Dopamine-GABA interactions in the nucleus accumbens and lateral septum of the rat (original) (raw)
Related papers
European Journal of Neuroscience, 1990
The aim of this study was to identify, at the ultrastructural level, the neuronal targets of dopamine afferents to the medial prefrontal and the anterior cingulate cortex of the adult rat. Since, in addition to pyramidal neurons, the cortical neuronal population mainly consists of GABAergic nonpyramidal intrinsic neurons, the simultaneous visualization of both dopamine-and GABA-containing neurons should leave the pyramidal neurons as the only unlabelled dopamine postsynaptic target. In this context, we used a double labelling immunocytochemical procedure: a pre-embedding PAP immunostaining to visualize monoclonal conjugateddopamine (DA) antibody, followed by postembedding immunogold staining with a polyclonal conjugated-GABA antibody. In a single section sampling of 369 DA-immunoreactive (DA-IR) varicosities observed and the GABA-containing elements, 75% of the DA-IR terminals showed no indication of any contact with a GABA neuron. Twenty-five per cent were found in nonsynaptic contiguity with a GABA-immunoreactive neuronal element: axon, dendrite or cell body. When a DA varicosity was in nonsynaptic contiguity with a neuronal perikaryon (5% of cases), this cell was GABA positive. Ten per cent of the DA varicosities were contiguous to a GABA axon, but axoaxonic synapses in either direction were never observed. A symmetrical synapse between a DA varicosity and a GABA-containing dendrite was observed only once. The other 13 DA-IR terminals exhibiting a clear synaptic junction were apposed to nonGABA-containing dendrites, spines and shafts. Triads were observed in which a DA varicosity, forming or not a symmetrical synapse, was apposed to an unlabelled dendrite already receiving a symmetrical junction from another unlabelled axon. These data confirm and extend previous results designating the pyramidal cell dendritic tree as the main synaptic target of DA cortical afferents in rat and primate cerebral cortex. However, a direct effect of dopamine on a subpopulation of intrinsic GABA neurons cannot be excluded.
BMC neuroscience, 2006
The striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections. We examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABAA, GABAB, norepine...
Organization and plasticity of GABAergic neurons in some extrapyramidal nuclei of the rat
The organization of GABAergic neurons in the extrapyramidal system has been investigated in the rat. Striatal hemitransections or electrolytic lesions anterior to the rostral pole of the globus pallidus (GP) decreased glutamic acid decarboxylase (GAD) activity in the GP and entopeduncular nucleus (EP), but did not significantly affect the activity of the enzyme in the substantia nigra (SN). Electrolytic lesions of the tail of the striatum produced only a small decrease in nigral GAD activity. Selective but extensive kainic acid lesions of the GP did not significantly affect the activity of GAD in the SN. These results indicate: (1) that different populations of striatal GABA-ergic neurons innervate the GP and the SN, the former being mainly precommissural and the latter mainly postcommissural; (2) that the pallidonigral projection is not GABAergic; and (3) that the source of the striatonigral GABAergic projection is a group of neurons situated immediately lateral, rostral and perhaps dorsal to the GP. In addition to striato-GP and striato-EP GABAergic projections, evidence is reviewed that demonstrates that the GP and EP send GABAergic efferents to the subthalamic and lateral habenular nuclei respectively. Similarly, the SN contains GABA-ergic perikarya some of which may innervate the tectum and certain thalamic nuclei. 6-Hydroxydopamine lesions of the ascending dopaminergic projections resulted in significant increases in GAD activities in the striatum, nucleus accumbens and GP, but not in the SN. Kinetic analyses indicated that the striatal increase was due to an increased number of enzyme molecules (Vmax) and not to enzyme activation (Km). These results raise the possibility that striatal GABAergic terminals "sprout" in response to a lesion of the dopaminergic terminals. The increase in striatal GAD activity is opposite to the decrease that has consistently been observed in Parkinson's disease. These results suggest that in addition to the documented pathology of dopaminergic neurons, Parkinson's disease is also characterized by significant degeneration of striatal GABAergic neurons. © 1980.
