Denervation supersensitivity for benzodiazepine receptors in the rat substantia nigra

The injection of kainic acid into the substantia nigra causes, 3 weeks after treatment, a 40% decrease in the total number of binding sites for [³H]diazepam with an increase in the dissociation constant. This decrease was restored to approximately normal by the subsequent injection of kainic acid into the striatum, homolateral to the lesioned substantia nigra. The injection of kainic acid into the striatum of intact animals failed to modify the number of [³H]diazepam binding sites but increased the K_D. The results indicate that benzodiazepine binding sites in the substantia nigra are partly located on kainic acid sensitive elements (probably interneurons) and, partly, on kainic acid resistant ones. These binding sites become supersensitive after degeneration of striato-nigral pathways. The possible role of GABAergic denervation of the substantia nigra in the development of benzodiazepine binding sites supersensitivity is discussed.     

3H]Ethynylbicycloorthobenzoate ([3H]EBOB) binding in recombinant GABAA receptors

Ethynylbicycloorthobenzoate (EBOB) is a recently developed ligand that binds to the convulsant site of the GABAA receptor. While a few studies have examined the binding of [3H]EBOB in vertebrate brain tissue and insect preparations, none have examined [3H]EBOB binding in preparations that express known configurations of the GABAA receptor. We have thus examined [3H]EBOB binding in HEK293 cells stably expressing human alpha1beta2gamma2 and alpha2beta2gamma2 GABAA receptors, and the effects of CNS convulsants on its binding. The ability of the CNS convulsants to displace the prototypical convulsant site ligand, [35S]TBPS, was also assessed. Saturation analysis revealed [3H]EBOB binding at a single site, with a K(d) of approximately 9 nM in alpha1beta2gamma2 and alpha2beta2gamma2 receptors. Binding of both [3H]EBOB and [35S]TBPS was inhibited by dieldrin, lindane, tert-butylbicycloorthobenzoate (TBOB), PTX, TBPS, and pentylenetetrazol (PTZ) at one site in a concentration-dependent fashion. Affinities were in the high nM to low microM range for all compounds except PTZ (low mM range), and the rank order of potency for these convulsants to displace [3H]EBOB and [35S]TBPS was the same. Low [GABA] stimulated [3H]EBOB binding, while higher [GABA] (greater than 10 microM) inhibited [3H]EBOB binding. Overall, our data demonstrate that [3H]EBOB binds to a single, high affinity site in alpha1beta2gamma2 and alpha2beta2gamma2 GABAA receptors, and modulation of its binding is similar to that seen with [35S]TBPS. [3H]EBOB has a number of desirable traits that may make it preferable to [35S]TBPS for analysis of the convulsant site of the GABAA receptor.     

In vivo release of newly synthesized [H]GABA in the substantia nigra of the rat: relative contribution of GABA striato-pallido-nigral afferents and nigral GABA neurons

The release of [3H]gamma-aminobutyric acid ([3H]GABA) continuously formed from [3H]glutamine has been measured with a push-pull cannula implanted in the substantia nigra of the rat anesthetized with ketamine. Consistent with the high density of GABA terminals coming from both the striato-pallido-nigral afferents, and from GABA nigrofugal neurons, our results showed that a large amount of [3H]GABA was spontaneously released in the reticulata, about 4 times higher than in the compacta. In the absence of calcium the spontaneous [3H]GABA release was reduced (-30%), as well as the K(+)-induced release of [3H]GABA (-66%). Bicuculline (10(-4) M) did not affect the K(+)-evoked release of [3H]GABA, suggesting that autoreceptors on GABA afferent fibers are distinct from the GABAA subtype. Partial lesions of striato- and pallido-nigral GABA neurons with kainic acid (1.2 micrograms) decrease by 40% the glutamic acid decarboxylase (GAD) activity in the ipsilateral SN without decreasing the spontaneous release of [3H]GABA; even following extensive lesions with kainic acid (2.5 micrograms), GAD activity (-72%) and spontaneous [3H]GABA release (-83%) were not completely abolished. These results suggest that a non-negligible contribution of GABA nigral neurons accounts for the spontaneous GABA release measured in the substantia nigra. This is further supported by the decrease (-20%), and the increase (+40%) of [3H]GABA release produced by the local application of glycine (10(-6) M), and bicuculline (10(-4) M), which respectively, inhibits and activates the nigral neuron activity. The contribution of nigral GABA neurons to the amount of [3H]GABA release from the substantia nigra, is likely linked to their high spontaneous firing rate.     

