Evidence for the presynaptic localization of opiate binding sites on striatal efferent fibers

Using quantitative receptor autoradiography, [3H]D-Ala-D-Leu-enkephalin (DADL) and [3H]naloxone binding were studied in rat striatum and striatal projection areas (globus pallidus (GP) and substantia nigra pars reticulata (SNr] after unilateral striatal kainic acid lesions. [3H]DADL and [3H]naloxone binding were each examined by two methods. Initially, [3H]DADL binding was performed in 50 mM Tris-HCl (pH 7.4), 30 mM NaCl, 3 mM manganese acetate and 2 microM GTP; [3H]naloxone binding was carried out in 50 mM Tris-HCl (pH 7.4) and 100 mM NaCl. Subsequent studies were carried out in 150 mM Tris-HCl (pH 7.4) and either [3H]DADL plus 500 nM morphiceptin (to block [3H]DADL binding to mu receptors) or [3H]naloxone plus 10 nM delta receptor peptide (to block [3H]naloxone binding to delta receptors). At one and eight weeks in the lesioned striatum, [3H]DADL binding was reduced by 70% and 82%, respectively, when compared to the control side. [3H]Naloxone binding was reduced by 35% and 20%. In GP and SNr, [3H]DADL binding was reduced by 31% and 41%, respectively, at one week and 27% and 26% at eight weeks. [3H]Naloxone binding was reduced 19% in GP at eight weeks. A parsimonious explanation of these results is that opiate binding sites are located on presynaptic terminals of striatal efferent fibers to globus pallidus and substantia nigra pars reticulata as well as on local striatal axon collaterals. Since opiate peptides have recently been found to coexist with GABA in some striatal neurons, opiate peptides may play a role in striatal function by controlling GABA release from striatal efferent fibers. It is possible that pallidal and nigral opiate binding could be utilized as a marker for striatal terminals.     

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. In rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([3H]CP 55,940), dopamine D1 3H]SCH-23390) and D2 ([3H]raclopride) receptors, and dopamine uptake sites ([3H]GBR-12935). Slides were exposed to 3H-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.     

Cerebral glucose utilization following striatal lesions: the effects of the GABA agonist, muscimol, and the dopaminergic agonist, apomorphine

Local cerebral glucose utilization was measured in 21 discrete regions of the rat CNS following unilateral kainic acid lesions of the caudate nucleus, and subsequent pharmacological challenge with GABAergic or dopaminergic agonists. The most pronounced increases in glucose use were observed in those ipsilateral areas of the brain to which the lesioned striatum normally projects (globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata), although several other brain regions with known anatomical connections to the striato-pallido-nigral system were also affected, most notably in the thalamus and epithalamus. These effects were similar to those reported previously from a different group of animals in which the injection protocol was slightly different. The consequences of striatal lesion, in terms of alterations in local rates of glucose use, were attenuated by i.v. administration of the putative GABA agonist, muscimol. In one area, the ventromedial thalamus, glucose use was more markedly affected by muscimol treatment bilaterally in lesioned animals than in intact animals. The consequences of striatal lesions upon the response to the putative dopaminergic agonist apomorphine, were both complex and profound. In some regions (e.g. globus pallidus), striatal lesion eliminated, or masked the normal response to apomorphine. Elsewhere, the apomorphine response, although in evidence, was significantly attenuated by striatal lesion (e.g. entopeduncular nucleus), but in only two brain areas, substantia nigra pars reticulata and ventrolateral thalamus, the apomorphine response was significantly potentiated by striatal lesion. These studies add further weight to the concept of disinhibition, mediated via striatal GABA fibres, as an organizing principle in striatonigral function and indicate a complex interaction of intrinsic GABAergic pathways with dopaminergic systems in the integrated response to stimulation of dopaminergic receptors in the extrapyramidal motor system.     

GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography

Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. [3H]Muscimol was used to label the GABAA receptors and [3H]flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, [3H]muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, [3H]flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in [3H]muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both [3H]muscimol and [3H]flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both [3H]muscimol and [3H]flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region.     