Human GABAA receptors on dopaminergic neurons in the pars compacta of the substantia nigra
The Journal of Comparative Neurology, 2002
The ␥-aminobutyric acid A (GABA A ) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABA A receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABA A receptor mRNA expression was quantified as ␣ 1 ϭ  2 Ͼ ␥ 2 Ͼ ␣ 3 . In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABA A receptor subunits, quantified as ␣ 1 ϭ  2 Ͼ ␥ 2 Ͼ ␣ 3 Ͼ ␣ 4 ϭ  3 . In approximately the same percentage of neurons, which were labeled by ␣ 1 -subunit-specific probe, the ␣ 1 -subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABA A receptors mainly of the ␣ 1  2 ␥ 2 subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease.
The Journal of Comparative Neurology, 1990
One of the major pathways of information flow through the basal ganglia is the pallidonigrofugal system. In order to better understand this system in the rat, experiments have been performed to study the topography, synaptic organization, and neurotransmitter content of the pallidonigral projection and to determine whether the pallidonigral neurones make direct synaptic contacts with nigrofugal cells. This was achieved by combining the anterograde transport of the lectin Phaseolus uulgaris-leucoagglutinin (PHA-L) with the retrograde transport of lectin-conjugated horseradish peroxidase (WGA-HRP), postembedding immunocytochemistry for gamma-aminobutyric acid (GABA), and pre-embedding immunocytochemistry for tyrosine hydroxylase (TH). Following injections of PHA-L in different regions of the lateral part of the globus pallidus, a substantial number of immunoreactive fibres and terminals occurred in the ipsilateral substantia nigra reticulata (SNr). The immunoreactive elements were distributed according to a rostral to medial and caudal to lateral topography. Injections that were restricted to the medial tip of the globus pallidus led to the anterograde labeling of a small number of fibres that were sparsely distributed in the SNr. The most characteristic feature of the pallidonigral fibres was the presence of large varicosities that were often grouped to form pericellular baskets. Injections of WGA-HRP in the ventromedial thalamic nucleus, superior colliculus, or midbrain tegmentum, including the pedunculopontine nucleus, showed that the perikarya and primary dendrites of the output cells of the SNr were often surrounded by the large pallidonigral varicosities. The number of varicosities surrounding a single cell varied from 2-12. Electron microscopic analysis showed that the varicosities contained round or slightly pleomorphic vesicles and numerous mitochondria and that they established symmetrical synaptic contacts. Quantitative measurements revealed that the varicosities had a maximum diameter varying from 0.5 to 2.5 pm and a mean cross-sectional area of 0.76 f 0.25 pm2 (N = 237, mean S.D.). The postsynaptic structures of the pallidonigral varicosities included perikarya (48%), large dendrites (38%), and small dendrites (14%). A large proportion of these postsynaptic targets were retrogradely labeled after injection of WGA-HRP in the ventromedial thalamic nucleus, superior colliculus, or midbrain tegmentum. Postembedding immunocytochemistry was used to show that the pallidonigral axons and terminals in contact with nigrofugal neurones displayed GABA immunoreactivity. The use of a double immunocytochemical method revealed, that in addition to the nondopaminergic SNr output neurones, the dendrites and perikarya of the dopaminergic cells of the substantia nigra pars compacta (SNc) receive an input from the globus pallidus. However, this input is very much sparser than that to the cells of the SNr. In conclusion, the results of our study 1) demonstrate that the pallidonigral projection arises predominantly from cells in the lateral third of the globus pallidus and arborizes in the SNr according to a rostral to medial and caudal to lateral topography, 2) suggest that the pallidonigral neurones exert a powerful control over the output neurones of the SNr, 3) reveal that the pallidonigral projection is a major source of GABA in the rat substantia nigra, and 4) show that the perikarya and dendrites of the dopaminergic cells in the SNc receive an input albeit sparse from the globus pallidus.