GABAA receptor blockers reverse the inhibitory effect of GABA on brain-specific [35S]TBPS binding

Thirteen substances previously reported to antagonize the electrophysiological effects of gamma-aminobutyric acid (GABA) on neurons also reversed the inhibitory effects of GABA on specific [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to sites on rat brain membranes in vitro with a rank-order of potencies similar to those found in electrophysiological systems (R 5135 greater than pitrazepin greater than bicuculline greater than SR 95103 greater than securinine) confirming the earlier conclusion that GABA inhibits [35S]TBPS binding by acting allosterically on physiologically relevant GABAA receptors. Pitrazepin is the most potent of a series of mono N-aryl piperazines that block GABAA receptors. The new aryl amino pyridazine GABA derivative SR 95531 was about 3-fold more potent than bicuculline and 39-fold more potent than the structurally related SR 95103. Four known GABA antagonists have the same rank orders of potencies as convulsants and as reversers of GABA's inhibitory action on [35S]TBPS binding (bicuculline greater than securinine greater than theophylline greater than caffeine). Reversal of GABA-induced suppression of [35S]TBPS binding provides a simple method for further characterizing GABAA receptors linked to TBPS binding sites, and facilitates identification of convulsants and novel, perhaps selective, GABA antagonists.     

gamma-Aminobutyric acid- and benzodiazepine-induced modulation of [35S]-t-butylbicyclophosphorothionate binding to cerebellar granule cells

t-Butylbicyclophosphorothionate (TBPS) is a bicyclophosphate derivative with potent picrotoxin-like convulsant activity that binds with high affinity and specificity to a Cl- channel-modulatory site of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor complex. Using intact cerebellar granule cells maintained in primary culture, we have studied the modifications induced by GABA and diazepam on the ion channel-modulatory binding site labeled by [35S]TBPS. At 25 degrees C, and in a modified Locke solution, the [35S]TBPS specific binding, determined by displacing the radioligand with an excess (10(-4) M) of picrotoxin, was approximately 70% of the total radioactivity bound to the cells. [35S]TBPS specific binding was saturable with a Kd of approximately 100 nM, a Bmax of approximately 440 fmol/mg of protein, and a Hill coefficient of 1.18. Neither cerebellar astrocytes maintained in culture for 2 weeks nor a neuroblastoma cell line (NB-2A) exhibited any specific [35S]TBPS binding. Muscimol (0.3 to 5 microM) enhanced and bicuculline (0.1 to 5 microM) inhibited [35S]TBPS specific binding to intact cerebellar granule cells. The effect of muscimol and bicuculline on [35S]TBPS binding was noncompetitive. Muscimol (0.1 to 5 microM) reversed bicuculline inhibition in a dose-dependent fashion but failed to reverse picrotoxin-induced inhibition. [35S]TBPS binding was also modulated by benzodiazepine receptor ligands. The binding was increased by diazepam and decreased by 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methylester. Muscimol (0.05 microM) failed to reverse bicuculline inhibition in the absence of diazepam, but it became effective in the presence of 0.1 to 1 microM diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)     

The localization of receptor binding sites in the substantia nigra and striatum of the rat

