Orthodromic and antidromic responses of nucleus accumbens neurons to stimulation of amygdala and substantia nigra in cats

Response of nucleus accumbens neurons to stimulation of the amygdala and the substantia nigra were investigated extracellularly in anesthetized cats. They were excited by stimulation of the basolateral amygdaloid nucleus with latencies of 9.0-20.0 ms (mean 12.8 ms). About 70% of them were activated antidromically with latencies of 5.5-33.0 ms (mean 18.8 ms) following stimulation of the substantia nigra pars reticulata. The nucleus accumbens thus relays signals from the amygdaloid complex to the substantia nigra, and may act to bridge the limbic system to the basal ganglia.     

Ascending projections of presumed dopamine-containing neurons in the ventral tegmentum of the rat as demonstrated by horseradish peroxidase

The projections of presumed dopamine-containing neurons in the zona compacta of the substantia nigra and the ventral tegmental area were examined by stereotaxic injections of horseradish peroxidase into diverse cortical and subcortical regions which are known to include dopamine-containing terminals. Neurons in the lateral half of the substantia nigra pars compacta were labelled after injections into the caudolateral aspect of the caudate-putamen, while neurons in the medial part of the substantia nigra pars compacta and lateral aspect of the ventral tegmental area projected to the anteromedial portion of the caudate putamen. Injections of horseradish peroxidase into the amygdala resulted in the appearance of reactive neurons in the anterior portion of the ventral tegmental area, but the more caudally located entorhinal cortex received projections from the posterior half of the ventral tegmental area. Injections of horseradish peroxidase into the frontal cortex, anterior to the genu, produced scattered labelled cells in the rostral half of the ventral tegmental area, whereas more posterior injections into the cingulate cortex resulted in the appearance of reactive cells which were confined to the medial one-quarter of the substantia nigra pars compacta. The near-midline structure, the lateral septum, was innervated by neurons with cell bodies primarily in the medial half of the ventral tegmental area. Injections of horseradish peroxidase into the nucleus accumbens, which contains very high levels of dopamine, resulted in the appearance of many labelled neurons throughout the ventral tegmental area and some reactive neurons in the medial part of the substantia nigra pars compacta. A few labelled cells were also occasionally observed in the contralateral ventral tegmental area after accumbens injections.These results suggest that although there is considerable overlap, and that the same subdivisions within the substantia nigra pars compacta and the ventral tegmental area appear to innervate diverse regions of the forebrain, there also exists a general topographical organization with respect to the projections of these neurons.Injections of horseradish peroxidase into some of the forebrain regions also resulted in the appearance of reactive cells in mesencephalic nuclei not known to contain dopaminergic perikarya. For example, labelled cells were observed in the supramamillary nucleus after injections into the frontal cortex, entorhinal cortex, accumbens and lateral septum. Injections into the amygdala produced reactive cells in the suprageniculate nucleus, the peripeduncular nucleus, and the magnocellular nucleus of the medial geniculate. These latter results are discussed with reference to the possibility that such pathways may mediate the responsiveness of cells in the amygdala to a wide range of sensory stimuli.     

Origin,course and termination of dopaminergic substantia nigra neurons projecting to the amygdaloid complex in the cat

The organization of dopaminergic neurons projecting to the amygdala was examined using retrograde (horseradish peroxidase histochemistry) and anterograde ([³H]leucine autoradiography) transport methods and Falck-Hillarp histofluorescence techniques combined with microspectrofluorometry and radiofrequency lesions. Cell bodies located within the pars lateralis and pars compacta of the substantia nigra were found to project to the lateral and central amygdaloid nuclei, respectively. Both of these areas within the substantia nigra contained dopaminergic perikarya, while the central and lateral amygdaloid nuclei contained fluorescent varicosities with features indicative of dopaminergic neurons. Lesions restricted to the pars lateralis of the substantia nigra resulted in a loss of fluorescence in the lateral amygdaloid nucleus. Autoradiographic experiments revealed that the projections from the pars lateralis did not run with fibers originating from the pars compacta in the nigrostriatal tract but rather had their own course occupying a lateral position adjacent to the cerebral peduncle and joining the ventral amygdalo-fugal bundle.The data indicate that, in the cat, there are two separate dopaminergic projections to the amygdala arising from the substantia nigra.     