Excitatory amino acid receptor regulation after subthalamic nucleus lesions in the rat

The subthalamic nucleus plays a pivotal role in the regulation of basal ganglia output. Recent electrophysiologic, lesion and immunocytochemical studies suggest that the subthalamic nucleus uses an excitatory amino acid as a neurotransmitter. After complete ablation of the subthalamic nucleus, we have examined the NMDA, AMPA, kainate and metabotropic subtypes of excitatory amino acid receptors in two major subthalamic projection areas (globus pallidus and substantia nigra pars reticulata) with quantitative autoradiography. Two weeks after ablation, binding sites for [³H]AMPA and [³H]kainate increased in substantia nigra pars reticulata ipsilateral to the lesion. In globus pallidus on the lesioned side, [³H]glutamate binding to the NMDA recognition site decreased. The results suggest that glutamate receptors regulate after interruption of subthalamic nucleus output.     

Extrastriatal circuits activated by intrastriatal muscimol: A[C]2-deoxyglucose investigation

The quantitative autoradiographic [¹⁴C]2-deoxyglucose technique has been employed in conscious, lightly restrained rats to investigate the functional consequences (which are reflected as alterations in local rates of glucose utilization) of unilateral intrastriatal administration of the GABAergic agonist, muscimol. Intrastriatal injections of muscimol (500 ng) effect a widespread, homogeneous reduction (by 33%) in glucose utilization throughout the ipsilateral striatum. Increased glucose utilization following intrastriatal muscimol injection was observed in each region to which the principal striatal efferent projections are directed (ipsilateral globus pallidus increased by 29%; ipsilateral entopeduncular nucleus increased by 33%; ipsilateral pars reticulata increased by 46%). Significant focal alterations in glucose utilization occurred in a number of other regions ipsilateral to the injection, including lateral habenular nucleus (increased by 16%), pars compacta of the substantia nigra (increased by 28%), ventrolateral nucleus of the thalamus (decreased by 40%), sensory-motor cortex (decreased by 47%), deep layer of the superior colliculus (decreased by 18%), and subthalamic nucleus (decreased by 18%). In the overwhelming majority of brain regions examined, glucose utilization was unaltered by intrastriatal administration of muscimol. All regions which displayed significant alterations in glucose use with intrastriatal muscimol are known to have direct connections with the striatum (e.g. pallidus and nigra), or to be anatomical components in polysynaptic striatal outflow pathways (e.g. striatal-pallidal-ventral thalamic-neocortical circuit). The present results indicate that activity within striatal efferent circuits can be differentially modified by the effects of the GABAergic agonist, muscimol, within the caudate nucleus.     

Extrastriatal circuits activated by intrastriatal muscimol: a [14C]2-deoxyglucose investigation

The quantitative autoradiographic [14C]2-deoxyglucose technique has been employed in conscious, lightly restrained rats to investigate the functional consequences (which are reflected as alterations in local rates of glucose utilization) of unilateral intrastriatal administration of the GABAergic agonist, muscimol. Intrastriatal injections of muscimol (500 ng) effect a widespread, homogeneous reduction (by 33%) in glucose utilization throughout the ipsilateral striatum. Increased glucose utilization following intrastriatal muscimol injection was observed in each region to which the principal striatal efferent projections are directed (ipsilateral globus pallidus increased by 29%; ipsilateral entopeduncular nucleus increased by 33%; ipsilateral pars reticulata increased by 46%). Significant focal alterations in glucose utilization occurred in a number of other regions ipsilateral to the injection, including lateral habenular nucleus (increased by 16%), pars compacta of the substantia nigra (increased by 28%), ventrolateral nucleus of the thalamus (decreased by 40%), sensory-motor cortex (decreased by 47%), deep layer of the superior colliculus (decreased by 18%), and subthalamic nucleus (decreased by 18%). In the overwhelming majority of brain regions examined, glucose utilization was unaltered by intrastriatal administration of muscimol. All regions which displayed significant alterations in glucose use with intrastriatal muscimol are known to have direct connections with the striatum (e.g. pallidus and nigra), or to be anatomical components in polysynaptic striatal outflow pathways (e.g. striatal-pallidal-ventral thalamic-neocortical circuit). The present results indicate that activity within striatal efferent circuits can be differentially modified by the effects of the GABAergic agonist, muscimol, within the caudate nucleus.     