Neurotransmitter receptor binding of 5 ligands was examined in the striatum, substantia nigra (SN) and frontal cortex of rats which had received either unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway (NSP) or unilateral kainic acid lesions of the striatum. 6-OHDA lesions of the NSP significantly reduced [3H]dihydroalprenolol ([3H]DHA) and [3H]naloxone ([3H]Nal) binding by 31% and 28% respectively, in the denervated striatum compared to the contralateral side. Scatchard analysis revealed that the alteration in [3H]DHA binding was not due to a change in the affinity of the beta-adrenergic receptor for [3H]DHA. In marked contrast to these changes in the striatum, destruction of the NSP resulted in a significant increase in [3H]DHA and [3H]Nal binding by 44% and 26%, respectively, in the frontal cortex of the lesioned compared to the control side. 6-OHDA lesions in the NSP did not alter striatal receptor binding for [3H]quinuclidinyl benzilate ([3H]QNB), [3H]muscimol ([3H]Mus) or [3H]flunitrazepam ([3H]Flu). Similarily, intrastriatal kainic acid injections did not alter striatal receptor binding for [3H]Nal, [3H]Flu or [3H]Mus. Of the various receptor densities measured in the SN after the above lesions the only alteration observed was a 43% increase in [3H]Flu binding following 6-OHDA lesions of the NSP. Scatchard analysis indicated no change in the affinity of the benzodiazepine receptor for [3H]Flu. 6-OHDA lesions of the NSP did not alter [13H]QNB or [3H]Nal binding in the SN. Striatal kainic acid lesions did not alter nigral [3H]QNB or [3H]Flu binding. The results are discussed in terms of neurotransmitter localization and plasticity within the striatum, SN and frontal cortex.     

Allosteric modulation of t-[35S]butylbicyclophosphorothionate binding in rat brain by melatonin

In order to clarify melatonin's pharmacological interaction with central gamma-aminobutyric acid (GABA) receptors, its effects on the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS), which specifically labels GABA-gated chloride channels, was examined in the rat brain. Saturation binding studies indicated that the effect of melatonin (500 microM) was due to a significant decrease in binding site density (Bmax) while the dissociation constant (Kd) was unchanged. The central-type benzodiazepine (BZ) receptor site antagonist Ro15-1788 (flumazenil) did not reverse the effect of melatonin but blocked the effect of diazepam, indicating that central-type BZ sites do not mediate the effects of melatonin. Since the ability to allosterically inhibit TBPS binding is characteristic of GABA-positive ligands, these findings provide further evidence that the pharmacological effects of melatonin involve enhancement of central GABAergic activity.     

Substantia nigra opiate receptors on basal ganglia efferents

Many behavioral effects of opiate narcotics and peptides have been linked to effects on dopamine neurons originating in the substantia nigra pars compacta and ventral tegmental area. Selective brain lesions were combined with quantitative autoradiography to determine whether opiate receptors are on dopaminergic somata and/or processes in the substantia nigra pars compacta and ventral tegmental area. 6-Hydroxydopamine lesions that eliminated dopamine neurons produced little change in the pattern or density of [³H]-naloxone binding in the substantia nigra pars compacta or ventral tegmental area. Radiofrequency lesions of the internal capsule or globus pallidus and kainic acid lesions of the striatum markedly decreased [³H]-naloxone binding in the pars compacta and pars reticulata. These results are consistent with a dense distribution of opiate receptors on pallido-nigral and/or striato-nigral fibers and strengthen the likelihood that local effects of opiates on dopamine function in the nigrostriatal pathway are mediated indirectly by actions on nondopaminergic processes.     

Effects of haloperidol and clozapine on preprotachykinin-A messenger RNA, tachykinin tissue levels, release and neurokinin-1 receptors in the striato-nigral system.