A lectin horseradish peroxidase study of the origin of ascending fibers in the medial forebrain bundle of the rat. The upper brainstem

The origins of projections within the medial forebrain bundle from the upper brainstem were examined with the horseradish peroxidase technique. Labeled cells were found in approximately 15 upper brainstem nuclei following injections of a conjugate of horseradish peroxidase and wheat germ agglutinin at various levels of the medial forebrain bundle. Labeled nuclei included (from caudal to rostral): dorsal and ventral parabrachial nuclei; Kolliker-Fuse nucleus; dorsolateral tegmental nucleus; A7 (lateral pontine tegmentum medial to lateral lemniscus); median and dorsal raphe nuclei; distinct group of cells oriented mediolaterally in the dorsal pontine tegmentum below the central gray; B9 (ventral midbrain tegmentum dorsal to medial lemniscus); retrorubral nucleus; nucleus of Darkschewitsch, interfascicular nucleus; rostral and caudal linear nuclei; ventral tegmental area; medial part of substantia nigra, pars compacta; and the supramammillary nucleus. With the exception of the ventral parabrachial nucleus, Kolliker-Fuse, A7, B9 and substantia nigra, pars compacta, each of the nuclei mentioned above sent strong projections along the medial forebrain bundle to the rostral forebrain. Sparse labeling was observed throughout the pontine and midbrain reticular formation. With the exception of the dorsal raphe nucleus, projections to the most anterior regions of the medial forebrain bundle (level of the anterior commissure) essentially only arose from presumed dopamine-containing nuclei-retrorubral nucleus (A8 area), interfascicular nucleus, rostral and caudal linear nuclei, substantia nigra pars compacta, and ventral tegmental area. Evidence was reviewed indicating that major forebrain sites of termination for these dopaminergic nuclei are structures that have been collectively referred to as the 'ventral striatum'. It is concluded from the present findings that several pontine and mesencephalic cell groups are in a position to exert a strong, direct effect on structures in the anterior forebrain and that the medial forebrain bundle is the main communication route between the upper brainstem and the forebrain.     

Corticonigral projections from area 6 in the raccoon

Summary The corticonigral projections from area 6 in the raccoon were investigated using the autoradiographic tracing method. Injections of tritiated proline and leucine were made into either medial or lateral area 6 subdivisions. Uniformly distributed silver grains were observed overlying the ipsilateral substantia nigra pars compacta (SNc) while more restricted foci of label indicative of fiber labeling were present in the substantia nigra pars reticulata (SNr). Autoradiographic label was also present in the substantia nigra pars lateralis (SNl), the retrorubral area and the ventral tegmental area of Tsai. The existence of corticonigral projections from area 6 may serve to modulate SNc activity as a whole and provide an important substrate for the cerebral control of movement.Abbreviations cp cerebral peduncle - IP interpeduncular nucleus - PG pontine gray - R red nucleus - RR retrorubral area - SNc substantia nigra, pars compacta - SNl substantia nigra, pars lateralis - SNr substantia nigra, pars reticularis - VTA ventral tegmental area     

Electrophysiological properties of catecholaminergic neurons in the norepinephrine-deficient mouse

To determine how norepinephrine affects the basic physiological properties of catecholaminergic neurons, brain slices containing the substantia nigra pars compacta and locus coeruleus were studied with cell-attached and whole-cell recordings in control and dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack norepinephrine. In the cell-attached configuration, the spontaneous firing rate and pattern of locus coeruleus neurons recorded from Dbh -/- mice were the same as the firing rate and pattern recorded from heterozygous littermates (Dbh +/-). During whole-cell recordings, synaptic stimulation produced an alpha-2 receptor-mediated outward current in the locus coeruleus of control mice that was absent in Dbh -/- mice. Normal alpha-2 mediated outward currents were restored in Dbh -/- slices after pre-incubation with norepinephrine. Locus coeruleus neurons also displayed similar changes in holding current in response to bath application of norepinephrine, UK 14304, and methionine-enkephalin. Dopamine neurons recorded in the substantia nigra pars compacta similarly showed no differences between slices harvested from Dbh -/- and control mice. These results indicate that endogenous norepinephrine is not necessary for the expression of catecholaminergic neuron firing properties or responses to direct agonists, but is necessary for auto-inhibition mediated by indirect alpha-2 receptor stimulation.     