Changes in 3H-substance P receptor binding in the rat brain after kainic acid lesion of the corpus striatum

Previous studies have indicated that the substantia nigra contains the highest concentration of substance P-like immunoreactivity (SPLI) in the brain. Paradoxically, it also appears to contain one of the lowest concentrations of substance P receptors in the brain. One possibility is that the massive amount of SPLI blocks the binding of the radioligand to the substance P receptor and/or "down-regulates" the number of substance P receptors present in this structure. Since greater than 95% of the SPLI within the substantia nigra originates from the corpus striatum, we have lesioned this area and measured the changes in substance P receptor concentration in the substantia nigra and other corpus striatal projection areas. A semiquantitative autoradiographic technique for measuring the binding of 3H-substance P to substance P receptors was used in conjunction with tritium-sensitive film. 3H-substance P binding was measured in both the corpus striatum and its projection areas after kainic acid lesion of the corpus striatum. At either 4 or 21 d after the lesion there was approximately a 90% loss of substance P receptors in the rostral striatum, a 74% loss in the globus pallidus, a 57% increase in receptor number in lamina I and II of the ipsilateral somatosensory cortex, and no apparent change in the number of receptors in the substantia nigra pars reticulata, superior colliculus, and central gray. These findings suggest that the low concentration of substance P receptors found within the substantia nigra is not due the massive SPLI innervation, since removal of greater than 95% of the SPLI had no measurable effect on the concentration of substance P receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in local cerebral glucose utilization during electrical stimulation of the striatum and globus pallidus in rats

Alterations in local cerebral glucose utilization (LCGU) in conscious rats during electrical stimulation of the striatum and the globus pallidus were investigated using the [14C]deoxyglucose method. Stimulation of the globus pallidus produced a marked contraversive circling behavior, while stimulation of the striatum led only to contraversive head turning. Unilateral stimulation of the striatum increased LCGU bilaterally in the globus pallidus and substantia nigra pars compacta, but only ipsilaterally in the entopeduncular nucleus, substantia nigra pars reticulata and subthalamic nucleus. Similar stimulation of the globus pallidus increased LGCU in the globus pallidus, substantia nigra pars reticulata and compacta, entopeduncular nucleus, subthalamic nucleus, lateral habenular nucleus, parafascicular nucleus of the thalamus, deep layers of the superior colliculus and pedunculopontine nucleus, exclusively on the ipsilateral side. These results indicate that the electrical stimulation induces LCGU changes in the respective structures having both monosynaptic and transsynaptic neuronal inputs. Some changes may also be mediated by antidromic activation. They also suggest that activation of a synaptic process whether excitatory or inhibitory results in increases in LCGU. The bilateral modulatory effects of striatal stimulation may cancel out the circling behavior seen during pallidal stimulation, and cause only head turning.     

GABA Receptor Agonist Promotes Reformation of the Striatonigral Pathway by Transplant Derived from Fetal Striatal Primordia in the Lesioned Striatum

Striatal lesions are known to cause the anterograde transneuronal degeneration of the substantia nigra pars reticulata (SNr) neurons in consequence to loss of GABAergic inhibitory striatonigral efferents. The present study was undertaken to examine whether long-term intraventricular administration of the GABA agonist muscimol could promote reformation of the striatonigral pathway arising from transplants by rescuing host SNr neurons from transneuronal death in rats with striatal ischemic lesions. Compared to nongrafted rats with striatal lesions, (i) a prominent axonal projection from the transplants to the ipsilateral substantia nigra, (ii) a significant increase in number of survived neurons in the ipsilateral SNr, and (iii) a significant reduction in number of apomorphine-induced turning behaviors were found in grafted animals with muscimol infusion, but not in those without muscimol administration. These findings suggest that preservation of the host target neurons for grafted cells may increase an efficacy of cerebral implants in establishment of the host–graft fiber connections, possibly, leading to functional restoration.     

Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat

Within the basal ganglia, gamma-aminobutyric acid (GABA) exerts a fundamental role as neurotransmitter of local circuit and projection neurons. Its fast hyperpolarizing action is mediated through GABA(A) receptors. These ligand-gated chloride channels are assembled from five subunits, which derive from multiple genes. Using immunocytochemistry, we investigated the distribution of 12 major GABA(A) receptor subunits (alpha1-5, beta1-3, gamma1-3, and delta) in the basal ganglia and associated limbic brain areas of the rat. Immunoreactivity for an additional subunit (subunit alpha6) was not observed. The striatum, the nucleus accumbens, and the olfactory tubercle displayed strong, diffuse staining for the subunits alpha2, alpha4, beta3, and delta presumably located on dendrites of the principal medium spiny neurons. Subunit alpha1-, beta2-, and gamma2-immunoreactivities were apparently mostly restricted to interneurons of these areas. In contrast, the globus pallidus, the entopeduncular nucleus, the ventral pallidum, the subthalamic nucleus, and the substantia nigra pars reticulata revealed dense networks of presumable dendrites of resident projection neurons, which were darkly labeled for subunit alpha1-, beta2-, and gamma2-immunoreactivities. The globus pallidus, ventral pallidum, entopeduncular nucleus, and substantia nigra pars reticulata, all areas receiving innervations from the striatum, displayed strong subunit gamma1-immunoreactivity compared to other brain areas. In the substantia nigra pars compacta and in the ventral tegmental area, numerous presumptive dopaminergic neurons were labeled for subunits alpha3, gamma3, and/or delta. This highly heterogeneous distribution of individual GABA(A) receptor subunits suggests the existence of differently assembled, and presumably also functionally different, GABA(A) receptors within individual nuclei of the basal ganglia and associated limbic brain areas.     

5-HT1D receptors in the guinea pig brain: pre- and postsynaptic localizations in the striatonigral pathway

The caudate-putamen, globus pallidus and substantia nigra pars reticulata of the guinea pig contain high densities of the 5-HT1D receptor subtype. The cellular localization of these sites in the striatonigral pathway was investigated using receptor autoradiography and selective neurotoxin lesions. In guinea pigs with unilateral 6-hydroxydopamine lesions of the nigral dopaminergic cells, no significant decrease was observed in any of the components of the striatonigral pathway. In contrast, when quinolinic acid was injected in the caudate-putamen, marked reductions in [3H]5-HT binding were seen in the caudate-putamen, the globus pallidus and the substantia nigra pars reticulata, on the side ipsilateral to the lesion. These data, which are comparable to previous results in human pathologies where similar cell populations are known to degenerate (Parkinson disease and Huntington's chorea), indicate a presynaptic localization of 5-HT1D receptors on the terminals of the striatal neurons projecting to the pars reticulata of the substantia nigra. In addition, these receptors could be located on the cell bodies or dendrites of these neurons in the striatum, postsynaptically to serotoninergic fibers.     

The Effects of Activation or Inhibition of the Subthalamic Nucleus on the Metabolic and Electrophysiological Activities Within the Pallidal Complex and Substantia Nigra in the Rat

The changes in local cerebral glucose utilization (LCGU) and neuronal unit activities in the subthalamic nucleus and its major target structures (the pars reticulata of the substantia nigra, the globus pallidus and the entopeduncular nucleus) following microinjection of a GABAergic antagonist (bicuculline methiodide, 0.08 nmol) or agonist (muscimol, 0.2 nmol) into the subthalamic nucleus were determined. The metabolic effect was assessed by measuring LCGU by quantitative [14C]-2-deoxyglucose autoradiography in ketamine-anaesthetized rats. Bicuculline methiodide induced increased LCGU in the ipsilateral globus pallidus, the entopeduncular nucleus and the substantia nigra pars reticulata. In contrast, muscimol decreased LCGU in these structures. The neuronal activities in the subthalamic nucleus and related structures increased following injection of bicuculline and decreased after injection of muscimol. The changes in LCGU within the structures directly related to the subthalamic nucleus were correlated with the changes in the unit activity either in the subthalamic nucleus and/or its projection structures. However, the amplitude of the relative changes in neuronal unit activity were greater than the changes in LCGU. Nevertheless, the results emphasize the functional role of the subthalamic nucleus as an activating structure within the basal ganglia.     