The effects of haloperidol and clozapine on tachykinin tissue levels, preprotachykinin-A messenger RNA, spontaneous and potassium-evoked tachykinin release, dopamine D2 receptors, and [125I]Bolton-Hunter-substance P binding sites in the striato-nigral system were examined. Chronic administration (10 days) of the dopamine receptor antagonist haloperidol (2 mg/kg i.p.) significantly decreased tissue levels of substance P like-immunoreactivity and neurokinin A like-immunoreactivity in the striatum and the substantia nigra. The corresponding preprotachykinin-A mRNA was decreased in the striatum. Haloperidol did not affect the potassium-evoked tachykinin release in the substantia nigra but significantly increased the spontaneous release. Haloperidol increased the number of D2-receptors but left [125I]Bolton-Hunter-substance P binding sites, representing neurokinin 1 (NK-1) receptors, as determined by competition experiments with selective ligands, unchanged. Clozapine (30 mg/kg, i.m.) did not influence nigral and striatal tachykinin tissue levels, preprotachykinin-A mRNA and potassium-evoked release or spontaneous efflux in the substantia nigra, or D2-receptors and [125I]Bolton-Hunter-substance P binding sites. The present data indicate that neuroleptics influence the striato-nigral tachykinin system in different ways. Tachykinins may, therefore, contribute to the therapeutic and/or untoward effects of certain neuroleptic drugs.     

Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats

Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H3 receptor system in a well-characterized model of Parkinson's disease--the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-gamma-[35S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum.     

Unilateral kindling of the inferior collicular cortex does not transfer to the contralateral seizure sensitive site or alter [3H]flunitrazepam and [35S]TBPS binding.

Acute electrical stimulation of a specific area in the inferior collicular cortex produced bilateral collicular afterdischarge and symmetrical wild running seizures. However, generalized seizures induced by kindling the inferior collicular cortex did not alter the kindling rate in the contralateral side. Furthermore, after both sides of the inferior collicular cortex have been kindled unilateral electrolytic lesions did not alter the seizure initiation or generalization elicited from the contralateral side. Since GABAergic function has been implicated in inferior collicular seizures, potential seizure-induced changes were measured for the chloride channel ([35S]TBPS) and the benzodiazepine receptor ([3H]flunitrazepam). Prior kindling did not alter [35S]TBPS or [3H]flunitrazepam binding in the central nucleus or cortex of the inferior colliculus, the medial geniculate, or the deep prepiriform cortex. Thus, the permanent neural change that subserves seizure generalization from the inferior collicular cortex is unilateral, but this change is not reflected by altered binding characteristics of the GABAA receptor complex.     

Is the anticonvulsant effect of substantia nigra infusion of gamma-vinyl-GABA (GVG) mediated by the GABAA receptor in rat pups?

The substantia nigra GABAergic system is considered important for the modification of seizures. Our previous studies have shown that, in rat pups, nigral infusions of baclofen suppressed flurothyl-induced seizures. In the present study, we determined, in rat pups, the effect of nigral infusions of gamma-vinyl-GABA (GVG) on clonic-tonic seizures induced by flurothyl, generated a dose-response curve of the GVG effect and investigated the possible role of the nigral GABAA receptor in mediating the GVG effect. Bilateral nigral infusions of GVG profoundly suppressed flurothyl-induced tonic seizures in a dose-dependent fashion. Flurothyl-induced clonic seizures were not modified. The lowest effective dose of nigral GVG administration was 5 micrograms/0.25 microliter per site. Nigral infusions of GVG at doses greater than 10 micrograms/0.25 microliter induced sedation as well. Infusions of GVG, 2 mm dorsal to the substantia nigra, did not alter seizure latencies. Bilateral nigral infusions of bicuculline, a specific GABAA receptor antagonist, reduced the protective potency of GVG against flurothyl-induced seizures. Nigrally administered muscimol, a GABAA receptor agonist, also attenuated the anticonvulsant effect of GVG. These findings suggest that the optimal dose of nigrally infused GVG against flurothyl-induced seizures is in the range of 5-10 micrograms/0.25 microliter and that GVG may be more efficient as an anticonvulsant for the treatment of tonic seizures in developing animals. The anticonvulsant effect of GVG may, in part, involve the nigral GABAA receptor. The data, together with the previous experiments, indicate that both nigral GABAA and GABAB receptors may play a role in the regulation of seizures in rat pups.(ABSTRACT TRUNCATED AT 250 WORDS)     

35S]TBPS binding sites are decreased in the colliculi of mice with a genetic predisposition to bicuculline-induced seizures