Neuronal responses to iontophoretically applied dopamine,glutamate, and GABA of identified dopaminergic cells in the rat substantia nigra after kainic acid-induced destruction of the striatum

Summary Kainic acid (KA 1.2–1.5 g) was injected unilaterally into the rat striatum (ST). Fifteen to 30 days later neurons of the substantia nigra (SN) were identified by antidromic stimulation from the ST or medial forebrain bundle (MFB). The projecting axons had conduction velocity similar to that recorded in unlesioned animals.Responses to iontophoretically applied dopamine (DA), glutamate (GLU), and GABA (5–100 nA) were recorded from neurons of the dopaminergic pars compacta-striatal projection. Control experiments were performed in intact rats. GABA and DA inhibited neurons tested in controls while GLU had an excitatory effect. Changes in firing rate induced by GABA and GLU developed 1–5 s after the beginning of their ejection while the action of DA appeared after a delay of 20–40 s.Neurons in lesioned animals showed a net decrease in sensitivity to all three neurotransmitters. The highest current tested gave responses 50–70% lower than in controls.The data suggest that destruction of striatal efferents with KA does not induce hypersensitivity in the pars compacta of the SN.     

Substantia nigra stimulation evoked antidromic responses in rat neostriatum

Summary Electrical stimulation of the substantia nigra of rats elicits a burst of small amplitude waves with a latency of 4–6 ms that may last for 10–15 ms throughout much of the neostriatum. Frontal cortex stimulation also elicits a burst response, which can occlude the substantia nigra response. The substantia nigra evoked burst response was still present after chronic neocortical ablation or thalamic transection or both treatments combined. The response corresponds to the first sharp negative wave of the substantia nigra evoked neostriatal field potential. Single substantia nigra evoked action potentials were recorded in neostriatum with a mean latency of 9.8 ms, ranging from 4–22 ms. These action potentials were considered to be antidromic because 1) they were occluded during appropriate collision intervals by orthodromic action potentials elicited by frontal cortex stimulation. Subthreshold frontal cortex conditioning stimulation did not alter the threshold for activation from substantia nigra. The refractory period for the axon was at least as long as that for the soma and ranged between 0.8–2.0 ms. The antidromic responses failed to follow low frequency stimulation (< 40 Hz for 3000 ms). This failure occurred in the axon between substantia nigra and globus pallidus. The burst response and first sharp negative wave of the field potential probably represent the antidromic activation of the ubiquitous and densely packed medium spiny neostriatal projection neurons. These responses 1) occur at the same latency, 2) respond in the same manner to twin pulse and repetitive stimulation and 3) are occluded by frontal cortex stimulation in the same manner as antidromic action potentials.     

The activity of pars compacta neurons of the monkey substantia nigra is depressed by apomorphine

In the substantia nigra of anesthetized and awake monkeys, presumptive dopamine cells of the pars compacta were electrophysiologically discriminated against non-dopaminergic cells of the pars reticulata by their lower discharge rate (0.5–8 vs 20–130 imp./s), their longer impulse duration (means 2.05 vs 0.92 ms), and their exclusive depression following systemic injection of the dopamine agonist apomorphine (24 out of 30 compacta neurons at 0.05–0.1 mg/kg s.c.).     