Effects of chronic cortical seizures on GABA and benzodiazepine receptors within seizure pathways

The effects of chronic cortical seizures on the autoradiographic distributions of two markers of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor--chloride ionophore complex within local and long circuits connected to the focus were examined. Rats were subjected to electrically triggered seizures of the forelimb--sensorimotor overlap zone either daily or once every other day. At the time of sacrifice the rats had received a mean of 39 +/- 3 stimulations and their seizure responses had grown in intensity and duration. [3H]Muscimol binding and [3H]flunitrazepam binding, at near saturating ligand concentrations were unchanged in the focus, mirror focus, dorsolateral caudate, globus pallidus, ventrolateral and ventrobasal thalamic nuclei, and the substantia nigra pars reticularis. These results indicate that the progressive increases in strength and duration of recurrent focal cortical seizures are not accompanied by changes in the density of either GABA receptors or benzodiazepine receptors within the focus or projection pathways.     

Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits

The GABA(B) receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABA(B)R1 and GABA(B)R2. In this study, the cellular distribution of the GABA(B)R1 and GABA(B)R2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABA(B) receptor subunits GABA(B)R1 and GABA(B)R2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABA(B)R1 and GABA(B)R2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABA(A) alpha(1) subunit and GABA(B) receptor subunits showed that the GABA(A) receptor alpha(1) subunit and the GABA(B)R1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABA(B)R1 and GABA(B)R2 were found on substantia nigra pars compacta neurons but the GABA(A) receptor alpha(1) subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABA(A) and GABA(B) receptors. That is, GABA acts through GABA(B) receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata.     

Enhancement of glutamate release in the rat striatum following electrical stimulation of the nigrothalamic pathway

The release of unlabelled amino acids and newly synthesized [3H]dopamine was estimated in the striatum of halothane-anaesthetized rats superfused using a push-pull cannula. Electrical stimulation of the substantia nigra pars reticulata (SNR), enhanced the release of glutamate (maximal effect +51%) in the ipsilateral striatum. The outflow of [3H]dopamine, aspartate, serine and glutamine was unchanged. Seven-12 days after electrolytic lesion of the ipsilateral ventromedial nucleus of the thalamus SNR, stimulation no longer increased the striatal release of glutamate. It is suggested that electrical stimulation of the SNR enhances the striatal release of glutamate, presumably originating from corticostriatal fibres, by activating a nigrothalamocortical polysynaptic pathway.     

Effect of electrical and chemical stimulation of the subthalamic nucleus on the release of striatal dopamine

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) alleviates the cardinal symptoms of Parkinson's disease, but the mechanisms underlying these clinical results remain to be clarified. The HFS of STN is associated with the release of dopamine (DA) in the striatum. This study examines possible mechanisms by which HFS-STN release DA. The experiments were performed in rats anesthetized with urethane. The STN was stimulated by electrical HF and chemical microinjections of an antagonist and an agonist of GABA(A) receptors, the bicuculline, and the muscimol, respectively. The extracellular striatal DA-DOPAC (3-4-dihydroxyphenilacetic acid) content was collected by means of intracerebral microdialysis cannula and analyzed with HPLC with an electrochemical detector. The HFS of STN and microinjection of bicuculline intrasubthalamic produced a significant increase of extracellular striatal DA, whereas DOPAC levels were unchanged. The microinjection of muscimol depresses spontaneous release of DA, without changes in DOPAC. The kainic acid lesion of the globus pallidus (GP) and the substantia nigra pars reticulata (SNr), ipsilateral to dialyzed striatum, did not modify the release of DA-DOPAC. These data provide evidence that the STN has a tonic action on the substantia nigra pars compacta (SNc), and the release of striatal DA by HFS-STN may be due to activation of the STN acting directly on SNc neurons.     

High affinity histamine binding site is the H3 receptor: characterization and autoradiographic localization in rat brain.