Several differences have been found in GABAergic function between the long sleep (LS) and short sleep (SS) mice which were genetically selected for different ethanol-induced sleeptimes, and it has been suggested that these differences may explain their differential ethanol sensitivity. However, these lines also differ in seizure susceptibility, a behavior which may also be mediated by GABAergic pathways. Thus, it is difficult to associate differences in GABA neurochemistry with either of these behaviors, particularly when only two selected lines are used. We measured differences in the density and affinity of the [35S]TBPS binding site on the GABAA receptor/Cl- ionophore complex in discrete brain areas; and in order to determine the relationship between receptor binding and behavioral differences, we included mice from 5 of the LS and SS recombinant inbred strains (LS x SS RI) in addition to mice from the LS and SS lines. [35S]TBPS binding in sagittal brain sections was analyzed by quantitative autoradiography, and the amount of binding differed depending on whether bicuculline was added to inhibit endogenous GABA binding. In the presence of bicuculline, the number of [35S]TBPS sites in SS mice was highest in the colliculi (4.5 +/- 0.5 pmol/mg protein), cerebellum (4.8 +/- 0.6 pmol/mg), hippocampus (3.2 +/- 0.7 pmol/mg) and cortex (2.9 +/- 0.3 pmol/mg). The Bmax was two-fold lower in both superior and inferior colliculi (IC) of LS mice. There were no differences between lines in Bmax in any other area and in Kd values in any area (58 +/- 4.0 nM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Persistent alterations in GABAA receptor binding and function after prenatal lorazepam administration in the chick

Behavioral abnormalities have been reported in young and adult animals exposed to benzodiazepines prenatally. The presence of neurochemical alterations in the GABAergic system after prenatal benzodiazepine exposure was assessed in a chick model which avoids prenatal and postnatal maternal effects. The GABAA receptor complex, the presumed site of benzodiazepine action, was altered in adult chickens previously exposed to lorazepam for 10 days in ovo. Binding was decreased at the putative chloride channel site labeled by [35S]TBPS, coupling was decreased between this site and the GABA binding site, and function of the GABAA receptor in chloride uptake was diminished in animals exposed to prenatal lorazepam. Persistent neurochemical alterations in the GABAergic system accompany prenatal benzodiazepine exposure, and may influence subsequent behavior and development.     

The effect of in vitro and in vivo ethanol administration on [S]t-Butylbicyclophosphorothionate binding in C57 mice

Previous studies have shown that ethanol may produce some of its effects by facilitation of GABAergic transmission. One of the potential sites of drug action at the GABA receptor complex is the picrotoxin site, which can be studied with [35S]t-butylbicyclophosphorothionate (TBPS). Ethanol inhibited the binding of [35S]TBPS to C57 mice brain regions in vitro. This inhibition appears to be noncompetitive since ethanol decreased the Bmax and not the KD value of [35S]TBPS. C57 mice were chronically treated with ethanol in liquid diet to determine if the sensitivity of TBPS binding is altered following chronic treatment or during withdrawal. Chronic treatment with ethanol and during withdrawal did not alter the KD or Bmax values of [35S]TBPS binding in C57 mice brain regions. It is suggested that the sensitivity of picrotoxin site on the oligomeric GABA receptor complex is not altered during ethanol tolerance or withdrawal. The effects of ethanol on GABA system may be mediated by its interaction with the coupling mechanism(s) or a direct effect on the chloride channels.     

Effects of Tyr-MIF-1 and MIF-1 at the GABAA receptor chloride channel site

The peptides Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and, to a lesser extent, MIF-1 (Pro-Leu-Gly-NH2) recently have been found to augment the effects of gamma-aminobutyric acid (GABA) on benzodiazepine receptor binding at the GABAA receptor complex. To assess their interaction with the chloride channel binding site on the GABAA receptor, we evaluated the effects of these two peptides on [35S]-t-butylbicyclophosphorothionate (TBPS) binding in mouse brain membranes. In cortex, neither peptide altered [35S]-TBPS binding over a broad dose range, but Tyr-MIF-1 significantly augmented displacement of radioligand binding by the GABA analog muscimol at peptide concentrations of 10(-10) to 10(-7) M; MIF-1 had little effect on muscimol displacement of [35S]-TBPS binding. In cerebellum and brainstem, neither peptide was active in altering muscimol displacement of binding. Thus, Tyr-MIF-1 augments the displacement of [35S]-TBPS binding by the GABA analog muscimol in mouse brain cortical membranes, indicating that this peptide enhances the effects of GABA at the chloride channel as well as at the benzodiazepine receptor.     