The Journal of Comparative Neurology, 2000
␥-Hydroxybutyrate (GHB) is an endogenous metabolite of ␥-aminobutyric acid (GABA), which is synthesized in the neuronal compartment of the central nervous system. This substance possesses several properties that support its role as a neurotransmitter/ neuromodulator in brain. In particular, it is synthesized by a specific pathway that transforms GABA into succinic semialdehyde via GABA-T activity; then succinic semialdehyde is converted into GHB by a specific succinic semialdehyde reductase (SSR). The last enzyme is considered as a marker for neurons that synthesize GHB. This compound binds in brain to receptors whose distribution, ontogenesis, kinetics, and pharmacology are specific. Endogenous GHB, but also GHB exogenously administered to rats, participate in the regulation of dopaminergic activity of the nigrostriatal pathway. To investigate the distribution of GHB neurons in this pathway and the anatomic relationships between dopaminergic and GHB neurons, immunocytochemical identification of dopamine, GABA, and GHB neurons was carried out in the substantia nigra and striatum of the rat. The following markers for these neurons were used: anti-tyrosine hydroxylase (TH) antibodies for dopamine neurons, antiglutamate decarboxylase (GAD) antibodies for GABA neurons, and anti-succinic semialdehyde reductase (SSR) antibodies for GHB neurons. GABA neurons were studied because GAD and SSR co-exist frequently in the same neuron, and GABA alone also exerts its own regulatory effects on dopaminergic neurons. This study reveals the co-existence of GAD/SSR and GAD/SSR/TH in numerous neurons of the substantia nigra. However, some neurons appear to be only GAD or SSR positive. In the striatum, TH-positive terminals surround many GHB neurons. GAD innervation is abundant in close contact with unlabeled neurons in the caudate-putamen, whereas distinct SSR-positive punctuates are also present. The existence of SSR-reactive synapses and neurons was confirmed in the striatum at the electron microscopic level. On the basis of these results, a clear anatomo-functional relationship between GHB and dopamine networks cannot be defined; however, we propose the modulation by GHB of striatal intrinsic neurons that could then interfere with the presynaptic control of dopaminergic activity.
Role of dopamine and GABA in the control of motor activity elicited from the rat nucleus accumbens
Pharmacology Biochemistry and Behavior, 1991
The application of 1.2 and 12.0 ixg/side of the GABA A receptor agonist 3-aminopropane sulphonic acid bilaterally into the nucleus accumbens (Acb) of rats nonsignificantly depressed locomotor activity as assessed in automated Animex® activity cages, while the highest dose (60 ixg/side) significantly stimulated activity. The GABAA receptor antagonists picrotoxinin (0.0625 and 0.125 I~g/side) and bicucuUine (0.895 i~g/side) produced forward locomotion around the cage accompanied by a number of other behaviours. The GABAB agonist baclofen (0.023 and 0.092 ~g/side) induced a short-lasting (18 min) locomotor depression. None of the GABA B antagonists tested (2-hydroxysaclofen 2.6 ~g/side, two novel beta-(benzo[b]furan) analogues of baclofen 9G or 9H each 6.8 ~g/side, 4-aminobutylphosphonic acid 1.32 ~g/side and phaclofen 0.535 and 2 ~g/side) significantly affected locomotor activity. In rats pretreated with reserpine and a-methyl-p-tyrosine, picrotoxinin (0.0625 and 0.125 ~g/side) did not significantly alter locomotor activity. Furthermore, when picrotoxinin (0.0625 i~g/side) was combined with either the selective dopamine (DA) D1 agonist SKF38393 or the selective D2 agonist quinpirole, no significant alteration in locomotor function occurred. When SKF38393 and quinpirole were coadministered, significant stimulation occurred which was further enhanced by the addition of picrotoxinin. It is concluded that GABA A receptors, together with D1 and D2 receptors, play a major role in modulating the control of motor function by the Acb of rats.