Morphological and physiological properties of neostriatal neurons: An intracellular horseradish peroxidase study in the rat

The physiological and morphological (light and electron microscopic) properties of four categories of neostriatal neurons (two types of medium spiny cells and two types of aspiny cells) were analyzed using the technique of intracellular recording and intracellular labeling with horseradish peroxidase. All of the neurons in this study had excitatory responses following stimulation of the cortex and substantia nigra except for the large aspiny neuron for which only substantia nigra inputs were tested. Morphologically, these neurons differed with respect to the size and shape of their somata, density and distribution of dendritic spines and distribution of their axons and axon collaterals. Ultrastructurally, observed somatic differences included the quantity and distribution of organelles and conformation of the nuclear envelope.The axons of one type of medium spiny neuron and the large aspiny neuron were myelinated. Unmyelinated axon collaterals arose from the axons of both types of medium spiny neurons and formed synapses on the dendritic shafts and possibly with the necks of spines of other neostriatal neurons. The parent axons of the most common type of medium spiny neurons were followed to the globus pallidus and, in some cases, to the internal capsule.     

The role of the substantia nigra in a striatally-evoked motor response in the rat: effects of intranigral drugs and lesions

Turning of the head towards the contralateral side was induced in the conscious unrestrained rat by electrical stimulation of the neostriatum through permanent indwelling electrodes. The importance of the substantia nigra in mediating this response was investigated using electrolytic and kainic acid lesions. Contralateral head-turning was attenuated by small electrolytic lesions of the substantia nigra on the stimulated side and abolished by large electrolytic lesions that destroyed the entire nucleus. The injection of kainic acid into the substantia nigra caused persistent circling behaviour but did not modify the head-turn response to striatal stimulation; these injections destroyed some of the neurons in the pars compacta but the majority of neurons in the pars reticulata were undamaged. Drugs that alter the function of nigral neurotransmitters were injected through an indwelling cannula in the zona reticulata. Interference with the function of γ-aminobutyrate in the nigra produced small changes in the latency of the motor response. However the following drugs did not modify the response: substance P, nicotine, atropine, apomorphine, glutamic acid diethylester, glycine, strychnine, met-enkephalin and 5-methoxy-N,N-dimethyltryptamine.It is concluded that descending projections from the basal ganglia which pass through or very close to the nigra, probably without forming synapses in the pars reticulata, may be important for the mediation of the striatally-evoked response.     

Striatal substance P cell clusters coincide with the high density terminal zones of the discontinuous nigrostriatal dopaminergic projection system in the cat: a study by combined immunohistochemistry and autoradiographic axon-tracing

A portion of the nigrostriatal projection that originates from presumably dopaminergic neurons in the caudal pars compacta of the substantia nigra and the suprajacent pars dorsalis (retrorubral area), was shown by [3H]amino acid autoradiographic tracing to distribute nonhomogeneously in the head of the caudate nucleus, such that zones of high density termination are in register with the archipelago of substance P cell clusters revealed immunohistochemically in the same and adjacent tissue sections of the cat's brain. Axons from this same portion of the substantia nigra distribute densely at caudal levels of the putamen where again substance P-immunoreactive striatal cells are numerous. In nearby tissue sections from the same cases, tyrosine hydroxylase-like immunoreactivity suggested only subtle variations in the density of the catecholamine axon network within the striatum. Thus, whereas dopamine axons are distributed densely throughout the striatum, those originating from cells in the caudal pars compacta et dorsalis of the substantia nigra and ending in the head of the caudate nucleus appear to terminate preferentially within the substance P cell clusters. These data suggest that the striatal substance P cells, which send their axons selectively to the entopeduncular nucleus and substantia nigra, but much less so the globus pallidus, are a major target of nigrostriatal dopamine transmission. This result is discussed with respect to the anatomical, neurochemical and functional organization of the striatifugal projection system.     