Activity of nigral dopaminergic neurons after lesion of the neostriatum in rats

As shown by post-mortem analysis the major neuropathological trait of Huntington's chorea is a degeneration of the intrinsic neurons of the neostriatum (caudate nucleus and putamen). Such a situation can be reproduced by a destruction of the neostriatum by kainic acid. When injected into the caudate nucleus this excitatory amino acid destroys the intrinsic neurons of the neostriatum and spares fairly well the passing fibers.In the present work, we have chosen to examine the influence of neostriatal destruction on the activity of identified dopaminergic cells in the pars compacta of the substantia nigra. As a key element in the nigro-neostriato-nigral loop, this structure is a relevant site for observing the functional effects of neostriatal lesion.Our research hypothesis was based on the generally accepted view that the suppression of the important neostriato-nigral pathway and in particular the inhibitory GABAergic contingent, could generate a hyperactivity of nigral dopaminergic cells. One may therefore consider that the dopaminergic hyperactivity produces abnormal messages which can influence via several pathways the motoneurons, and which participates in the genesis of the hyperkinetic movements characteristic of chorea.After destruction of the neostriatum, we have shown that the pattern of discharge of most identified nigral dopaminergic neurons becomes greatly disorganized. This drastic change in the pattern of activity cannot be interpreted as the simple ‘lift of brake’ on these cells by the suppression of the inhibitory GABAergic striato-nigral tract.     

Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography

A quantitative autoradiographic technique for measuring the binding of [3H]muscimol to central nervous system GABA receptors is described using tritium-sensitive film. [3H]Muscimol binding was studied in primary and secondary striatal projection areas of rat brain following kainic acid lesions of the striatum. Seven days after the lesion, binding affinities in the striatum and its projection areas were not altered significantly. There was a loss of [3H]muscimol receptors in the striatum. Receptors increased in numbers in the ipsilateral globus pallidus (19%), entopeduncular nucleus (22%), and substantia nigra pars reticulata (38%). [3H]Muscimol binding was decreased in the ipsilateral anteroventrolateral and ventromedial (8%) thalamic nuclei. [3H]Muscimol binding in other brain areas (layer IV of the cerebral cortex, central gray, superior colliculus, and stratum moleculare of hippocampus) was not affected. The findings suggest that a loss of striatal innervation resulted in increased numbers of GABA receptors in striatal projection sites. It is further suggested that loss of inhibitory striatal inputs to neurons in the entopeduncular nucleus and substantia nigra pars reticulata may activate GABAergic projections to thalamus and thus result in decreased numbers of thalamic GABA receptors.     

Glutamic acid decar☐ylase (GAD) activity in the rat substantia nigra after discrete bilateral kainic acid-inducedlesions of the caudate-putamen and globus pallidus: correlation with locomotor activity

Bilateral injections of kainic acid into the head (both anterior and posterior postions) of the caudate nucleus, the body of the caudate and the globus pallidus showed that the descending GABAergic innervation to the substantia nigra originates predominantly from the body of the caudate nucleus. Locomotor activity was enhanced following the lesions but thwere was no correlation with the severity of nigral GAD depletion.     

Selective activation of tuberoinfundibular dopaminergic neurons in the chronically restrained rat

Bilateral injections of kainic acid into the head (both anterior and posterior postions) of the caudate nucleus, the body of the caudate and the globus pallidus showed that the descending GABAergic innervation to the substantia nigra originates predominantly from the body of the caudate nucleus. Locomotor activity was enhanced following the lesions but thwere was no correlation with the severity of nigral GAD depletion.