, and proenk mRNA expression was studied by in situ hybridization and densitometry. Ethanol transiently increased proenk mRNA expression in the CP 1 h after drug administration. Proenk mRNA levels remained elevated 2 h post treatment in the anterior–medial and medial–posterior regions of the CP. In contrast, ethanol decreased proenk mRNA expression in the substantia nigra pars compacta and pars reticulata 2 h after drug exposure. Alterations in enkephalin expression in the substantia nigra and CP in response to ethanol exposure could be involved in the mechanisms underlying brain sensitivity to the drug.