不同剂量6-羟基多巴胺注射大鼠单侧前脑内侧束后对中脑多巴胺能神经元损伤作用的观察

将不同剂量的６－羟基多巴胺（６－ＯＨＤＡ）注入大鼠一侧黑质（ＳＮ）头端的前脑内侧束（ＭＦＢ），４７天后用酪氨酸羟化酶（ＴＨ）免疫细胞化学染色法，观察旋转鼠整个ＳＮ和腹侧被盖区（ＶＴＡ）不同切面上ＤＡ神经元的损伤程度，结果发现：损伤侧ＳＮ和ＶＴＡ的ＴＨ阳性神经元数在所有观察水平上均有明显下降，并从前囟后５．１ｍｍ开始呈现６－ＯＨＤＡ剂量依赖性。而下降率（与健侧相比）为ＳＮ致密部（ｓｎｃ）＞网状部和外侧部（ｓｎｒ＋ｓｎｌ）＞ＶＴＡ。同时还发现，ｓｎｃ的ＴＨ阳性细胞在黑质两端分布比率较高，而ＶＴＡ的相应细胞在黑质中部分布率较高。另外，在健侧前囟后４．８ｍｍ处出现非６－ＯＨＤＡ剂量依赖性的ＴＨ阳性神经元计数明显增加的现象。本文的结果提示：６－ＯＨＤＡ对中脑ＤＡ神经元的总体损伤程度取决于多种因素，如６－ＯＨＤＡ剂量、神经元对６－ＯＨＤＡ的敏感度以及敏感神经元的分布等。同时健侧中脑组织对邻侧发生的损伤并非毫无反应，一些交叉投射的纤维可能起着传递损伤信息的作用     

Organization and efferent projections of nucleus tegmenti pedunculopontinus pars compacta with special reference to its cholinergic aspects

In an attempt to evaluate the cellular organization and efferent projections of the nucleus tegmenti pedunculopontinus pars compacta, several experiments were performed in the rat. From measurements of neurons in the nucleus tegmenti pedunculopontinus pars compacta in Nissl-stained sections, the nucleus was observed to contain many large neurons which made it possible to demarcate this nucleus from surrounding pontomesencephalic reticular formation. Two other neuronal populations, medium and small neurons, were also seen in the nucleus tegmenti pedunculopontinus pars compacta. Detailed measurements showed that 90% by volume of all neurons in the nucleus tegmenti pedunculopontinus pars compacta were large and medium-sized neurons. After injections of [ ³H]leucine into the nucleus tegmenti pedunculopontinus pars compacta, transported label was observed in dorsally and ventrally coursing ascending fibers. The dorsally coursing fibers entered the centrolateral nucleus and centre median-parafascicular complex of the thalamus. The ventrally coursing fibers produced accumulation of silver grains in the ventral tegmental area, substantia nigra pars compacta, subthalamic nucleus, zona incerta and lateral hypothalamus. Crossed fibers of the nucleus tegmenti pedunculopontinus pars compacta were observed sparsely at the levels of the thalamus and posterior commissure, and to a greater degree through the supraoptic commissure of Meynert. Much less anterograde labeling was seen in the equivalent terminal sites on the contralateral side of the brain. By electron microscopic autoradiography major terminal sites of axons of the nucleus tegmenti pedunculopontinus pars compacta were examined in rats injected with [ ³H]leucine in the nucleus tegmenti pedunculopontinus pars compacta and later injected with horseradish peroxidase in the striatum and pallidum. Statistical data showed preferential radiolabeling of terminals forming asymmetrical synaptic contact with dendrites in the centrolateral nucleus, centre median-parafascicular complex and subthalamic nucleus. Apparent terminations in the substantia nigra pars compacta proposed in earlier studies and shown in the present light microscopic autoradiograms were not supported by this ultrastructural analysis. Several radiolabeled terminals of the asymmetrical type contacting horseradish peroxidase labeled dendrites in the thalamus confirmed direct input from the nucleus tegmenti pedunculopontinus pars compacta to the thalamostriate projection neurons. [ ³H]choline injections into the thalamus and subthalamic nucleus produced retrograde perikaryal labeling of large neurons in the nucleus tegmenti pedunculopontinus pars compacta. These neurons were unlabeled after [ ³H]choline injections in the substantia nigra. Other findings suggested retrograde transport of [ ³H]choline through cholinergic terminals as well as cholinergic fibers of passage. These data suggested a selective uptake mechanism for cholinergic fibers of passage.The results emphasize the cholinergic nature of the nucleus tegmenti pedunculopontinus pars compacta innervation of the thalamus and subthalamic nucleus. Large neurons in the nucleus tegmenti pedunculopontinus pars compacta seem responsible for this cholinergic innervation and probably provide the axon terminals making asymmetrical synapses in the thalamus and subthalamic nucleus as described above. In addition, large neurons as well as medium and small ones in the nucleus tegmenti pedunculopontinus pars compacta whose transmitters and exact destinations remain unknown send a number of axons through the supraoptic commissure of Meynert to innervate the contralateral subthalamic nucleus.     