The binding of the histamine autoreceptor (H3) agonist [3H]-N alpha-methyl-histamine ([3H]-N-MeHA) was examined in 25 micron thick rat forebrain sections. The specific binding was saturable and of high affinity: Scatchard analysis indicated a Kd of 2 nM and a Bmax of 25 +/- 3 fmol/section. Under similar conditions, [3H]-histamine [( 3H]-HA) bound with a Kd of 8 nM and a Bmax of 20 +/- 2 fmol/section. Competition studies indicated that both ligands bound an identical site which had the pharmacological characteristics of the H3 binding site. The high affinity binding of [3H-N-MeHA was sensitive to the presence of 5'-guanylyl-imidodiphosphate, indicating that the binding site is likely coupled to a G-protein. Autoradiographic studies indicated the [3H]-N-MeHA binding to be greatest in the nucleus accumbens, striatum, substantia nigra pars reticulata, and certain cortical areas. Striatal quinolinic acid lesions greatly reduced binding in both the striatum and ipsilateral substantia nigra, while 6-hydroxydopamine lesions of the nigrostriatal dopamine system were without effect on binding. Therefore, most of the H3 binding sites in the basal ganglia are on striatonigral projection neurons. Cortical quinolinic acid lesions greatly reduced H3 binding in cortex, indicating that the binding in cortex, as in striatum, is largely on intrinsic neurons, rather than on afferents such as histamine nerve terminals.     

A role of the striatum in premotor cortical seizure development

Striatal function in partial seizure development induced by low frequency cortical stimulation of the ipsilateral premotor cortex was investigated by either electrolytic lesion placement or microinjection of putative neurotransmitter-related drugs into the ipsilateral striatum. Unilateral striatal lesioning and intrastriatal injection of muscimol, a GABA-agonist, and glutamic acid diethylester, a presumed antagonist for glutamatergic neurotransmission, were effective in suppressing seizure development, whereas intrastriatal injection of a subconvulsive dose of carbamylcholine chloride (carbachol), a cholinergic agonist, decreased the seizure threshold. In contrast to the ipsilaterally dominant metabolic activation in the intact animal, an inverse asymmetry due to a considerable reduction of deoxyglucose uptake in the ipsilateral thalamus, entopeduncular nucleus, substantia nigra, striatum and surrounding cortex of the focus was found in those brains with striatal lesion. Altogether, the findings suggest that experimental reduction of the inhibitory striatal outputs to both the entopeduncular nucleus and the substantia nigra enhances tonic activities of the projection GABAergic neurons in those nuclei, thereby inhibiting seizure development.     

A dopamine-sensitive striatal efferent system mapped with [C]deoxyglucose in the rat

Rats which had exhibited contralateral rotation following unilateral injection of dopamine (DA) through a striatal cannula were given 0.5–50 μg DA intrastriatally and then were injected with [¹⁴C]deoxyglucose peripherally to measure glucose utilization in the striatum and its projection nuclei. Quantitative autoradiographic techniques were used to measure glucose utilization. Brain areas which showed L-R asymmetries and changes in glucose utilization different from vehicle-injected animals were: the substantia nigra (pars compacta and pars reticulata), the subthalamic n., entopeduncular n., lateral habenula, and deep layers of the superior colliculus. The globus pallidus was affected also, but only in one group for which the injected DA may have spread and affected it directly. Each of these areas receives projections from the striatum or is one additional synapse away. Intrastriatal injections of norepinephrine, isoproterenol, and procaine did not produce changes in glucose utilization in the striatal projection nuclei. The results support the existence of a DA-sensitive strionigral system to both the reticulata and compacta regions of the nigra, and suggest that this activity is paralleled by a strio-subthalamic and strio-entopeduncular-habenular system. The onset of changes in glucose utilization in the entopeduncular-habenular system was later than in the strio-subthalamic and strionigral systems and correlated with the onset of rotation. However, data from 4 animals which did not rotate suggest that each of these systems is necessary but not sufficient for rotation. It is concluded that DA receptors in the striatum play a significant role in the effects of peripherally administered DA agonists on other nuclei, even though most of these other nuclei also have their own DA receptors.