Experimental Brain Research, 1990
The density of neuropeptide Y (NPY) immunostained neurons examined in the rat nucleus accumbens (NAcc) was shown to be constant across the anteroposterior extent of the nucleus and did not present any right-left hemispheric difference. Selective unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigral dopaminergic neurons induced, 15 to 21 days later, a bilateral decrease in the NPY neuron density which was, interestingly, more marked in the contralateral than in the ipsilateral NAcc. Dopamine depletion induced by ~-methylparatyrosine treatment elicited a decrease in NPY neuronal density similar in amplitude to that induced by the 6-OHDA lesion in the ipsilateral NAcc suggesting that similar mechanisms underly both NPY responses. In both experimental conditions, changes in NPY immunostaining were quite homogeneous in the two antero-posterior NAcc portions arbitrarily considered. Apomorphine treatment in animals with 6-OHDA injury completely reversed the ipsilateral lesion effect in the anterior part of the NAcc but only partially the contralateral one. In contrast, no significant effect of apomorphine was observed in either side of the NAcc posterior portion. This data suggests the involvement of at least 2 components in the NPY neuron responses to the lesion. The component reversed by apomorphine treatment was presumed to be directly linked to the DA depletion, while the second component not antagonized by apomorphine was considered independant on DA transmission. These data therefore provide morphological evidence for the occurence of complex functional interactions between dopaminergic afferents and NPYcontaining neurons within the NAcc. * Laboratoire associ6 ~t l'Universit~ Aix-Marseilte II, Facult6 des Sciences de Luminy Offprint requests to: P. Salin (address see above)
Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat brain
British Journal of Pharmacology, 1987
The ability of γ‐aminobutyric acid (GABA) to affect the release of [3H]‐dopamine in rat brain synaptosomes prepared from corpus striatum, frontal cortex and hypothalamus and prelabelled with the radioactive catecholamine in the presence of desipramine was examined. GABA (10–300 μm) increased in a concentration‐dependent way the basal release of [3H]‐dopamine from striatum and cortical synaptosomes; however, its effect was much less pronounced in hypothalamic nerve terminals. 2,4‐Diaminobutyric acid (DABA) mimicked GABA although less potently. Neutral amino acids such as leucine, valine or α‐aminoisobutyric acid (100–300 μm) did not affect or increased minimally the release of [3H]‐dopamine. The GABA‐induced [3H]‐dopamine release was not prevented by the GABAA‐receptor antagonists, bicuculline or picrotoxin. The GABAA‐receptor agonist, muscimol (10–300 μm), displayed only a very weak, not significant, enhancing effect on [3H]‐dopamine release. The GABAB‐receptor agonist (—)‐ baclofen...
Journal of Neurochemistry, 1988
Glutamic acid decarboxylase (GAD), Y-[~H]aminobutyric acid ([3H]GABA) high-affinity uptake into synaptosomes, and endogenous GABA content were measured in the rat striatum 2-3 weeks following 6-hydroxydopamine injection in the ipsilateral substantia nigra to destroy the nigrostriatal dopaminergic pathway and after kainic acid injection into the centromedial-parafascicular complex of the ipsilateral thalamus to lesion the thalamostriatal input. Both lesions resulted in apparent GAD increase concomitant with a decreased [3H]GABA uptake into striatal synaptosomes. GABA content was increased selectively following the dopaminergic lesion. Kinetic analysis of the uptake process for [3H]GABA showed selectively a decreased V,,, following the dopaminergic lesion; in animals with thalamic lesion, however, the change only concerned the K,, which showed a decreased affinity of the transport sites for [3H]GABA. Determination of K , and V,,, for GAD action on its substrate glutamic acid showed an increased affinity of GAD for glu-tamic acid in the case of the dopaminergic lesion without any change in V