Time of neuron origin and gradients of neurogenesis in midbrain dopaminergic neurons in the mouse

Previous [³H]thymidine studies in Nisslstained sections in rats established that the substantia nigra pars compacta and the ventral tegmental area originate sequentially according to an anterolateral to posteromedial neurogenetic gradient. We investigated whether that same pattern is found in mice in the dopaminergic neurons in each of these structures. Using tyrosine hydroxylase immunostaining combined with [³H]thymidine autoradiography, the time of origin of dopaminergic midbrain neurons in the retrorubral field, the substantia nigra pars compacta, the ventral tegmental area, and the interfascicular nucleus was determined in postnatal day 20 mice. The dams of the experimental animals were injected with [³H]thymidine on embryonic days (E) 11–E12, E12–E13, E13–E14, and E14–E15. The time of origin profiles for each group indicated significant differences between populations. The retrorubral field and the substantia nigra pars compacta arose nearly simultaneously and contained the highest proportion of neurons, 49 to 37%, generated on or before E11. Progressively fewer early-generated neurons were found in the ventral tegmental area (20%), and the interfascicular nucleus (8.5%). In addition, anterior dorsolateral neurons in the substantia nigra and ventral tegmental area were more likely to be generated early than the posterior ventromedial neurons. These findings indicate that mouse and rat brains have nearly identical developmental patterns in the midbrain, and neurogenetic gradients in dopaminergic neurons are similar to those found in Nissl studies in rats.     

MPTP-induced ventral mesencephalic cell loss in the cat

Immunohistochemical analysis of tyrosine hydroxylase (TH)-containing neurons in the cat ventral mesencephalon revealed a marked loss of substantia nigra pars compacta neurons and moderate losses of TH-positive neurons in the ventral tegmental area, retrorubral or A8 region, and in the substantia nigra pars lateralis of cats treated with the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The pattern and magnitude of cell loss in these ventral mesencephalic regions parallels that previously reported for the MPTP-treated monkey. These results further support the use of the cat as a model for studying the pathology to catecholaminergic neurons induced by MPTP.     

Depression of nigral pars compacta cell discharge by exogenous acetylcholinesterase

Pars compacta cells in the substantia nigra of rabbits were identified using the following criteria: slow spontaneous firing rate, characteristic responses upon stimulation of the caudate nucleus and excitation by chlorpromazine. Commercial or highly purified exogenous acetylcholinesterase was micro-injected in the vicinity of these cells. Both samples had a depressant effect on the spontaneous firing rate of the neurons in the pars compacta. Rapidly discharging cells, possibly in the pars reticulata, were insensitive to chlorpromazine and to stimulation of the caudate nucleus, and were unaffected by exogenous acetylcholinesterase. Following stimulation of the caudate nucleus, long latency inhibition of the slow firing pars compacta neurons was enhanced by application of acetylcholinesterase; however, short latency excitation was unmodified. Butytylcholinesterase, applied at a concentration with ten times the acetylcholine-hydrolysing activity of the acetylcholinesterase employed had no effect on either spontaneous or stimulus-linked firing.The results are discussed with reference to observations that most nigral acetylcholinesterase is situated in the dopamine-containing pars compacta cells, and that acetylcholine is not thought to be a neurotransmitter in this region.     

多巴胺能中脑——杏仁核通路

本实验用神经元逆行荧光标记和单胺荧光组化联合法研究了大白鼠杏仁核内多巴胺能神经纤维的起源及投射特点。一侧杏仁核注射荧光标记物后,同侧黑质致密部背内份和被盖腹侧区背外份有较多的多巴胺神经元被标记。黑质外侧部、A_8群所在部位及对侧黑质致密部和被盖腹侧区亦有少数多巴胺细胞被标记。同侧黑质致密部和被盖腹侧区内还观察到少数非多巴胺能逆行标记细胞。杏仁核与同侧尾壳核、伏隔核或额前皮质配对注射不同荧光标记物后,同侧被盖腹侧区与黑质致密部的背侧区与腹侧区之间有不少多巴胺神经元被逆行荧光双标记。     

Subthalamic stimulation-induced synaptic responses in substantia nigra pars compacta dopaminergic neurons in vitro.

The subthalamic nucleus (STN) is one of the principal sources of excitatory glutamatergic input to dopaminergic neurons of the substantia nigra, yet stimulation of the STN produces both excitatory and inhibitory effects on nigral dopaminergic neurons recorded extracellularly in vivo. The present experiments were designed to determine the sources of the excitatory and inhibitory effects. Synaptic potentials were recorded intracellularly from substantia nigra pars compacta dopaminergic neurons in parasagittal slices in response to stimulation of the STN. Synaptic potentials were analyzed for onset latency, amplitude, duration, and reversal potential in the presence and absence of GABA and glutamate receptor antagonists. STN-evoked depolarizing synaptic responses in dopaminergic neurons reversed at approximately -31 mV, intermediate between the expected reversal potential for an excitatory and an inhibitory postsynaptic potential (EPSP and IPSP). Blockade of GABA(A) receptors with bicuculline caused a positive shift in the reversal potential to near 0 mV, suggesting that STN stimulation evoked a near simultaneous EPSP and IPSP. Both synaptic responses were blocked by application of the glutamate receptor antagonist, 6-cyano-7-nitroquinoxalene-2,3-dione. The confounding influence of inhibitory fibers of passage from globus pallidus and/or striatum by STN stimulation was eliminated by unilaterally transecting striatonigral and pallidonigral fibers 3 days before recording. The reversal potential of STN-evoked synaptic responses in dopaminergic neurons in slices from transected animals was approximately -30 mV. Bath application of bicuculline shifted the reversal potential to approximately 5 mV as it did in intact animals, suggesting that the source of the IPSP was within substantia nigra. These data indicate that electrical stimulation of the STN elicits a mixed EPSP-IPSP in nigral dopaminergic neurons due to the coactivation of an excitatory monosynaptic and an inhibitory polysynaptic connection between the STN and the dopaminergic neurons of substantia nigra pars compacta. The EPSP arises from a direct monosynaptic excitatory glutamatergic input from the STN. The IPSP arises polysynaptically, most likely through STN-evoked excitation of GABAergic neurons in substantia nigra pars reticulata, which produces feed-forward GABA(A)-mediated inhibition of dopaminergic neurons through inhibitory intranigral axon collaterals.     

Behavioral and electrophysiological changes following microinjections of colchicine into the substantia nigra.

Male Sprague-Dawley rats received bilateral microinjections of colchicine (2 or 4 μg in 1 μl) into the substantia nigra. During the first 2 days the animals were hyperactive, intense gnawing and chewing were observed, and food intake was significantly increased. During the next 3 or 4 days, activity, food and water intakes and body weight gain were markedly reduced; the behavior was similar to that previously observed following damage to the substantia nigra and nigrostriatal pathway from 6-hydroxydopamine or electrolytic lesions. This period of hypophagia and hypodipsia was followed by a rebound increase in food and water intake for several days until body weight returned to normal levels. Field potentials recorded from the caudate nucleus in response to electrical stimulation of the substantia nigra were reduced in amplitude during the first 4 days following microinjections of colchicine into the substantia nigra and recovered by Day 7.These reversible behavioral effects of microinjections of colchicine into the substantia nigra confirm the importance of the nigrostriatal pathway in motor and ingestive behaviors.